FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Normand, J Li, JH Thomson, N Jarlais, DD AF Normand, Jacques Li, Jih-Heng Thomson, Nicholas Jarlais, Don Des TI Harm reduction SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Article; Proceedings Paper CT International Conference on Global Health (ICGH) CY APR 17-19, 2013 CL Taipei, TAIWAN DE Harm reduction; Methadone; Needle/syringe programs AB The "Harm Reduction" session was chaired by Dr Jacques Normand, Director of the AIDS Research Program of the United States National Institute on Drug Abuse. The three presenters (and their presentation topics) were: Dr Don Des Jarlais (High coverage needle/syringe programs for people who inject drugs in low and middle income countries: a systematic review), Dr Nicholas Thomson (Harm reduction history, response, and current trends in Asia), and Dr Jih-Heng Li (Harm reduction strategies in Taiwan). Copyright (C) 2013, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. C1 [Normand, Jacques] Natl Inst Drug Abuse, AIDS Res Program, Bethesda, MD 20892 USA. [Li, Jih-Heng] Kaohsiung Med Univ, Coll Pharm, Sch Pharm, Kaohsiung, Taiwan. [Li, Jih-Heng] Kaohsiung Med Univ, Coll Pharm, PhD Program Toxicol, Kaohsiung, Taiwan. [Thomson, Nicholas] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Thomson, Nicholas] Univ Melbourne, Nossal Inst Global Hlth, Melbourne, Vic, Australia. [Jarlais, Don Des] Beth Israel Deaconess Med Ctr, Baron Edmond De Rothschild Chem Dependency Inst, New York, NY 10003 USA. RP Normand, J (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,MSC 9581, Bethesda, MD 20892 USA. EM jnormand@nida.nih.gov FU NIDA NIH HHS [P30 DA016383, R13 DA035084] NR 3 TC 0 Z9 0 U1 1 U2 5 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD DEC PY 2013 VL 21 SU 4 BP S10 EP S12 DI 10.1016/j.jfda.2013.09.022 PG 3 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA 285VJ UT WOS:000329422800006 PM 25278732 ER PT J AU Normand, J Montaner, J Fang, CT Wu, ZY Chen, YM AF Normand, Jacques Montaner, Julio Fang, Chi-Tai Wu, Zunyou Chen, Yi-Ming TI HIV: Seek, test, treat, and retain SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Article; Proceedings Paper CT International Conference on Global Health (ICGH) CY APR 17-19, 2013 CL Taipei, TAIWAN DE HIV; Retain; Seek; Test; Treat AB The "HIV: Seek, Test, Treat, and Retain" session was chaired by Dr Jacques Normand, the director of AIDS Research at the US National Institute on Drug Abuse. Dr Yi-Ming Chen served as the discussant. The three presenters (and their presentation topics) were: Dr Julio Montaner (Treatment as Prevention The Key to an AIDS-free Generation), Dr Chi-Tai Fang (Population-level Effect of Free Access to HAART on Reducing HIV Transmission in Taiwan), and Dr Zunyou Wu (Challenges in Promoting HIV Test and Treat Strategy in China). Copyright (C) 2013, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. C1 [Normand, Jacques] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Montaner, Julio] Univ British Columbia, British Columbia Ctr Excellence HIV AIDS, Vancouver, BC V5Z 1M9, Canada. [Fang, Chi-Tai] Natl Taiwan Univ, Coll Publ Hlth, Taipei 10764, Taiwan. [Wu, Zunyou] China CDC, Natl Ctr AIDS STD Control & Prevent, Beijing, Peoples R China. [Chen, Yi-Ming] Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan. RP Normand, J (reprint author), Natl Inst Drug Abuse, AIDS Res Program, 6001 Execut Blvd,MSC 9581, Bethesda, MD 20892 USA. EM jnormand@nida.nih.gov RI Fang, Chi-Tai/P-2908-2016 OI Fang, Chi-Tai/0000-0002-7380-1699 FU NIDA NIH HHS [R13 DA035084, P30 DA016383] NR 3 TC 2 Z9 3 U1 0 U2 1 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD DEC PY 2013 VL 21 SU 4 BP S4 EP S6 DI 10.1016/j.jfda.2013.09.020 PG 3 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA 285VJ UT WOS:000329422800004 PM 25278735 ER PT J AU Tai, B Saxon, AJ Ling, W AF Tai, Betty Saxon, Andrew J. Ling, Walter TI Medication-assisted therapy for opioid addiction SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Article; Proceedings Paper CT International Conference on Global Health (ICGH) CY APR 17-19, 2013 CL Taipei, TAIWAN DE Buprenorphine; Chronic care model; Methadone; Opioid addiction ID BUPRENORPHINE-NALOXONE; CARE AB The "Medication-Assisted Therapy for Opioid Addiction" session was chaired by Dr Betty Tai and had three presenters. The presenters (and their topics) were: Dr Andrew J. Saxon (methadone and buprenorphine for treatment of opioid addiction and human immunodeficiency virus risk reduction); Dr Walter Ling (opioid antagonist treatment for opioid addiction); and Dr Betty Tai (chronic care model for substance use disorder). Copyright (C) 2013, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. C1 [Tai, Betty] Natl Inst Drug Abuse, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Saxon, Andrew J.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. [Saxon, Andrew J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Ling, Walter] Univ Calif Los Angeles, David Geffen Sch Med, Integrated Subst Abuse Programs, Los Angeles, CA 90095 USA. RP Tai, B (reprint author), Natl Inst Drug Abuse, Ctr Clin Trials Network, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM btai@nida.nih.gov FU NIDA NIH HHS [R13 DA035084, P30 DA016383] NR 11 TC 4 Z9 4 U1 0 U2 4 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD DEC PY 2013 VL 21 SU 4 BP S13 EP S15 DI 10.1016/j.jfda.2013.09.023 PG 3 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA 285VJ UT WOS:000329422800007 PM 25264415 ER PT J AU Volkow, ND AF Volkow, Nora D. TI Special Issue on Promoting Global Health-Treatment and Prevention of Substance Abuse and HIV in Asia Foreword SO JOURNAL OF FOOD AND DRUG ANALYSIS LA English DT Editorial Material C1 Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. FU NIDA NIH HHS [R13 DA035084, P30 DA016383] NR 0 TC 0 Z9 0 U1 0 U2 2 PU FOOD & DRUG ADMINSTRATION PI TAIPEI PA 161-2 KUNYANG STREET, NANGANG, TAIPEI, 00000, TAIWAN SN 1021-9498 J9 J FOOD DRUG ANAL JI J. Food Drug Anal. PD DEC PY 2013 VL 21 SU 4 BP S2 EP S2 DI 10.1016/j.jfda.2013.09.018 PG 1 WC Food Science & Technology; Pharmacology & Pharmacy SC Food Science & Technology; Pharmacology & Pharmacy GA 285VJ UT WOS:000329422800002 PM 25530687 ER PT J AU Joo, JS Song, JY Baik, SC Lee, WK Cho, MJ Lee, KH Cho, Y Youn, HS Seo, JH Rhee, KH Kang, HL AF Joo, Jung-Soo Song, Jae-Young Baik, Seung-Chul Lee, Woo-Kon Cho, Myung-Je Lee, Kon-Ho Cho, YoungAh Youn, Hee-Shang Seo, Ji-Hyun Rhee, Kwang-Ho Kang, Hyung-Lyun TI Genetic organization and conjugal plasmid DNA transfer of pHP69, a plasmid from a Korean isolate of Helicobacter pylori (vol 50, pg 955, 2012) SO JOURNAL OF MICROBIOLOGY LA English DT Correction C1 [Song, Jae-Young; Baik, Seung-Chul; Lee, Woo-Kon; Cho, Myung-Je; Lee, Kon-Ho; Cho, YoungAh; Rhee, Kwang-Ho; Kang, Hyung-Lyun] Gyeongsang Natl Univ, Sch Med, Dept Microbiol, Jinju 660751, South Korea. [Youn, Hee-Shang; Seo, Ji-Hyun] Gyeongsang Natl Univ, Sch Med, Dept Pediat, Jinju 660751, South Korea. [Song, Jae-Young; Baik, Seung-Chul; Lee, Woo-Kon; Cho, Myung-Je; Lee, Kon-Ho; Rhee, Kwang-Ho; Kang, Hyung-Lyun] Gyeongsang Natl Univ, Life Sci Res Inst, Jinju 660701, South Korea. [Joo, Jung-Soo] Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Joo, JS (reprint author), Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 2 PU MICROBIOLOGICAL SOCIETY KOREA PI SEOUL PA KOREA SCIENCE & TECHNOLOGY CENTER 803, 635-4 YEOGSAM-DONG, KANGNAM-KU, SEOUL 135-703, SOUTH KOREA SN 1225-8873 EI 1976-3794 J9 J MICROBIOL JI J. Microbiol. PD DEC PY 2013 VL 51 IS 6 BP 889 EP 889 DI 10.1007/s12275-013-0727-y PG 1 WC Microbiology SC Microbiology GA 283IE UT WOS:000329238900029 ER PT J AU Yoon, JH Abdelmohsen, K Kim, J Yang, XL Martindale, JL Tominaga-Yamanaka, K White, EJ Orjalo, AV Rinn, JL Kreft, SG Wilson, GM Gorospe, M AF Yoon, Je-Hyun Abdelmohsen, Kotb Kim, Jiyoung Yang, Xiaoling Martindale, Jennifer L. Tominaga-Yamanaka, Kumiko White, Elizabeth J. Orjalo, Arturo V. Rinn, John L. Kreft, Stefan G. Wilson, Gerald M. Gorospe, Myriam TI Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination SO NATURE COMMUNICATIONS LA English DT Article ID BINDING PROTEIN; REPLICATIVE SENESCENCE; INTERACTION NETWORK; HUR; PHOSPHORYLATION; EXPRESSION; ATAXIN-1; DECAY; DIFFERENTIATION; IDENTIFICATION AB Although mammalian long non-coding (lnc) RNAs are best known for modulating transcription, their post-transcriptional influence on mRNA splicing, stability and translation is emerging. Here we report a post-translational function for the lncRNA HOTAIR as an inducer of ubiquitin-mediated proteolysis. HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. HOTAIR levels are highly upregulated in senescent cells, causing rapid decay of targets Ataxin-1 and Snurportin-1, and preventing premature senescence. These results uncover a role for a lncRNA, HOTAIR, as a platform for protein ubiquitination. C1 [Yoon, Je-Hyun; Abdelmohsen, Kotb; Kim, Jiyoung; Yang, Xiaoling; Martindale, Jennifer L.; Tominaga-Yamanaka, Kumiko; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [White, Elizabeth J.; Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [White, Elizabeth J.; Wilson, Gerald M.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Orjalo, Arturo V.] Biosearch Technol Inc, Novato, CA 94949 USA. [Rinn, John L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Kreft, Stefan G.] Univ Constance, Dept Biol, D-78457 Constance, Germany. RP Yoon, JH (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM yoonjehyun@gmail.com FU NIH [R01 CA102428]; NIA-IRP, NIH; [R01 ES020260-02] FX We thank G.J. Hannon, H.Y. Chang, L.E. Maquat, H.T. Orr, R.P. Wersto, S. Kang and J. Campisi for providing reagents and assistance. J.L.R. was supported by R01 ES020260-02. E.J.W. and G.M.W. were supported by NIH R01 CA102428. J.-H.Y., K.A., J.K., X.Y., J.L.M., K.T.-Y. and M.G. were supported by NIA-IRP, NIH. NR 39 TC 31 Z9 31 U1 2 U2 32 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 DEC PY 2013 VL 4 DI 10.1038/ncomms3939 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 285LY UT WOS:000329396700003 ER PT J AU Borotikar, BS Sheehan, FT AF Borotikar, B. S. Sheehan, F. T. TI In vivo patellofemoral contact mechanics during active extension using a novel dynamic MRI-based methodology SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Patella; Femur; Knee; Magnetic resonance imaging; Sensitivity; Accuracy; Cartilage; Osteoarthritis; Patellofemoral pain syndrome ID IMPACTED ARTICULAR-CARTILAGE; CINE-PC MRI; WEIGHT-BEARING; CHONDROCYTE VIABILITY; PATELLAR TRACKING; JOINT MECHANICS; KNEE EXTENSION; WATER-LOSS; KINEMATICS; OSTEOARTHRITIS AB Objectives: To establish an in vivo, normative patellofemoral (PF) cartilage contact mechanics database acquired during voluntary muscle control using a novel, dynamic, magnetic resonance (MR) imagingbased, computational methodology and validate the contact mechanics sensitivity to the known submillimeter methodological accuracies. Design: Dynamic cine phase-contrast and multi-plane cine (MPC) images were acquired while female subjects (n = 20, sample of convenience) performed an open kinetic chain (knee flexion-extension) exercise inside a 3-T MR scanner. Static cartilage models were created from high resolution threedimensional static MR data and accurately placed in their dynamic pose at each time frame based on the cine-PC (CPC) data. Cartilage contact parameters were calculated based on the surface overlap. Statistical analysis was performed using paired t-test and a one-sample repeated measures ANOVA. The sensitivity of the contact parameters to the known errors in the PF kinematics was determined. Results: Peak mean PF contact area was 228.7 +/- 173.6 mm(2) at 40 degrees knee angle. During extension, contact centroid and peak strain locations tracked medially on the femoral and patellar cartilage and were not significantly different from each other. At 25 degrees, 30 degrees, 35 degrees, and 40 degrees of knee extension, contact area was significantly different. Contact area and centroid locations were insensitive to rotational and translational perturbations. Conclusion: This study is a first step towards unfolding the biomechanical pathways to anterior PF pain and osteoarthritis (OA) using dynamic, in vivo, and accurate methodologies. The database provides crucial data for future studies and for validation of, or as an input to, computational models. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. C1 [Borotikar, B. S.; Sheehan, F. T.] NIH, Dept Rehabil Med, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. RP Sheehan, FT (reprint author), NIH, Bldg 10 CRC RM 1-1469,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov RI sheehan, frances/B-6962-2009 FU Intramural Research Program of the NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 49 TC 10 Z9 11 U1 2 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD DEC PY 2013 VL 21 IS 12 BP 1886 EP 1894 DI 10.1016/j.joca.2013.08.023 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 283SG UT WOS:000329266700009 PM 24012620 ER PT J AU Inge, TH King, WC Jenkins, TM Courcoulas, AP Mitsnefes, M Flum, DR Wolfe, BM Pomp, A Dakin, GF Khandelwal, S Zeller, MH Horlick, M Pender, JR Chen, JY Daniels, SR AF Inge, Thomas H. King, Wendy C. Jenkins, Todd M. Courcoulas, Anita P. Mitsnefes, Mark Flum, David R. Wolfe, Bruce M. Pomp, Alfons Dakin, Greg F. Khandelwal, Saurabh Zeller, Meg H. Horlick, Mary Pender, John R. Chen, Jia-Yuh Daniels, Stephen R. TI The Effect of Obesity in Adolescence on Adult Health Status SO PEDIATRICS LA English DT Article DE obesity; bariatric; weight history ID BODY-MASS INDEX; CARDIOVASCULAR RISK-FACTORS; BARIATRIC SURGERY; FOLLOW-UP; DURATION; WEIGHT; OVERWEIGHT; BMI; ADIPOSITY; HISTORY AB OBJECTIVE: To test the hypothesis that adolescent obesity would be associated with greater risks of adverse health in severely obese adults. METHODS: Before weight loss surgery, adult participants in the Longitudinal Assessment of Bariatric Surgery-2 underwent detailed anthropometric and comorbidity assessment. Weight status at age 18 was retrospectively determined. Participants who were >= 80% certain of recalled height and weight at age 18 (1502 of 2308) were included. Log binomial regression was used to evaluate whether weight status at age 18 was independently associated with risk of comorbid conditions at time of surgery controlling for potential confounders. RESULTS: Median age and adult body mass index (BMI) were 47 years and 46, respectively. At age 18, 42% of subjects were healthy weight, 29% overweight, 16% class 1 obese, and 13% class >= 2 obese. Compared with healthy weight at age 18, class >= 2 obesity at age 18 independently increased the risk of lower-extremity venous edema with skin manifestations by 435% (P < .0001), severe walking limitation by 321% (P < .0001), abnormal kidney function by 302% (P < .0001), polycystic ovary syndrome by 74% (P = .03), asthma by 48% (P = .01), diabetes by 42% (P < .01), obstructive sleep apnea by 25% (P < .01), and hypertension (by varying degrees based on age and gender). Conversely, the associated risk of hyperlipidemia was reduced by 61% (P < .01). CONCLUSIONS: Severe obesity at age 18 was independently associated with increased risk of several comorbid conditions in adults undergoing bariatric surgery. C1 [Inge, Thomas H.; Jenkins, Todd M.; Mitsnefes, Mark; Zeller, Meg H.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat & Pediat Surg, Cincinnati, OH 45229 USA. [Inge, Thomas H.; Jenkins, Todd M.; Mitsnefes, Mark; Zeller, Meg H.] Univ Cincinnati, Cincinnati, OH USA. [King, Wendy C.; Chen, Jia-Yuh] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Courcoulas, Anita P.] Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA USA. [Flum, David R.; Khandelwal, Saurabh] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Pomp, Alfons; Dakin, Greg F.] Weill Cornell Med Coll, Dept Surg, New York, NY USA. [Horlick, Mary] Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Pender, John R.] E Carolina Univ, Dept Surg, Greenville, NC USA. [Daniels, Stephen R.] Univ Colorado, Dept Pediat, Denver, CO 80202 USA. RP Inge, TH (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,MLC 2023, Cincinnati, OH 45229 USA. EM thomas.inge@cchmc.org OI King, Wendy/0000-0002-0740-0029 FU National Institute of Diabetes and Digestive and Kidney Diseases: LABS-2 [DCC-U01DK066557]; National Institute of Diabetes and Digestive and Kidney Diseases: Cincinnati Childrens Hospital Medical Center [U01DK072493, UM1DK072493, UM1DK095710]; National Institute of Diabetes and Digestive and Kidney Diseases: Columbia [U01DK66667]; National Institute of Diabetes and Digestive and Kidney Diseases: Cornell University Medical Center CTRC [UL1RR024996]; National Institute of Diabetes and Digestive and Kidney Diseases: University of Washington [U01DK66568]; National Institute of Diabetes and Digestive and Kidney Diseases: CTRC [M01RR-00037, UL1RR024153]; National Institute of Diabetes and Digestive and Kidney Diseases: Neuropsychiatric Research Institute [U01DK66471]; National Institute of Diabetes and Digestive and Kidney Diseases: East Carolina University [U01DK66526]; National Institute of Diabetes and Digestive and Kidney Diseases: University of Pittsburgh Medical Center [U01DK66585]; National Institute of Diabetes and Digestive and Kidney Diseases: Oregon Health & Science University [U01DK66555]; National Institute of Diabetes and Digestive and Kidney Diseases: Teen LABS-2 consortium [1U01DK072493-01] FX This analysis was conducted as a joint collaboration between members of the LABS-2 and Teen-LABS consortia. These consortia were funded by cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases: LABS-2, grant DCC-U01DK066557; Cincinnati Childrens Hospital Medical Center, grants U01DK072493, UM1DK072493, and UM1DK095710; Columbia, grant U01DK66667 (in collaboration with Cornell University Medical Center CTRC, grant UL1RR024996); University of Washington, U01DK66568 (in collaboration with CTRC, grant M01RR-00037); Neuropsychiatric Research Institute, grant U01DK66471; East Carolina University, grant U01DK66526; University of Pittsburgh Medical Center, grant U01DK66585 (in collaboration with CTRC, grant UL1RR024153); Oregon Health & Science University, grant U01DK66555.; The LABS-2 consortium acknowledges the Teen LABS-2 consortium (grant 1U01DK072493-01) for development and use of the Weight History Questionnaire. NR 24 TC 26 Z9 26 U1 4 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 DEC PY 2013 VL 132 IS 6 BP 1098 EP 1104 DI 10.1542/peds.2013-2185 PG 7 WC Pediatrics SC Pediatrics GA 282IG UT WOS:000329163900051 PM 24249816 ER PT J AU Bell, EF Hansen, NI Brion, LP Ehrenkranz, RA Kennedy, KA Walsh, MC Shankaran, S Acarregui, MJ Johnson, KJ Hale, EC Messina, LA Crawford, MM Laptook, AR Goldberg, RN Van Meurs, KP Carlo, WA Poindexter, BB Faix, RG Carlton, DP Watterberg, KL Ellsbury, DL Das, A Higgins, RD AF Bell, Edward F. Hansen, Nellie I. Brion, Luc P. Ehrenkranz, Richard A. Kennedy, Kathleen A. Walsh, Michele C. Shankaran, Seetha Acarregui, Michael J. Johnson, Karen J. Hale, Ellen C. Messina, Lynn A. Crawford, Margaret M. Laptook, Abbot R. Goldberg, Ronald N. Van Meurs, Krisa P. Carlo, Waldemar A. Poindexter, Brenda B. Faix, Roger G. Carlton, David P. Watterberg, Kristi L. Ellsbury, Dan L. Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C Neonatal Res Network TI Serum Tocopherol Levels in Very Preterm Infants After a Single Dose of Vitamin E at Birth SO PEDIATRICS LA English DT Article DE vitamin E; preterm infants ID PREMATURE-INFANTS; INTRAVENTRICULAR HEMORRHAGE; NECROTIZING ENTEROCOLITIS; E SUPPLEMENTATION; WEIGHT INFANTS; BREAST-MILK; CHILDREN; LESS; ABSORPTION; NUTRITION AB OBJECTIVE: Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low alpha-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage. METHODS: Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-alpha-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing. RESULTS: Eighty-eight infants received the study drug and were included in the analyses. The alpha-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in gamma-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had a-tocopherol levels <0.5 mg/dL. CONCLUSIONS: A 50-IU/kg dose of vitamin E raised serum alpha-tocopherol levels, but to consistently achieve a-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed. C1 [Bell, Edward F.; Acarregui, Michael J.; Johnson, Karen J.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Hansen, Nellie I.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Brion, Luc P.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Kennedy, Kathleen A.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Walsh, Michele C.] Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Walsh, Michele C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Hale, Ellen C.; Carlton, David P.] Emory Univ, Sch Med & Childrens Healthcare Atlanta, Dept Pediat, Atlanta, GA 30322 USA. [Messina, Lynn A.] St Johns Mercy Med Ctr, Des Moines, IA USA. [Crawford, Margaret M.; Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Laptook, Abbot R.] Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI 02908 USA. [Laptook, Abbot R.] Brown Univ, Providence, RI 02912 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Van Meurs, Krisa P.] Lucile Packard Childrens Hosp, Palo Alto, CA 94304 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Poindexter, Brenda B.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Faix, Roger G.] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Watterberg, Kristi L.] Univ New Mexico, Hlth Sci Ctr, Dept Pediat, Albuquerque, NM 87131 USA. [Ellsbury, Dan L.] Ctr Res Educ & Qual, Pediat Med Grp, Sunrise, FL USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bell, EF (reprint author), Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM edward-bell@uiowa.edu FU The National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NICHD; National Institutes of Health (NIH) FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network's Generic Database Study. Dr Higgins is employed by the NICHD. The institutions of most of the other authors received grant funding from NICHD in support of this study. Funded by the National Institutes of Health (NIH). NR 39 TC 5 Z9 5 U1 1 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 DEC PY 2013 VL 132 IS 6 BP E1626 EP E1633 DI 10.1542/peds.2013-1684 PG 8 WC Pediatrics SC Pediatrics GA 282IG UT WOS:000329163900021 PM 24218460 ER PT J AU Mire, CE Geisbert, JB Marzi, A Agans, KN Feldmann, H Geisbert, TW AF Mire, Chad E. Geisbert, Joan B. Marzi, Andrea Agans, Krystle N. Feldmann, Heinz Geisbert, Thomas W. TI Vesicular Stomatitis Virus-Based Vaccines Protect Nonhuman Primates against Bundibugyo ebolavirus SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID ATTENUATED RECOMBINANT VACCINE; MARBURG HEMORRHAGIC-FEVER; RESTON-EBOLAVIRUS; POSTEXPOSURE PROTECTION; AEROSOL CHALLENGE; GUINEA-PIGS; INFECTION; IMMUNIZATION; ADENOVIRUS; VECTOR AB Ebola virus (EBOV) causes severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Currently, there are no licensed vaccines or therapeutics for human use. Recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode an EBOV glycoprotein in place of the VSV glycoprotein, have shown 100% efficacy against homologous Sudan ebolavirus (SEBOV) or Zaire ebolavirus (ZEBOV) challenge in NHPs. In addition, a single injection of a blend of three rVSV vectors completely protected NHPs against challenge with SEBOV, ZEBOV, the former Cote d'Ivoire ebolavirus, and Marburg virus. However, recent studies suggest that complete protection against the newly discovered Bundibugyo ebolavirus (BEBOV) using several different heterologous filovirus vaccines is more difficult and presents a new challenge. As BEBOV caused nearly 50% mortality in a recent outbreak any filovirus vaccine advanced for human use must be able to protect against this new species. Here, we evaluated several different strategies against BEBOV using rVSV-based vaccines. Groups of cynomolgus macaques were vaccinated with a single injection of a homologous BEBOV vaccine, a single injection of a blended heterologous vaccine (SEBOV/ZEBOV), or a prime-boost using heterologous SEBOV and ZEBOV vectors. Animals were challenged with BEBOV 29-36 days after initial vaccination. Macaques vaccinated with the homologous BEBOV vaccine or the prime-boost showed no overt signs of illness and survived challenge. In contrast, animals vaccinated with the heterologous blended vaccine and unvaccinated control animals developed severe clinical symptoms consistent with BEBOV infection with 2 of 3 animals in each group succumbing. These data show that complete protection against BEBOV will likely require incorporation of BEBOV glycoprotein into the vaccine or employment of a prime-boost regimen. Fortunately, our results demonstrate that heterologous rVSV-based filovirus vaccine vectors employed in the prime-boost approach can provide protection against BEBOV using an abbreviated regimen, which may have utility in outbreak settings. Author Summary Ebola viruses (EBOV), of which there are five species, are categorized as Category A Priority Pathogens and Tier 1 Select Agents by several US Government agencies as a result of their high mortality rates and potential for use as agents of bioterrorism. Currently, there are no vaccines or therapeutics approved for human use. Replication-competent, recombinant vesicular stomatitis virus (rVSV) vectors expressing filovirus glycoproteins (GP), in place of the VSV glycoprotein have shown promise in lethal nonhuman primate (NHP) models of filovirus infection as both single injection preventive vaccines and as post-exposure treatments. The recent outbreak of the fifth recognized EBOV species, Bundibugyo ebolavirus (BEBOV), demonstrates the need for vaccines that can be rapidly deployed to combat an outbreak of a new filovirus species. To date, rVSV-filovirus GP-based vaccines have only been able to protect against challenge with a homologous species of EBOV. Here, we show that the two heterologous rVSV-based filovirus vaccines available at the time of the original BEBOV outbreak can protect NHPs against BEBOV challenge using a short prime-boost vaccination strategy. While the prime-boost strategy was successful, a single injection blended vaccination strategy with the same vaccine vectors failed to provide protection. These data suggest that an abbreviated prime-boost regimen of 36 days may have utility for quickly responding to outbreaks caused by new species of EBOV. C1 [Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. RP Mire, CE (reprint author), Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. EM twgeisbe@utmb.edu FU University of Texas Medical Branch at Galveston; Intramural Research Program of the NIH, NIAID; Department of Health and Human Services, NIH [AI098817] FX The animal portion of this research was supported by the University of Texas Medical Branch at Galveston. Non-animal portions of the work were supported by the Intramural Research Program of the NIH, NIAID and the Department of Health and Human Services, NIH, grant AI098817 to Dr. John Eldridge and TWG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript NR 44 TC 26 Z9 28 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2013 VL 7 IS 12 AR e2600 DI 10.1371/journal.pntd.0002600 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 282JU UT WOS:000329168100022 PM 24367715 ER PT J AU Rabaa, MA Simmons, CP Fox, A Le, MQ Nguyen, TTT Le, HY Gibbons, RV Nguyen, XT Holmes, EC Aaskov, JG AF Rabaa, Maia A. Simmons, Cameron P. Fox, Annette Mai Quynh Le Thuy Thi Thu Nguyen Hai Yen Le Gibbons, Robert V. Xuyen Thanh Nguyen Holmes, Edward C. Aaskov, John G. TI Dengue Virus in Sub-tropical Northern and Central Viet Nam: Population Immunity and Climate Shape Patterns of Viral Invasion and Maintenance SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID AEDES-AEGYPTI; MOLECULAR CHARACTERIZATION; PHYLOGENETIC UNCERTAINTY; GUANGDONG PROVINCE; SOUTHERN VIETNAM; KAMPHAENG-PHET; CHINA; OUTBREAK; THAILAND; FEVER AB Dengue virus transmission occurs in both epidemic and endemic cycles across tropical and sub-tropical regions of the world. Incidence is particularly high in much of Southeast Asia, where hyperendemic transmission plagues both urban and rural populations. However, endemicity has not been established in some areas with climates that may not support year-round viral transmission. An understanding of how dengue viruses (DENV) enter these environments and whether the viruses persist in inapparent local transmission cycles is central to understanding how dengue emerges in areas at the margins of endemic transmission. Dengue is highly endemic in tropical southern Vietnam, while increasingly large seasonal epidemics have occurred in northern Viet Nam over the last decade. We have investigated the spread of DENV-1 throughout Vietnam to determine the routes by which the virus enters northern and central regions of the country. Phylogeographic analysis of 1,765 envelope (E) gene sequences from Southeast Asia revealed frequent movement of DENV between neighboring human populations and strong local clustering of viral lineages. Long-distance migration of DENV between human population centers also occurred regularly and on short time-scales, indicating human-mediated viral invasion into northern Vietnam. Human populations in southern Vietnam were found to be the primary source of DENV circulating throughout the country, while central and northern Vietnam acted as sink populations, likely due to reduced connectedness to other populations in the case of the central regions and to the influence of temperature variability on DENV replication and vector survival and competence in the north. Finally, phylogeographic analyses suggested that viral movement follows a gravity model and indicates that population immunity and physical and economic connections between populations may play important roles in shaping patterns of DENV transmission. Author Summary Reports from sub-tropical regions of the world suggest a growing risk of introduction and establishment of dengue viruses (DENV) in new locales. Recent dengue epidemics in northern Viet Nam present an opportunity to study how DENV invades and spreads in these environments. The proximity of this region to tropical areas experiencing year-round endemic DENV transmission makes it an ideal site for studying the effects of human population movement and climate on DENV emergence. We performed a phylogenetic analysis using DENV-1 envelope gene sequences from Southeast Asia. We show that DENV are regularly imported into northern and central Viet Nam from southern Vietnam, and that increasingly large seasonal epidemics in the north are caused by newly introduced viruses each year. While tropical Vietnam maintains localized virus populations for multiple years, cool winter temperatures in sub-tropical northern Viet Nam may reduce mosquito populations and virus replication to levels that are not conducive to year-round DENV transmission. Finally, we found that the dispersal of DENV across the region is well-described using human movement and immunity data, and believe that increased epidemiological, entomological, and virological surveillance are needed to understand the processes by which endemic DENV transmission becomes established in new populations. C1 [Rabaa, Maia A.] Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. [Rabaa, Maia A.; Simmons, Cameron P.] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Simmons, Cameron P.; Fox, Annette] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England. [Fox, Annette] Univ Oxford, Clin Res Unit, Wellcome Trust Major Overseas Programme, Hanoi, Vietnam. [Mai Quynh Le; Thuy Thi Thu Nguyen] Natl Inst Hyg & Epidemiol, Hanoi, Vietnam. [Hai Yen Le; Xuyen Thanh Nguyen] Mil Inst Hyg & Epidemiol, Hanoi, Vietnam. [Gibbons, Robert V.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Marie Bashir Inst Emerging Dis & Biosecur, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Aaskov, John G.] Queensland Univ Technol, Brisbane, Qld 4001, Australia. [Aaskov, John G.] Australian Army Malaria Inst, Brisbane, Qld, Australia. RP Rabaa, MA (reprint author), Univ Edinburgh, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland. EM j.aaskov@qut.edu.au OI Rabaa, Maia/0000-0003-0529-2228; Simmons, Cameron P./0000-0002-9039-7392; Holmes, Edward/0000-0001-9596-3552 FU National Science Foundation Graduate Research Fellowship; Wellcome Trust of the United Kingdom through the Vietnamese Initiative on Zoonotic InfectiONS (WT-VIZIONS); National Health and Medical Research Council of Australia; U.S. Global Emerging Infections Surveillance and Response System; National Institutes of Health [R01 GM087405] FX Funding to MAR was provided by a National Science Foundation Graduate Research Fellowship and by the Wellcome Trust of the United Kingdom through the Vietnamese Initiative on Zoonotic InfectiONS (WT-VIZIONS). This study was supported by grants from the National Health and Medical Research Council of Australia (including an Australia Fellowship to ECH), the U.S. Global Emerging Infections Surveillance and Response System, and the National Institutes of Health (grant R01 GM087405 to ECH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 10 Z9 10 U1 0 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2013 VL 7 IS 12 AR e2581 DI 10.1371/journal.pntd.0002581 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 282JU UT WOS:000329168100016 PM 24340118 ER PT J AU Safronetz, D Sogoba, N Lopez, JE Maiga, O Dahlstrom, E Zivcec, M Feldmann, F Haddock, E Fischer, RJ Anderson, JM Munster, VJ Branco, L Garry, R Porcella, SF Schwan, TG Feldmann, H AF Safronetz, David Sogoba, Nafomon Lopez, Job E. Maiga, Ousmane Dahlstrom, Eric Zivcec, Marko Feldmann, Friederike Haddock, Elaine Fischer, Robert J. Anderson, Jennifer M. Munster, Vincent J. Branco, Luis Garry, Robert Porcella, Stephen F. Schwan, Tom G. Feldmann, Heinz TI Geographic Distribution and Genetic Characterization of Lassa Virus in Sub-Saharan Mali SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID WEST-AFRICA; MASTOMYS-NATALENSIS; FEVER; INFECTION; ARENAVIRUSES; DISEASE; RODENTS; REGION AB Background Lassa fever is an acute viral illness characterized by multi-organ failure and hemorrhagic manifestations. Lassa fever is most frequently diagnosed in Nigeria, Sierra Leone, Liberia, and Guinea, although sporadic cases have been recorded in other West African countries, including Mali. The etiological agent of Lassa fever is Lassa virus (LASV), an Arenavirus which is maintained in nature and frequently transmitted to humans by Mastomys natalensis. The purpose of this study was to better define the geographic distribution of LASV-infected rodents in sub-Saharan Mali. Methodologies/Principal Findings Small mammals were live-trapped at various locations across Mali for the purpose of identifying potential zoonotic pathogens. Serological and molecular assays were employed and determined LASV infected rodents were exclusively found in the southern Mali near the border of Cote d'Ivoire. Overall, 19.4% of Mastomys natalensis sampled in this region had evidence of LASV infection, with prevalence rates for individual villages ranging from 0 to 52%. Full-length genomic sequences were determined using high throughput sequencing methodologies for LASV isolates generated from tissue samples of rodents collected in four villages and confirmed the phylogenetic clustering of Malian LASV with strain AV. Conclusions/Significance The risk of human infections with LASV is greatest in villages in southern Mali. Lassa fever should be considered in the differential diagnosis for febrile individuals and appropriate diagnostic techniques need to be established to determine the incidence of infection and disease in these regions. Author Summary Lassa fever is an acute infection associated with hemorrhagic manifestations and multi-organ failure in West Africa. The etiological agent of Lassa fever is Lassa virus (LASV), a rodent-borne arenavirus, which is maintained in nature and transmitted to humans by the multimammate rat, Mastomys natalensis. Despite the ubiquitous nature of the rodent reservoir, LASV-infected animals are most commonly documented in Nigeria, Sierra Leone, Guinea and Liberia. These four countries represent the historic endemic region for Lassa fever, although there is increasing evidence of sporadic cases occurring in other West African nations including Mali. To better define the geographic distribution of LASV-infected rodents in Mali, we tested samples from small animals collected at 27 sites across the country. Although M. natalensis was the predominant rodent species in the majority of villages, evidence of LASV infection was exclusively found in southern Mali, where overall nearly 20% of rodents were positive. The full genomic sequence was determined for five isolates and confirmed LASV in Mali is closely related to strain AV. We conclude that there is a risk of human exposure to LASV in villages in southern Mali and Lassa fever should be considered in the differential diagnosis for acutely ill, febrile patients. C1 [Safronetz, David; Zivcec, Marko; Haddock, Elaine; Munster, Vincent J.; Feldmann, Heinz] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Sogoba, Nafomon; Maiga, Ousmane] Univ Sci Tech & Technol Bamako, Malaria Res & Training Ctr, Bamako, Mali. [Lopez, Job E.; Fischer, Robert J.; Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Dahlstrom, Eric; Porcella, Stephen F.] NIAID, Rocky Mt Lab, Res Technol Sect, Genom Unit,Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Zivcec, Marko; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Anderson, Jennifer M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Branco, Luis; Garry, Robert] Tulane Sch Med, Dept Microbiol & Immunol, New Orleans, LA USA. [Branco, Luis] Autoimmune Technol LLC, New Orleans, LA USA. RP Safronetz, D (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM safronetzd@naidi.nih.gov; feldmannh@niaid.nih.gov OI Fischer, Robert/0000-0002-1816-472X; Zivcec, Marko/0000-0003-4337-8487; Munster, Vincent/0000-0002-2288-3196; Branco, Luis/0000-0001-8161-0182 FU International Centers for Excellence in Research program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was funded by the International Centers for Excellence in Research program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 12 Z9 12 U1 3 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2013 VL 7 IS 12 AR e2582 DI 10.1371/journal.pntd.0002582 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 282JU UT WOS:000329168100013 PM 24340119 ER PT J AU Nguyen, THT Nguyen, THQ Vu, TT Farrar, J Hoang, TL Dong, THT Tran, VN Phung, KL Wolbers, M Whitehead, SS Hibberd, ML Wills, B Simmons, CP AF Thi Hanh Tien Nguyen Than Ha Quyen Nguyen Tuan Trung Vu Farrar, Jeremy Truong Long Hoang Thi Hoai Tam Dong Van Ngoc Tran Khanh Lam Phung Wolbers, Marcel Whitehead, Stephen S. Hibberd, Martin L. Wills, Bridget Simmons, Cameron P. TI Corticosteroids for Dengue - Why Don't They Work? SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID IMMUNE ACTIVATION; VIRUS-INFECTIONS; DISEASE SEVERITY; RECEPTOR; LEAKAGE; BURDEN AB Background Dysregulated immune responses may contribute to the clinical complications that occur in some patients with dengue. Findings In Vietnamese pediatric dengue cases randomized to early prednisolone therapy, 81 gene-transcripts (0.2% of the 47,231 evaluated) were differentially abundant in whole-blood between high-dose (2 mg/kg) prednisolone and placebo-treated patients two days after commencing therapy. Prominent among the 81 transcripts were those associated with T and NK cell cytolytic functions. Additionally, prednisolone therapy was not associated with changes in plasma cytokine levels. Conclusion The inability of prednisolone treatment to markedly attenuate the host immune response is instructive for planning future therapeutic strategies for dengue. Author Summary Dengue is an acute, mosquito-borne febrile illness and around 390 million cases occur annually in more than 100 countries. A host pro-inflammatory immune response is widely believed to contribute to the clinical complications that occur in some patients with dengue. Synthetic glucocorticoids, which are immunomodulatory agents commonly used in medicine, have been suggested as a therapy for dengue. We recently performed a randomized, controlled trial of early oral glucocorticoid therapy in 225 dengue cases in Vietnam, comparing a three day regimen of high (2 mg/kg) or low (0.5 mg/kg) dose prednisolone with placebo. Here, we report on immunological changes occurring during prednisolone therapy with a view to understanding the lack of clinical benefit by glucocorticoid therapy and to guide future intervention strategies for dengue. In whole-blood gene expression arrays we found 81 transcripts from 64 genes differentially abundant between high-dose prednisolone and placebo treated patients. Prominent were the genes associated with T and NK cell cytolytic functions. These results are a reminder that the mechanisms causally behind some of the complications of dengue (e.g. altered capillary permeability) are very poorly understood and represent a major knowledge gap in our understanding of disease pathogenesis that also undermines attempts to improve clinical management. C1 [Thi Hanh Tien Nguyen; Than Ha Quyen Nguyen; Tuan Trung Vu; Farrar, Jeremy; Khanh Lam Phung; Wolbers, Marcel; Wills, Bridget; Simmons, Cameron P.] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Farrar, Jeremy; Wolbers, Marcel; Wills, Bridget; Simmons, Cameron P.] Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford, England. [Truong Long Hoang; Hibberd, Martin L.] Genome Inst Singapore, Singapore, Singapore. [Thi Hoai Tam Dong; Van Ngoc Tran] Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Whitehead, Stephen S.] NIAID, LID, Bethesda, MD 20892 USA. [Simmons, Cameron P.] Univ Melbourne, Nossal Inst Global Hlth, Sch Populat & Global Hlth, Parkville, Vic 3052, Australia. RP Nguyen, THT (reprint author), Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. EM tiennth@oucru.org OI Simmons, Cameron P./0000-0002-9039-7392; Hibberd, Martin/0000-0001-8587-1849; Farrar, Jeremy/0000-0002-2700-623X FU Wellcome Trust [084368/Z/07/Z] FX This work was supported by Wellcome Trust [084368/Z/07/Z]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript NR 17 TC 10 Z9 10 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2013 VL 7 IS 12 AR e2592 DI 10.1371/journal.pntd.0002592 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 282JU UT WOS:000329168100030 PM 24349598 ER PT J AU Dere, E Anderson, LM Coulson, M McIntyre, BS Boekelheide, K Chapin, RE AF Dere, Edward Anderson, Linnea M. Coulson, Michelle McIntyre, Barry S. Boekelheide, Kim Chapin, Robert E. TI SOT Symposium Highlight: Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material DE biomarkers; testicular toxicity; inhibin B; microRNA; sperm ID GLYCOL MONOMETHYL ETHER; MALE-RATS; LACTATE-DEHYDROGENASE; HUMAN SPERMATOZOA; URINARY CREATINE; POTENTIAL BIOMARKER; GENE-EXPRESSION; DIMERIC INHIBIN; INFERTILE MEN; C-ELEGANS AB Testicular toxicity is an important safety endpoint in drug development and risk assessment, but reliable and translatable biomarkers for predicting injury have eluded researchers. However, this area shows great potential for improvement, with several avenues currently being pursued. This was the topic of a symposium session during the 2013 Society of Toxicology Annual Meeting in San Antonio, TX, entitled Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures. This symposium brought together stakeholders from academia, government, and industry to present the limitations and drawbacks of currently used indicators of injury and discussed the ongoing efforts in developing more predictive biomarkers of injury. The presentations highlighted the early challenges of using circulating inhibin B and microRNA levels, and sperm messenger RNA transcript abundance and DNA methylation profiles, as novel biomarkers of testicular toxicity. C1 [Dere, Edward] Rhode Isl Hosp, Div Urol, Providence, RI 02903 USA. [Dere, Edward; Anderson, Linnea M.; Boekelheide, Kim] Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. [Coulson, Michelle] AstraZeneca Res & Dev, Global Safety Assessment, Macclesfield SK10 4TG, Cheshire, England. [McIntyre, Barry S.] NIEHS, NIH, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Chapin, Robert E.] Pfizer Drug Safety Res & Dev, Groton, CT 06340 USA. RP Dere, E (reprint author), Brown Univ, Dept Pathol & Lab Med, Box G-E, Providence, RI 02912 USA. EM edward_dere@brown.edu OI Dere, Edward/0000-0002-8233-9774 FU NIEHS NIH HHS [P42 ES013660, T32ES007272-17, P42ES013660] NR 87 TC 4 Z9 4 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD DEC PY 2013 VL 136 IS 2 BP 265 EP 273 DI 10.1093/toxsci/kft207 PG 9 WC Toxicology SC Toxicology GA 275RQ UT WOS:000328695500001 PM 24052563 ER PT J AU Burns, KA Zorrilla, LM Hamilton, KJ Reed, CE Birnbaum, LS Korach, KS AF Burns, Katherine A. Zorrilla, Leah M. Hamilton, Katherine J. Reed, Casey E. Birnbaum, Linda S. Korach, Kenneth S. TI A Single Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Disrupts the Adult Uterine Response to Estradiol in Mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE TCDD; uterus; developmental exposure ID LACTOFERRIN GENE-EXPRESSION; ARYL-HYDROCARBON RECEPTOR; TRANSCRIPTION IN-VIVO; DIOXIN-LIKE CHEMICALS; ESTROGEN-RECEPTOR; MOUSE UTERUS; POLYCHLORINATED-BIPHENYLS; LACTATIONAL EXPOSURE; OVARIAN-STEROIDS; AH-RECEPTOR AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) given as a cotreatment with estrogen exhibits antiestrogenic properties on the rodent adult uterus, but less is understood regarding hormonal responsiveness of the adult uterus from animals having been exposed to TCDD during critical periods of development. We characterized the inhibitory effects of TCDD (T) exposure at gestational day 15 (GD15), 4 weeks, and 9 weeks of age (TTT) on the adult uterus following hormone treatment. TTT-exposed mice in response to hormone treatment exhibited a blunted weight increase, had fewer uterine glands, displayed morphological anomalies, and had marked decreases in the hormonal regulation of genes involved in fluid transport (Aqp3 and Aqp5), cytoarchitectural (Dsc2 and Sprr2A), and immune (Lcn2 and Ltf) regulation. To determine if the 9-week exposure was responsible for the blunted uterine response, due to the 7- to 11-day half-life of TCDD in mice, a second set of experiments was performed to examine exposure to TCDD given at GD15, GD15 only (cross-fostered at birth), only during lactation (cross-fostered at birth), or at GD15 and 4 weeks of age. Our studies demonstrate that a single developmental TCDD exposure at GD15 is sufficient to elicit a blunted adult uterine response to estradiol and is due in part to fewer gland numbers and the reduced expression of forkhead box A2 (FoxA2), a gene involved in gland development. Together, these results provide insight regarding the critical nature of in utero exposure and the potential impact on ensuing uterine biology and reproductive health later in life. C1 [Burns, Katherine A.; Hamilton, Katherine J.; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Zorrilla, Leah M.] Integrated Lab Syst Inc, Invest Toxicol Div, Res Triangle Pk, NC 27709 USA. [Reed, Casey E.] NIEHS, Reprod Endocrinol Grp, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, NCI, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, LRDT, NIH, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Division of Intramural Research of the National Institute of Environmental Health Sciences [Z01 ES70065]; National Institute of Environmental Health Sciences contract [N01 ES00005]; Division of Intramural Research of the National Cancer Institute at National Institute of Environmental Health Science [ZIA BC011476] FX Division of Intramural Research of the National Institute of Environmental Health Sciences (Z01 ES70065 to K. S. K. and K. A. B.); National Institute of Environmental Health Sciences contract (N01 ES00005 to L.M.Z.); Division of Intramural Research of the National Cancer Institute at National Institute of Environmental Health Sciences (ZIA BC011476 to L.S.B.). NR 62 TC 4 Z9 4 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD DEC PY 2013 VL 136 IS 2 BP 514 EP 526 DI 10.1093/toxsci/kft208 PG 13 WC Toxicology SC Toxicology GA 275RQ UT WOS:000328695500021 PM 24052564 ER PT J AU Cunnington, AJ Riley, EM Walther, M AF Cunnington, Aubrey J. Riley, Eleanor M. Walther, Michael TI Stuck in a rut? Reconsidering the role of parasite sequestration in severe malaria syndromes SO TRENDS IN PARASITOLOGY LA English DT Review DE severe malaria; sequestration; inflammation; endothelial activation; biomass ID PLASMODIUM-FALCIPARUM MALARIA; LIFE-THREATENING MALARIA; TUMOR-NECROSIS-FACTOR; RED-BLOOD-CELLS; CEREBRAL MALARIA; INFECTED ERYTHROCYTES; AFRICAN CHILDREN; ENDOTHELIAL-CELLS; MICROVASCULAR DYSFUNCTION; MALAWIAN CHILDREN AB Severe malaria defines individuals at increased risk of death from their infection. Proposed pathogenic mechanisms include parasite sequestration, inflammation, and endothelial dysfunction. Severe malaria is not a single entity, manifesting with distinct syndromes such as severe anemia, severe respiratory distress or coma, each characterized by differences in epidemiology, underlying biology, and risk of death. The relative contribution of the various pathogenic mechanisms may differ between syndromes, and this is supported by accumulating evidence, which challenges sequestration as the initiating event. Here we propose that high parasite biomass is the common initiating feature, but subtle variations in the interaction between the host and parasite exist, and understanding these differences may be crucial to improve outcomes in patients with severe malaria. C1 [Cunnington, Aubrey J.] Univ London Imperial Coll Sci Technol & Med, Paediat Sect, London W2 1PG, England. [Riley, Eleanor M.] Univ London London Sch Hyg & Trop Med, Dept Immunol & Infect, London WC1E 7HT, England. [Walther, Michael] NIAID, Immune Regulat Sect, Lab Malaria Immunol & Vaccinol, Div Intramural Res,NIH, Rockville, MD 20852 USA. RP Cunnington, AJ (reprint author), Univ London Imperial Coll Sci Technol & Med, Paediat Sect, Norfolk Pl, London W2 1PG, England. EM a.cunnington@imperial.ac.uk RI Riley, Eleanor/C-8960-2013; OI Riley, Eleanor/0000-0003-3447-3570; Cunnington, Aubrey/0000-0002-1305-3529 FU Intramural NIH HHS [Z99 AI999999]; Medical Research Council [G0701427, MC_U190081986] NR 75 TC 19 Z9 19 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD DEC PY 2013 VL 29 IS 12 BP 585 EP 592 DI 10.1016/j.pt.2013.10.004 PG 8 WC Parasitology SC Parasitology GA 270IR UT WOS:000328312600003 PM 24210256 ER PT J AU Li, J Yuan, J Cheng, KCC Inglese, J Su, XZ AF Li, Jian Yuan, Jing Cheng, Ken Chih-Chien Inglese, James Su, Xin-zhuan TI Chemical genomics for studying parasite gene function and interaction SO TRENDS IN PARASITOLOGY LA English DT Review DE high-throughput screening; genetics; genomics; gene function ID PROTEIN IDENTIFICATION TECHNOLOGY; PLASMODIUM-FALCIPARUM GENOME; HIGH-THROUGHPUT SCREEN; CANCER-CELL-LINES; SMALL MOLECULES; DRUG DISCOVERY; DETERMINING CHEMOSENSITIVITY; ASSOCIATION ANALYSES; SHOTGUN PROTEOMICS; TRYPANOSOMA-BRUCEI AB With the development of new technologies in genome sequencing, gene expression profiling, genotyping, and high-throughput screening of chemical compound libraries, small molecules are playing increasingly important roles in studying gene expression regulation, gene-gene interaction, and gene function. Here we briefly review and discuss some recent advancements in drug target identification and phenotype characterization using combinations of high-throughput screening of small-molecule libraries and various genome-wide methods such as whole-genome sequencing, genome-wide association studies (GWAS), and genome-wide expression analysis. These approaches can be used to search for new drugs against parasite infections, to identify drug targets or drug resistance genes, and to infer gene function. C1 [Li, Jian; Yuan, Jing] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. [Cheng, Ken Chih-Chien; Inglese, James] Natl Ctr Adv Translat Sci, NIH, Bethesda, MD 20982 USA. [Inglese, James] NHGRI, NIH, Bethesda, MD 20892 USA. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. EM xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU National Natural Science Foundation of China [81220108019, 81271858, 81201324]; Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China [B06016]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the National Natural Science Foundation of China (grants 81220108019, 81271858, and 81201324), by Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Center for Advancing Translational Sciences, National Institutes of Health. We thank Dr Ronald Johnson for comments, and intramural editor Brenda Rae Marshall [Division of Intramural Research (DIR) Program Support Staff (DPSS)], NIAID, for assistance. We apologize to those whose work on screening for antiparasite drugs cannot be cited here owing to space constraints. NR 101 TC 2 Z9 3 U1 0 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD DEC PY 2013 VL 29 IS 12 BP 603 EP 611 PG 9 WC Parasitology SC Parasitology GA 270IR UT WOS:000328312600005 PM 24215777 ER PT J AU Meier, JL AF Meier, Jordan L. TI Metabolic Mechanisms of Epigenetic Regulation SO ACS CHEMICAL BIOLOGY LA English DT Article ID ATP-CITRATE LYASE; HISTONE ACETYLTRANSFERASE ACTIVITY; NICOTINAMIDE N-METHYLTRANSFERASE; NAD(+) SALVAGE PATHWAY; ADENOSYL-L-METHIONINE; CHEMICAL PROBE; BREAST-CANCER; TRANSCRIPTIONAL COACTIVATOR; ALPHA-KETOGLUTARATE; DNA METHYLATION AB Chromatin modifications have been well-established to play a critical role in the regulation of genome function. Many of these modifications are introduced and removed by enzymes that utilize cofactors derived from primary metabolism. Recently, it has been shown that endogenous cofactors and metabolites can regulate the activity of chromatin-modifying enzymes, providing a direct link between the metabolic state of the cell and epigenetics. Here we review metabolic mechanisms of epigenetic regulation with an emphasis on their role in cancer. Focusing on three core mechanisms, we detail and draw parallels between metabolic and chemical strategies to modulate epigenetic signaling, and highlight opportunities for chemical biologists to help shape our knowledge of this emerging phenomenon. Continuing to integrate our understanding of metabolic and genomic regulatory mechanisms may help elucidate the role of nutrition in diseases such as cancer, while also providing a basis for new approaches to modulate epigenetic signaling for therapeutic benefit. C1 NCI, Chem Genom Sect, Biol Chem Lab, Frederick, MD 21702 USA. RP Meier, JL (reprint author), NCI, Chem Genom Sect, Biol Chem Lab, Frederick, MD 21702 USA. RI Meier, Jordan/N-2608-2014 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We apologize to colleagues whose work could not be cited here due to space limitations. We thank members of the Meier laboratory (D. Montgomery, A. Sorum) and colleagues in the Chemical Biology Laboratory for careful reading of this manuscript and many helpful comments. J.L.M. is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 155 TC 17 Z9 17 U1 2 U2 43 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD DEC PY 2013 VL 8 IS 12 BP 2607 EP 2621 DI 10.1021/cb400689r PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 281CW UT WOS:000329078100002 PM 24228614 ER PT J AU Xu, W Liu, CY Kaartinen, V Chen, H Lu, CH Zhang, WM Luo, YF Shi, W AF Xu, Wei Liu, Chengyu Kaartinen, Vesa Chen, Hui Lu, Chi-Han Zhang, Wenming Luo, Yongfeng Shi, Wei TI TACE in perinatal mouse lung epithelial cells promotes lung saccular formation SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE tumor necrosis factor-alpha converting enzyme; lung development ID NECROSIS-FACTOR-ALPHA; CONVERTING-ENZYME; ADAM METALLOPROTEINASES; DIFFERENTIATION; ERBB4; GENE AB Tumor necrosis factor-alpha converting enzyme (TACE) is a cell membrane sheddase, expressed in both developmental lung epithelia and mesenchyme. Global abrogation of TACE results in neonatal lethality and multiple organ developmental abnormalities, including dysplastic lung. To further define the roles of TACE in regulating lung development, lung epithelial and/or mesenchymal specific TACE conditional knockout mice were generated. Blockade of TACE function in developing lung epithelial cells caused reduced saccular formation, decreased cell proliferation, and reduced mid-distal lung epithelial cell differentiation. In contrast, mesenchymal TACE knockout did not have any phenotypic change in developing lung. Simultaneous abrogation of TACE in both lung epithelial and mesenchymal cells did not result in a more severe lung abnormality. Interestingly, these lung-specific TACE conditional knockout mice were not neonatal lethal, and their lung structures were essentially normal after alveolarization. In addition, TACE conditional knockout in developing cardiomyocytes resulted in noncompaction of ventricular myocardium, as seen in TACE conventional knockout mice. However, these mice were also not neonatal lethal. In conclusion, lung epithelial TACE is essential for promoting fetal lung saccular formation, but not postnatal lung alveolarization in mice. Because the developmental abnormality of either lung or heart induced by TACE deficiency does not directly lead to neonatal lethality, the neonatal death of TACE conventional knockout mice is likely a result of synergistic effects of multiple organ abnormalities. C1 [Xu, Wei; Chen, Hui; Lu, Chi-Han; Zhang, Wenming; Luo, Yongfeng; Shi, Wei] Childrens Hosp Los Angeles, Dev Biol & Regenerat Med Program, Saban Res Inst, Los Angeles, CA 90027 USA. [Xu, Wei] Nanchang Univ, Affiliated Hosp 2, Dept Resp Med, Nanchang, Peoples R China. [Liu, Chengyu] NHLBI, IPSC & Genome Engn Core, NIH, Bethesda, MD 20892 USA. [Kaartinen, Vesa] Univ Michigan, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. RP Shi, W (reprint author), Childrens Hosp Los Angeles, Dev Biol & Regenerat Med Program, 4650 Sunset Blvd,Mailstop 35, Los Angeles, CA 90027 USA. EM wshi@chla.usc.edu OI Kaartinen, Vesa/0000-0002-9432-510X FU National Heart, Lung, and Blood Institute [HL-109932, HL-068597]; American Heart Association; California Institute of Regenerative Medicine Training FX This work was supported by National Heart, Lung, and Blood Institute Grants HL-109932 and HL-068597 (W. Shi), an American Heart Association Grant in Aid (W. Shi), and a California Institute of Regenerative Medicine Training Grant (W. Xu and Y. Luo). NR 27 TC 4 Z9 4 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD DEC PY 2013 VL 305 IS 12 BP L953 EP L963 DI 10.1152/ajplung.00189.2013 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 276LD UT WOS:000328750900006 PM 24142516 ER PT J AU Lee, IH Finkel, T AF Lee, In Hye Finkel, Toren TI Metabolic regulation of the cell cycle SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; GENOME-WIDE ASSOCIATION; PROTEIN-KINASE; RAG GTPASES; SACCHAROMYCES-CEREVISIAE; SIGNALS CONTROL; AMINO-ACIDS; MITOCHONDRIAL; CHECKPOINT; PATHWAY AB There is a growing appreciation that metabolic signals are integrated and coupled to cell cycle progression. However, the molecular wiring that connects nutrient availability, biosynthetic intermediates and energetic balance to the core cell cycle machinery remains incompletely understood. In this review, we explore the recent progress in this area with particular emphasis on how nutrient and energetic status is sensed within the cell to ultimately regulate cell growth and division. The role these pathways play in normal cell function including stem cell biology is also discussed. Furthermore, we describe the growing appreciation that dysregulation of these pathways might contribute to a variety of pathological conditions including metabolic diseases and tumor formation. C1 [Lee, In Hye; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Lee, In Hye] Ewha Womans Univ, Dept Life Sci, Div Life & Pharmaceut Sci, Seoul, South Korea. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU NIH FX We are grateful to Ilsa Rovira for help with the figures. This work was supported by NIH Intramural funds. NR 55 TC 10 Z9 10 U1 2 U2 16 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2013 VL 25 IS 6 BP 724 EP 729 DI 10.1016/j.ceb.2013.07.002 PG 6 WC Cell Biology SC Cell Biology GA 277CO UT WOS:000328796200008 PM 23890700 ER PT J AU Dunn, BM Wlodawer, A AF Dunn, Ben M. Wlodawer, Alexander TI The regulation of proteolysis around the World SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Editorial Material C1 [Dunn, Ben M.] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Dunn, BM (reprint author), Univ Florida, Dept Biochem & Mol Biol, 1600 SW Archer Rd, Gainesville, FL 32610 USA. EM bdunn@ufl.edu; wlodawer@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 2013 VL 23 IS 6 BP 795 EP 796 DI 10.1016/j.sbi.2013.10.004 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 282CU UT WOS:000329148700001 PM 24210951 ER PT J AU Aiello, FB Graciotti, L Procopio, AD Keller, JR Durum, SK AF Aiello, Francesca B. Graciotti, Laura Procopio, Antonio D. Keller, Jonathan R. Durum, Scott K. TI Stemness of T cells and the hematopoietic stem cells: Fate, memory, niche, cytokines SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Hematopoietic stem cells; T memory stem cells; T memory cells; Stem cell markers; Self renewal ID LONG-TERM MAINTENANCE; SLAM FAMILY RECEPTORS; HELPER TYPE-2 CELLS; DNA-DAMAGE RESPONSE; RENEWAL IN-VIVO; C-KIT LIGAND; SELF-RENEWAL; PROGENITOR CELLS; CD8(+) MEMORY; BETA-CATENIN AB Stem cells are able to generate both cells that differentiate and cells that remain undifferentiated but potentially have the same developmental program. The prolonged duration of the protective immune memory for infectious diseases such as polio, small pox, and measles, suggested that memory T cells may have stem cell properties. Understanding the molecular basis for the life-long persistence of memory T cells may be useful to project targeted therapies for immune deficiencies and infectious diseases and to formulate vaccines. In the last decade evidence from different laboratories shows that memory T cells may share self-renewal pathways with bone marrow hematopoietic stem cells. In stem cells the intrinsic self-renewal activity, which depends on gene expression, is known to be modulated by extrinsic signals from the environment that may be tissue specific. These extrinsic signals for sternness of memory T cells include cytokines such as IL-7 and IL-15 and there are other cytokine signals for maintaining the cytokine signature (TH1, TH2, etc.) of memory T cells. Intrinsic and extrinsic pathways that might be common to bone marrow hematopoietic stem cells and memory T lymphocytes are discussed and related to self-renewal functions. Published by Elsevier Ltd. C1 [Aiello, Francesca B.; Durum, Scott K.] Mol Immunoregulat Lab, Frederick, MD 21702 USA. [Aiello, Francesca B.] Univ G dAnnunzio, Dept Med & Aging Sci, I-66013 Chieti, Italy. [Graciotti, Laura; Procopio, Antonio D.] Marche Polytech Univ, Dept Clin & Med Sci, I-60100 Ancona, Italy. [Keller, Jonathan R.] Lab Canc Prevent, Frederick, MD 21702 USA. RP Durum, SK (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Bldg 560, Frederick, MD 21702 USA. EM aiellofb@nih.mail.gov; 1.graciotti@univpm.it; a.d.procopio@univpm.it; kellerjo@nih.mail.gov; durums@nih.mail.gov NR 218 TC 4 Z9 4 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD DEC PY 2013 VL 24 IS 6 BP 485 EP 501 DI 10.1016/j.cytogfr.2013.10.002 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 278XT UT WOS:000328923900001 PM 24231048 ER PT J AU Swaminathan, S Dai, L Lane, HC Imamichi, T AF Swaminathan, Sanjay Dai, Luc Lane, H. Clifford Imamichi, Tomozumi TI Evaluating the potential of IL-27 as a novel therapeutic agent in HIV-1 infection SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Interleukin-27; HIV; Cytokines; SPTBN1; Therapy ID VIRUS-LIKE PARTICLES; REGULATORY T-CELLS; HUMAN MACROPHAGES; DENDRITIC CELLS; IMMUNE-RESPONSES; GENE-EXPRESSION; HUMAN MONOCYTES; CUTTING EDGE; DC-SIGN; C-MAF AB Interleukin 27 (IL-27) is an immunomodulatory cytokine with important roles in both the innate and adaptive immune systems. In the last five years, the addition of exogenous IL-27 to primary cell cultures has been demonstrated to decrease HIV-1 replication in a number of cell types including peripheral blood mononuclear cells (PBMCs), CD4+ T cells, macrophages and dendritic cells. These in vitro findings suggest that IL-27 may have therapeutic value in the setting of HIV-1 infection. In this review, we describe the current knowledge of the biology of IL-27, its effects primarily on HIV-1 replication but also in other viral infections and explore its potential role as a therapeutic cytokine for the treatment of patients with HIV-1 infection. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Swaminathan, Sanjay; Dai, Luc; Imamichi, Tomozumi] Sci Applicat Int Corp SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol, Appl & Dev Res Directorate, Frederick, MD 21702 USA. [Lane, H. Clifford] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), Sci Applicat Int Corp SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol, Bldg 550,Room 126,1050 Boyles St, Frederick, MD 21702 USA. EM sanjay.swaminathan@nih.gov; lue.dai@nih.gov; CLANE@niaid.nih.gov; timamichi@mail.nih.gov OI Swaminathan, Sanjay/0000-0001-5315-6445 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Disease FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the National Institute of Allergy and Infectious Disease. NR 56 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 EI 1879-0305 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD DEC PY 2013 VL 24 IS 6 BP 571 EP 577 DI 10.1016/j.cytogfr.2013.07.001 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 278XT UT WOS:000328923900008 PM 23962745 ER PT J AU Antony, S Wu, YZ Hewitt, SM Anver, MR Butcher, D Jiang, GJ Meitzler, JL Liu, H Juhasz, A Lu, JM Roy, KK Doroshow, JH AF Antony, Smitha Wu, Yongzhong Hewitt, Stephen M. Anver, Miriam R. Butcher, Donna Jiang, Guojian Meitzler, Jennifer L. Liu, Han Juhasz, Agnes Lu, Jiamo Roy, Krishnendu K. Doroshow, James H. TI Characterization of NADPH oxidase 5 expression in human tumors and tumor cell lines with a novel mouse monoclonal antibody SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE NADPH oxidase 5; Tissue microarray; Mouse monoclonal Nox5 antibody; Melanoma; UACC-257 cells; Reactive oxygen species; Superoxide; Free radicals ID PROSTATE-CANCER CELLS; ESOPHAGEAL ADENOCARCINOMA CELLS; SMOOTH-MUSCLE-CELLS; REACTIVE OXYGEN; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; NAD(P)H OXIDASE; ENDOTHELIAL-CELLS; MELANOMA-CELLS; NOX ENZYMES AB Reactive oxygen species generated by NADPH oxidase 5 (Nox5) have been implicated in physiological and pathophysiological signaling pathways, including cancer development and progression. However, because immunological tools are lacking, knowledge of the role of Nox5 in tumor biology has been limited; the expression of Nox5 protein across tumors and normal tissues is essentially unknown. Here, we report the characterization and use of a mouse monoclonal antibody against a recombinant Nox5 protein (bp 600-746) for expression profiling of Nox5 in human tumors by tissue microarray analysis. Using our novel antibody, we also report the detection of endogenous Nox5 protein in human UACC-257 melanoma cells. Immunofluorescence, confocal microscopy, and immunohistochemical techniques were employed to demonstrate Nox5 localization throughout UACC-257 cells, with perinuclear enhancement. Tissue microarray analysis revealed, for the first time, substantial Nox5 overexpression in several human cancers, including those of prostate, breast, colon, lung, brain, and ovary, as well as in malignant melanoma and non-Hodgkin lymphoma; expression in most nonmalignant tissues was negative to weak. This validated mouse monoclonal antibody will promote further exploration of the functional significance of Nox5 in human pathophysiology, including tumor cell growth and proliferation. (C) 2013 Published by Elsevier Inc. C1 [Antony, Smitha; Wu, Yongzhong; Jiang, Guojian; Meitzler, Jennifer L.; Juhasz, Agnes; Lu, Jiamo; Doroshow, James H.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Liu, Han; Roy, Krishnendu K.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Anver, Miriam R.; Butcher, Donna] NIH, Pathol Histotechnol Lab, SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Doroshow, JH (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM doroshoj@mail.NIH.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Center for Cancer Research; Division of Cancer Treatment and Diagnosis; NCI [HHSN261200800001E]; National Cancer Institute; National Institutes of Health FX This work was supported with federal funds from the Center for Cancer Research, the Division of Cancer Treatment and Diagnosis, and NCI Contract No. HHSN261200800001E, National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 79 TC 18 Z9 18 U1 0 U2 7 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 DEC PY 2013 VL 65 BP 497 EP 508 DI 10.1016/j.freeradbiomed.2013.07.005 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278DI UT WOS:000328868900049 PM 23851018 ER PT J AU Towner, RA Garteiser, P Bozza, F Smith, N Saunders, D d'Avila, JCP Magno, F Oliveira, MF Ehrenshaft, M Lupu, F Silasi-Mansat, R Ramirez, DC Gomez-Mejiba, SE Mason, RP Faria-Neto, HCC AF Towner, Rheal A. Garteiser, Philippe Bozza, Fernando Smith, Nataliya Saunders, Debra d'Avila, Joana C. P. Magno, Flora Oliveira, Marcus F. Ehrenshaft, Marilyn Lupu, Florea Silasi-Mansat, Robert Ramirez, Dario C. Gomez-Mejiba, Sandra E. Mason, Ronald P. Castro Faria-Neto, Hugo C. TI In vivo detection of free radicals in mouse septic encephalopathy using molecular MRI and immuno-spin trapping SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Immuno-spin trapping; Free radicals; Molecular MRI; Sepsis; Cecal ligation and puncture; Mice; in vivo; DMPO; Fluorescence microscopy; 4-Hydroxynonenal; 3-Nitrotyrosine ID NECROSIS-FACTOR-ALPHA; OXIDATIVE STRESS; GROWTH-FACTOR; SEPSIS; BRAIN; INFLAMMATION; DYSFUNCTION; MODEL; LIPOPOLYSACCHARIDE; ENDOTOXEMIA AB Free radicals are known to play a major role in sepsis. Combined immuno-spin trapping and molecular magnetic resonance imaging (MRI) was used to detect in vivo and in situ levels of free radicals in murine septic encephalopathy after cecal ligation and puncture (CLP). DMPO (5,5-dimethyl pyrroline N-oxide) was injected over 6 h after CLP, before administration of an anti-DMPO probe (anti-DMPO antibody bound to albumin-gadolinium-diethylene triamine pentaacetic acid-biotin MRI targeting contrast agent). In vitro assessment of the anti-DMPO probe in oxidatively stressed mouse astrocytes significantly decreased T-1 relaxation (P < 0.0001) compared to controls. MRI detected the presence of anti-DMPO adducts via a substantial decrease in % T1 change within the hippocampus, striatum, occipital, and medial cortex brain regions (p < 0.01 for all) in septic animals compared to shams, which was sustained for over 60 mm (p < 0.05 for all). Fluorescently labeled streptavidin was used to target the anti-DMPO probe biotin, which was elevated in septic brain, liver, and lungs compared to sham. Ex vivo DMPO adducts (qualitative) and oxidative products, including 4-hydroxynonenal and 3-nitrotyrosine (quantitative, p < 0.05 for both), were elevated in septic brains compared to shams. This is the first study that has reported on the detection of in vivo and in situ levels of free radicals in murine septic encephalopathy. (C) 2013 Elsevier Inc. All rights reserved. C1 [Towner, Rheal A.; Garteiser, Philippe; Smith, Nataliya; Saunders, Debra] Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, Oklahoma City, OK 73104 USA. [Bozza, Fernando; d'Avila, Joana C. P.; Magno, Flora] Inst Oswaldo Cruz, Inst Pesquisa Clin Evandro Chagas, BR-20001 Rio De Janeiro, Brazil. [Oliveira, Marcus F.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Programa Biol Mol & Biotecnol, Lab Bioquim Resposta Estresse, Rio De Janeiro, RJ, Brazil. [Ehrenshaft, Marilyn; Mason, Ronald P.] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Lupu, Florea; Silasi-Mansat, Robert] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Ramirez, Dario C.; Gomez-Mejiba, Sandra E.] Natl Univ San Luis, CONICET, Inst Multidisciplinario Invest Biol San Luis, Lab Expt Med & Therapeut, RA-5700 San Luis, Argentina. [Castro Faria-Neto, Hugo C.] Inst Oswaldo Cruz, Lab Imunofarmacol, BR-20001 Rio De Janeiro, RJ, Brazil. RP Towner, RA (reprint author), Oklahoma Med Res Fdn, Adv Magnet Resonance Ctr, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM Rheal-Towner@omrf.org RI RAMIREZ, DARIO/K-3312-2013; OI Silasi, Robert/0000-0001-9590-6160; RAMIREZ, DARIO/0000-0001-6725-3326; Garteiser, Philippe/0000-0003-0157-8851 FU Oklahoma Medical Research Foundation; National Institute of Environmental Health Sciences; CNPq; PAPES; FAPERJ FX Funding was obtained by the Oklahoma Medical Research Foundation (R.A.T.) and the National Institute of Environmental Health Sciences (R.P.M.). H.C.C.F.-N. and F.A.B. were supported by CNPq, PAPES, and FAPERJ. F.A.B., M.F.O., and H.C.C.F.-N. are research scholars from CNPq and FAPERJ. NR 43 TC 5 Z9 5 U1 1 U2 15 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 DEC PY 2013 VL 65 BP 828 EP 837 DI 10.1016/j.freeradbiomed.2013.08.172 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278DI UT WOS:000328868900078 PM 23978375 ER PT J AU Abdelmegeed, MA Banerjee, A Jang, S Yoo, SH Yun, JW Gonzalez, FJ Keshavarzian, A Song, BJ AF Abdelmegeed, Mohamed A. Banerjee, Atrayee Jang, Sehwan Yoo, Seong-Ho Yun, Jun-Won Gonzalez, Frank J. Keshavarzian, Ali Song, Byoung-Joon TI CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Liver; Binge ethanol; CYP2E1; Oxidative stress; Gut leakiness; Steatohepatitis; Apoptosis; Free radicals ID INDUCED LIVER-INJURY; INDUCED FATTY LIVER; MITOCHONDRIAL DYSFUNCTION; CYTOCHROME P4502E1; PROTEIN-KINASE; ETHANOL; MICE; ACTIVATION; STEATOSIS; STRESS AB Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2el-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6 g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6 h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-alpha, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-ART, p-AMPK, and peroxisome proliferator-activated receptor-a, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2el-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis. Published by Elsevier Inc. C1 [Abdelmegeed, Mohamed A.; Banerjee, Atrayee; Jang, Sehwan; Yun, Jun-Won; Song, Byoung-Joon] Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. [Yoo, Seong-Ho] Seoul Natl Univ, Coll Med, Dept Forens Med, Seoul, South Korea. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Keshavarzian, Ali] Rush Univ, Med Ctr, Div Gastroenterol, Chicago, IL 60612 USA. RP Song, BJ (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. EM bj.song@nih.gov FU Intramural Program of the National Institute on Alcohol Abuse and Alcoholism FX This research was supported by the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism. We thank Dr. Klaus Gawrisch for supporting this study. NR 44 TC 36 Z9 37 U1 1 U2 13 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 DEC PY 2013 VL 65 BP 1238 EP 1245 DI 10.1016/j.freeradbiomed.2013.09.009 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278DI UT WOS:000328868900117 PM 24064383 ER PT J AU Esworthy, RS Kim, BW Wang, YF Gao, Q Doroshow, JH Leto, TL Chu, FF AF Esworthy, R. Steven Kim, Byung-Wook Wang, Yufeng Gao, Qiang Doroshow, James H. Leto, Thomas L. Chu, Fong-Fong TI The Gdac1 locus modifies spontaneous and Salmonella-induced colitis in mice deficient in either Gpx2 or Gpx1 gene SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE DUOX2; GPX1; GPX2; GPX-deficiency-associated-colitis locus-1; Gdac1; Gut dysbiosis; Metronidazole; Mouse genetics; Salmonella enterica serotype typhimurium; Selenium; Free radicals ID INFLAMMATORY-BOWEL-DISEASE; GLUTATHIONE-PEROXIDASE; NADPH-OXIDASE; SELENIUM DEFICIENCY; EPITHELIAL-CELLS; TYPHIMURIUM INFECTION; INTESTINAL EPITHELIUM; ENDOTHELIAL-CELLS; HOST-DEFENSE; DUAL OXIDASE AB We previously identified the Gdac1 (Gpx-deficiency-associated colitis 1) locus, which influences the severity of spontaneous colitis in Gpxl- and Gpx2-double-knockout (Gpx1/2-DKO) mice. Congenic Gpx1/2-DKO mice in the 129S1/SvImJ (129) background but carrying the Gdac1(B6) allele have milder spontaneous colitis than 129 Gpx1/2-DKO mice carrying the Gdac/(129) allele. Here, we evaluated the effect of the Gdac1(B6) allele on 129 strain non-DKO mice that had a wild-type (WT) Gpx1 or Gpx2 allele and WT mice. We found that the congenic Gdac1(B6) Gpx2-KO, Gpx1-KO, and WT mice also had better health than the corresponding 129 mice measured by at least one of the parameters including disease signs, colon length, or weight gain. The Gdac1(B6) allele prevented loss of goblet cells and crypt epithelium exfoliation in the Gpx1/2-DKO mice, but did not affect epithelial cell apoptosis or proliferation. Because Gdac1(B6) affects gut dysbiosis in the DKO mice, we then tested its impact on bacteria-induced colitis in non-DKO mice. First, we found both Gpx1-KO and Gpx2-KO mice were susceptible to Salmonella enterica serotype typhimurium (S. Tm)-induced colitis under conditions where WT B6 and 129 mice were resistant. Second, the S. Tm-infected Gdac1(B6) Gpx1-KO mice had stronger inflammatory responses than 129 Gpx1-KO or 129 Gpx2-KO with both Gdac1 alleles and WT mice by having higher mRNA levels of Nod2, Nox2, Tnf and Cox2. We conclude that the Gdoc1 locus affects both spontaneous and S. Tm-induced colitis in 129 non-DKO mice, although in opposite directions. (C) 2013 Elsevier Inc. All rights reserved. C1 [Esworthy, R. Steven; Kim, Byung-Wook; Chu, Fong-Fong] City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Biol, Duarte, CA 91010 USA. [Wang, Yufeng; Gao, Qiang] Henan Univ Sci & Technol, Affiliated Hosp 1, Dept Gastroenterol & Hepatol, Luoyang 471000, Henan, Peoples R China. [Doroshow, James H.] Natl Canc Inst, Bethesda, MD 20816 USA. [Leto, Thomas L.] NIAID, Natl Inst Hlth, Host Def Lab, Rockville, MD 20852 USA. RP Chu, FF (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Biol, Duarte, CA 91010 USA. EM fchu@coh.org FU National Cancer Institute of the National Institutes of Health [P30CA033572] FX We thank Sofia Loera and Tina Montgomery at the Anatomic Pathology Core of City of Hope for tissue processing. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Grant P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 56 TC 4 Z9 4 U1 0 U2 0 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 DEC PY 2013 VL 65 BP 1273 EP 1283 DI 10.1016/j.freeradbiomed.2013.09.013 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278DI UT WOS:000328868900121 PM 24090658 ER PT J AU Uddin, MJ Joe, Y Zheng, M Blackshear, PJ Ryter, SW Park, JW Chung, HT AF Uddin, Md Jamal Joe, Yeonsoo Zheng, Min Blackshear, Perry J. Ryter, Stefan W. Park, Jeong Woo Chung, Hun Taeg TI A functional link between heme oxygenase-1 and tristetraprolin in the anti-inflammatory effects of nicotine SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Nicotine; Anti-inflammatory effects; HO-1; STAT3; TTP; Free radicals ID NECROSIS-FACTOR-ALPHA; INFLAMMATORY RESPONSE; GENE-EXPRESSION; VAGUS NERVE; POSTTRANSCRIPTIONAL REGULATION; CYTOKINE PRODUCTION; ENDOTHELIAL-CELLS; INDUCTION; MACROPHAGES; ACTIVATION AB Nicotine stimulates the cholinergic anti-inflammatory pathway and prevents excessive inflammation by inhibiting the release of inflammatory cytokines from macrophages. We have previously reported that heme oxygenase-1 (HO-1) and tristetraprolin (UP) are induced by nicotine and mediate the anti-inflammatory function of nicotine in macrophages. However, it was not clear whether the two molecules are functionally linked. In this study, we sought to determine whether HO-1 associates with UP to mediate the anti-inflammatory effects of nicotine. Inhibition of HO-1 activity or HO-1 expression attenuated the effects of nicotine on STAT3 activation, UP induction, and TNF-alpha production in LPS-treated macrophages. Induction of HO-1 expression increased the level of UP in the absence of nicotine. In an LPS-induced endotoxemia model, HO-1 deficiency blocked the effects of nicotine on the STAT3 phosphorylation, UP induction, and LPS-induced TNF-alpha production in the liver. Downregulation of STAT3 by siRNA attenuated the effect of nicotine on UP expression and TNF-alpha production but did not affect the nicotine-mediated induction of HO-1. In UP knockout mice, nicotine treatment enhanced HO-1 expression and STAT3 activation but failed to inhibit LPS-induced TNF-alpha production. Our results suggest that HO-1 and UP are functionally linked in mediating the anti-inflammatory effects of nicotine; HO-1 is necessary for the induction of UP by nicotine. This novel nicotine-HO-1-UP signaling pathway provides new possibilities for the treatment of inflammatory diseases.(C) 2013 Elsevier Inc. All rights reserved. C1 [Uddin, Md Jamal; Joe, Yeonsoo; Zheng, Min; Park, Jeong Woo; Chung, Hun Taeg] Univ Ulsan, Sch Biol Sci, Ulsan 680749, South Korea. [Zheng, Min] YanBian Univ, Affiliated Hosp, Dept Thorac & Cardiovasc Surg, Yanji, Jilin, Peoples R China. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Ryter, Stefan W.] Harvard Univ, Brigham & Womens Hosp, Dept Pulm & Crit Care Med, Boston, MA 02115 USA. RP Chung, HT (reprint author), Univ Ulsan, Sch Biol Sci, Ulsan 680749, South Korea. EM chung@ulsan.ac.kr OI Uddin, Md. Jamal/0000-0003-2911-3255 FU Korea Research Foundation; Korean government (MOEHRD) [BRL-2009-0087350]; Bio & Medical Technology Development Program of the National Research Foundation; Korean government (MEST) [2012M3A9C3048687] FX This study was supported by a Korea Research Foundation grant funded by the Korean government (MOEHRD, BRL-2009-0087350) and the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (MEST) (2012M3A9C3048687). NR 44 TC 6 Z9 6 U1 0 U2 5 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 DEC PY 2013 VL 65 BP 1331 EP 1339 DI 10.1016/j.freeradbiomed.2013.09.027 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278DI UT WOS:000328868900128 ER PT J AU Leinisch, F Jiang, JJ DeRose, EF Khramtsov, VV Mason, RP AF Leinisch, Fabian Jiang, Jinjie DeRose, Eugene F. Khramtsov, Valery V. Mason, Ronald P. TI Investigation of spin-trapping artifacts formed by the Forrester-Hepburn mechanism SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Forrester-Hepburn mechanism; Spin trapping; False-positive; Artifact; Nucleophile ID PEROXIDASE-CATALYZED OXIDATION; FREE-RADICAL FORMATION; NUCLEOPHILIC-ADDITION; NONRADICAL ADDITION; NITROSO-COMPOUNDS; CAUTIONARY NOTE; SULFUR-DIOXIDE; RESONANCE; ADDUCTS; EPR AB Free radical detection with ESR spin trapping relies on the specific addition of the radical to nitrone/nitroso compounds. It also has been proposed that spin traps can react in biological systems to give false-positive results. For nitrone spin traps, the reaction with nucleophiles, first described by Forrester and Hepburn, has been discussed as the most critical source of artifacts. For artifact identification, the ESR preincubation method may be used, which employs isotopically marked spin traps. Here we investigated the influence of fast sulfite-hydroxylamine equilibrium chemistry on the validity of this assay. Using the (faster) aspiration technique, we found that the Forrester-Hepburn mechanism also contributes to DMPO/(SO3-)-S-center dot adduct formation during ferricyanide-mediated sulfite oxidation, but no evidence for artifactual DMPO/(SO3-)-S-center dot formation was found if the more potent horseradish peroxidase was used. This is ESR evidence that the Forrester-Hepburn mechanism can occur under mild conditions, depending on the experimental details. This technique can also be used to test for other artifact mechanisms. We investigated the known ene reaction of DBNBS and tryptophan in more detail. We found that a strong artifact signal is induced by light; however, with atypically long incubations, we found that the artifact is also formed thermally. Published by Elsevier Inc. C1 [Leinisch, Fabian; Jiang, Jinjie; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [DeRose, Eugene F.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Khramtsov, Valery V.] Ohio State Univ, Dept Internal Med, Div Pulm Allergy Crit Care & Sleep Med, Columbus, OH 43210 USA. RP Leinisch, F (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM leinischf@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX We thank Dr. Ann G. Motten, Ms. Mary J. Mason, and Ms. Jean Corbett for their help with the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 39 TC 3 Z9 3 U1 1 U2 24 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 DEC PY 2013 VL 65 BP 1497 EP 1505 DI 10.1016/j.freeradbiomed.2013.07.006 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278DI UT WOS:000328868900144 PM 23851031 ER PT J AU Mason, RP AF Mason, Ronald P. TI Two hypotheses for the peroxidase activity of Mn-superoxide dismutase SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Letter C1 NIEHS, NIH, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. RP Mason, RP (reprint author), NIEHS, NIH, Lab Toxicol & Pharmacol, POB 12233, Res Triangle Pk, NC 27709 USA. EM mason4@niehs.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 1 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 DEC PY 2013 VL 65 BP 1533 EP 1533 DI 10.1016/j.freeradbiomed.2013.02.013 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 278DI UT WOS:000328868900149 PM 23429047 ER PT J AU Chew, EY AF Chew, Emily Y. TI Nutrition Effects on Ocular Diseases in the Aging Eye SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE age-related macular degeneration; cataract type; antioxidants ID AGE-RELATED MACULOPATHY; BLUE MOUNTAINS EYE; HIGH-DOSE SUPPLEMENTATION; FATTY-ACID INTAKE; MACULAR DEGENERATION; BETA-CAROTENE; VITAMIN-E; RANDOMIZED-TRIAL; CLINICAL-TRIAL; LENS OPACITIES AB PURPOSE. We reviewed the data from the clinical trials of nutritional supplements for the treatment of age-related cataract and age-related macular degeneration (AMD) to determine future directions of research and treatment. METHODS. Data from the controlled clinical trials are presented and reviewed for potential opportunities for further research into the treatment of cataracts and AMD. RESULTS. Two trials using daily multivitamins/minerals demonstrated a reduction in the progression of nuclear cataract, but increased the risk of posterior subcapsular cataract. For AMD, the Age-Related Eye Disease Study (AREDS) formulation (vitamins C, E, beta-carotene, zinc, and copper) reduced the risk of progression to advanced AMD by 25% at 5 years. Because beta-carotene is associated with increased lung cancer in former smokers, lutein/zeaxanthin could replace beta-carotene and provide an incremental increase in the beneficial effects beyond the effects of the AREDS formulation. In addition, a randomized clinical trial of B vitamins demonstrated a beneficial effect for AMD with the vitamin B complex. CONCLUSIONS. Future evaluation may include additional assessments of nutrients for the treatment of progression of cataract and AMD. A modest reduction would have significant impact as the numbers of persons affected with these two leading causes of blindness are projected to double in the next decade. An important step would be to develop surrogate outcomes to increase efficiency in clinical trials. More detailed phenotyping, especially of AMD, is required as it appears to be not one disease, but a group of diseases. Genotype-phenotype analyses may help to target pathways that are important in AMD. C1 NEI, NIH, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, NIH, Bldg 10,CRC Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov NR 51 TC 2 Z9 2 U1 3 U2 15 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2013 VL 54 IS 14 SI SI DI 10.1167/iovs.13-12914 PG 6 WC Ophthalmology SC Ophthalmology GA 278IX UT WOS:000328884600009 ER PT J AU Shiels, MS Pfeiffer, RM Hildesheim, A Engels, EA Kemp, TJ Park, JH Katki, HA Koshiol, J Shelton, G Caporaso, NE Pinto, LA Chaturvedi, AK AF Shiels, Meredith S. Pfeiffer, Ruth M. Hildesheim, Allan Engels, Eric A. Kemp, Troy J. Park, Ju-Hyun Katki, Hormuzd A. Koshiol, Jill Shelton, Gloriana Caporaso, Neil E. Pinto, Ligia A. Chaturvedi, Anil K. TI Circulating Inflammation Markers and Prospective Risk for Lung Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID C-REACTIVE PROTEIN; SCREENING TRIAL; TUMOR MICROENVIRONMENT; PNEUMONIAE INFECTION; SUBSEQUENT RISK; PREDICTION; PROSTATE; DISEASE; SMOKERS; COHORT AB Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer. We conducted a nested casecontrol study (n 526 lung cancer patients and n 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively. Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P-trend across marker categories < .05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cellattracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR 0.71; 95% confidence interval 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 1.1% vs Q4 3.1%) and current smokers (Q1 2.3% vs Q4 7.9%) even after adjustment for smoking. Some circulating inflammation marker levels are associated with prospective lung cancer risk. C1 [Shiels, Meredith S.; Hildesheim, Allan; Engels, Eric A.; Koshiol, Jill; Chaturvedi, Anil K.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Pfeiffer, Ruth M.; Katki, Hormuzd A.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Kemp, Troy J.; Shelton, Gloriana; Pinto, Ligia A.] SAIC Frederick Inc, HPV Immunol Lab, Frederick, MD USA. [Park, Ju-Hyun] Dongguk Univ, Dept Stat, Seoul, South Korea. RP Shiels, MS (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7059, Rockville, MD USA. EM shielsms@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Hildesheim, Allan/B-9760-2015; Chaturvedi, Anil/J-2024-2015 OI Hildesheim, Allan/0000-0003-0257-2363; Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 44 TC 62 Z9 62 U1 1 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD DEC PY 2013 VL 105 IS 24 BP 1871 EP 1880 DI 10.1093/jnci/djt309 PG 10 WC Oncology SC Oncology GA 280UU UT WOS:000329057100008 PM 24249745 ER PT J AU Polley, MYC Leung, SCY McShane, LM Gao, DX Hugh, JC Mastropasqua, MG Viale, G Zabaglo, LA Penault-Llorca, F Bartlett, JMS Gown, AM Symmans, WF Piper, T Mehl, E Enos, RA Hayes, DF Dowsett, M Nielsen, TO AF Polley, Mei-Yin C. Leung, Samuel C. Y. McShane, Lisa M. Gao, Dongxia Hugh, Judith C. Mastropasqua, Mauro G. Viale, Giuseppe Zabaglo, Lila A. Penault-Llorca, Frdrique Bartlett, John M. S. Gown, Allen M. Symmans, W. Fraser Piper, Tammy Mehl, Erika Enos, Rebecca A. Hayes, Daniel F. Dowsett, Mitch Nielsen, Torsten O. CA Breast Int Grp North Amer Breast Cancer Grp TI An International Ki67 Reproducibility Study SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID EARLY BREAST-CANCER; DIGITAL-IMAGE-ANALYSIS; NEUROENDOCRINE TUMORS; POSTMENOPAUSAL WOMEN; NEOADJUVANT ANASTROZOLE; PREDICTIVE-VALUE; LABELING INDEX; WORKING GROUP; KI-67; PROLIFERATION AB In breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67s value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study. Eight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarraysuone set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. Intralaboratory reproducibility was high (ICC 0.94; 95% CI 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC 0.71, 95% CI 0.47 to 0.78; local staining: ICC 0.59, 95% CI 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation. Substantial variability in Ki67 scoring was observed among some of the worlds most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without standardizing scoring methodology because analytical validity is limited. C1 [Polley, Mei-Yin C.; McShane, Lisa M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Leung, Samuel C. Y.; Gao, Dongxia; Mehl, Erika; Nielsen, Torsten O.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Hugh, Judith C.] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB T6G 2M7, Canada. [Mastropasqua, Mauro G.; Viale, Giuseppe] European Inst Oncol, Div Pathol & Lab Med, Milan, Italy. [Viale, Giuseppe] Univ Milan, Milan, Italy. [Zabaglo, Lila A.] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Penault-Llorca, Frdrique] Ctr Jean Perrin, Dept Pathol, Clermont Ferrand, France. [Penault-Llorca, Frdrique] Univ Auvergne, Clermont Ferrand, France. [Bartlett, John M. S.] Ontario Inst Canc Res, Toronto, ON, Canada. [Gown, Allen M.] PhenoPath Labs, Seattle, WA USA. [Symmans, W. Fraser] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Piper, Tammy] Western Gen Hosp, Edinburgh Canc Res Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. [Enos, Rebecca A.] EMMES Corp, Rockville, MD USA. [Hayes, Daniel F.] Univ Michigan, Ctr Comprehens Canc, Breast Oncol Program, Ann Arbor, MI 48109 USA. [Dowsett, Mitch] Royal Marsden Hosp, Acad Dept Biochem, London SW3 6JJ, England. RP Nielsen, TO (reprint author), Univ British Columbia, JP 1401,855 W 12th Ave, Vancouver, BC V5Z 1M9, Canada. EM torsten@mail.ubc.ca FU Breast Cancer Research Foundation; Breakthrough Breast Cancer; National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital; Government of Ontario FX This work was supported by the Breast Cancer Research Foundation. Additional funding for the UK labs was received from Breakthrough Breast Cancer and the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. Funding for the Ontario Institute for Cancer Research is provided by the Government of Ontario. NR 31 TC 147 Z9 155 U1 1 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD DEC PY 2013 VL 105 IS 24 BP 1897 EP 1906 DI 10.1093/jnci/djt306 PG 10 WC Oncology SC Oncology GA 280UU UT WOS:000329057100011 PM 24203987 ER PT J AU Ahn, J Sinha, R Pei, ZH Dominianni, C Wu, J Shi, JX Goedert, JJ Hayes, RB Yang, LY AF Ahn, Jiyoung Sinha, Rashmi Pei, Zhiheng Dominianni, Christine Wu, Jing Shi, Jianxin Goedert, James J. Hayes, Richard B. Yang, Liying TI Human Gut Microbiome and Risk for Colorectal Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COLON-CANCER; BACTERIA; DIVERSITY; DISEASE; INDUCTION; COLITIS; PRIMERS; HEALTH AB We tested the hypothesis that an altered community of gut microbes is associated with risk of colorectal cancer (CRC) in a study of 47 CRC case subjects and 94 control subjects. 16S rRNA genes in fecal bacterial DNA were amplified by universal primers, sequenced by 454 FLX technology, and aligned for taxonomic classification to microbial genomes using the QIIME pipeline. Taxonomic differences were confirmed with quantitative polymerase chain reaction and adjusted for false discovery rate. All statistical tests were two-sided. From 794 217 16S rRNA gene sequences, we found that CRC case subjects had decreased overall microbial community diversity (P=.02). In taxonomy-based analyses, lower relative abundance of Clostridia (68.6% vs 77.8%) and increased carriage of Fusobacterium (multivariable odds ratio [OR] = 4.11; 95% confidence interval [CI] = 1.62 to 10.47) and Porphyromonas (OR = 5.17; 95% CI = 1.75 to 15.25) were found in case subjects compared with control subjects. Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for CRC prevention. C1 [Ahn, Jiyoung; Dominianni, Christine; Wu, Jing; Hayes, Richard B.] NYU, Div Epidemiol, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Pei, Zhiheng] NYU, Dept Pathol, Sch Med, New York, NY 10016 USA. [Pei, Zhiheng; Yang, Liying] NYU, Sch Med, Dept Med, New York, NY 10010 USA. [Ahn, Jiyoung; Pei, Zhiheng; Dominianni, Christine; Wu, Jing; Hayes, Richard B.] NYU, Inst Canc, New York, NY 10016 USA. [Sinha, Rashmi; Shi, Jianxin; Goedert, James J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pei, Zhiheng] New York Vet Affairs Med Ctr, Dept Pathol & Lab Med, New York, NY USA. RP Ahn, J (reprint author), NYU, Div Epidemiol, Sch Med, Dept Populat Hlth, 650 1st Ave, New York, NY 10016 USA. EM jiyoung.ahn@nyumc.org; liying.yang@nyumc.org RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Yang, Liying/0000-0003-1442-4915; Pei, Zhiheng/0000-0001-8570-6747; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute [R03CA159414, R01CA159036]; Pancreatic Cancer Action Network-AACR Career Development Award; Daniel and Janet Mordecai Foundation [12-20-25-AHN]; Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the National Cancer Institute (R03CA159414 and R01CA159036); a 2012 Pancreatic Cancer Action Network-AACR Career Development Award, supported by the Daniel and Janet Mordecai Foundation (grant 12-20-25-AHN); and the Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 29 TC 110 Z9 113 U1 10 U2 71 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD DEC PY 2013 VL 105 IS 24 BP 1907 EP 1911 DI 10.1093/jnci/djt300 PG 5 WC Oncology SC Oncology GA 280UU UT WOS:000329057100012 PM 24316595 ER PT J AU Clay, JR AF Clay, John R. TI A novel analysis of excitatory currents during an action potential from suprachiasmatic nucleus neurons (Retracted article. See vol. 112, pg. 2668, 2014) SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE action potential clamp; suprachiasmatic nucleus neurons; mathematical models ID EFFICIENT ACTION-POTENTIALS; POTASSIUM CURRENT; CALCIUM CURRENTS; DYNAMIC CLAMP; CHANNEL; SODIUM; INACTIVATION; MODEL; ELECTROPHYSIOLOGY; MECHANISM AB A new application of the action potential (AP) voltage-clamp technique is described based on computational analysis. An experimentally recorded AP is digitized. The resulting V-i vs. t(i) data set is applied to mathematical models of the ionic conductances underlying excitability for the cell from which the AP was recorded to test model validity. The method is illustrated for APs from suprachiasmatic nucleus (SCN) neurons and the underlying tetrodotoxin-sensitive Na+ current, I-Na, and the Ca2+ current, I-Ca. Voltage-step recordings have been made for both components from SCN neurons (Jackson et al. 2004). The combination of voltage-step and AP clamp results provides richer constraints for mathematical models of voltage-gated ionic conductances than either set of results alone, in particular the voltage-step results. For SCN neurons the long-term goal of this work is a realistic mathematical model of the SCN AP in which the equations for I-Na and I-Ca obtained from this analysis will be a part. Moreover, the method described in this report is general. It can be applied to any excitable cell. C1 [Clay, John R.] NINDS, NIH, Bethesda, MD 20892 USA. RP Clay, JR (reprint author), Twinbrook TN-41,5625 Fishers Lane, Rockville, MD 20852 USA. EM jrclay@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. NR 33 TC 2 Z9 2 U1 3 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD DEC PY 2013 VL 110 IS 11 BP 2574 EP 2579 DI 10.1152/jn.00462.2013 PG 6 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 278JJ UT WOS:000328886300008 PM 24047903 ER PT J AU Zhu, B Dunson, DB AF Zhu, Bin Dunson, David B. TI Locally Adaptive Bayes Nonparametric Regression via Nested Gaussian Processes SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Bayesian nonparametric regression; Nested smoothing spline; Penalized sum-of-square; Reproducing kernel Hilbert space; Stochastic differential equations ID MASS-SPECTROMETRY DATA; VARIABLE SELECTION; POSTERIOR CONSISTENCY; SPATIAL ADAPTATION; PENALIZED SPLINES; BINARY REGRESSION; WAVELET SHRINKAGE; PROCESS PRIORS; QUANTIFICATION; PENALTIES AB We propose a nested Gaussian process (nGP) as a locally adaptive prior for Bayesian nonparametric regression. Specified through a set of stochastic differential equations (SDEs), the nGP imposes a Gaussian process prior for the function's mth-order derivative. The nesting comes in through including a local instantaneous mean function, which is drawn from another Gaussian process inducing adaptivity to locally varying smoothness. We discuss the support of the nGP prior in terms of the closure of a reproducing kernel Hilbert space, and consider theoretical properties of the posterior. The posterior mean under the nGP prior is shown to be equivalent to the minimizer of a nested penalized sum-of-squares involving penalties for both the global and local roughness of the function. Using highly efficient Markov chain Monte Carlo for posterior inference, the proposed method performs well in simulation studies compared to several alternatives, and is scalable to massive data, illustrated through a proteomics application. C1 [Zhu, Bin] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Dunson, David B.] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. RP Zhu, B (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM bin.zhu@nih.gov; dunson@stat.duke.edu FU National Institute of Environmental Health Sciences [R01ES017436, R01ES17240]; National Institutes of Health [5P2O-RR020782-O3]; U.S. Environmental Protection Agency [RD-83329301-0]; Intramural Research Program of the National Cancer Institute, National Institutes of Health, Maryland, USA FX This work was supported by Award Numbers R01ES017436 and R01ES17240 from the National Institute of Environmental Health Sciences, by funding from the National Institutes of Health (5P2O-RR020782-O3) and the U.S. Environmental Protection Agency (RD-83329301-0) and by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Maryland, USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences, the National Institutes of Health or the U. S. Environmental Protection Agency. NR 57 TC 4 Z9 4 U1 0 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2013 VL 108 IS 504 BP 1445 EP 1456 DI 10.1080/01621459.2013.838568 PG 12 WC Statistics & Probability SC Mathematics GA 278RZ UT WOS:000328908700029 ER PT J AU Minakawa, EN Yamakado, H Tanaka, A Uemura, K Takeda, S Takahashi, R AF Minakawa, Eiko N. Yamakado, Hodaka Tanaka, Atsushi Uemura, Kengo Takeda, Shunichi Takahashi, Ryosuke TI Chicken DT40 cell line lacking DJ-1, the gene responsible for familial Parkinson's disease, displays mitochondrial dysfunction SO NEUROSCIENCE RESEARCH LA English DT Article DE Parkinson's disease; DJ-1; DT40; Mitochondria; Oxidative stress ID PINK1; MUTATIONS; AUTOPHAGY; DYNAMICS; DROSOPHILA-PINK1; DEGENERATION; PATHOLOGY AB Parkinson's disease (PD) is the most common neurodegenerative movement disorder mainly due to gradual loss of dopaminergic neurons in the substantia nigra. Although the causative genes for autosomai recessive PD, Parkin, PINK1 and DJ-1, share a common pathway, at least in part, in mitochondrial quality control and protein quality control, their precise relationship remains elusive. Previous studies suggested the limitation of gene-modified mice model to solve this problem. DT40 is an avian leukosis virus-induced chicken B cell line with an exceptionally high ratio of targeted to random DNA integration, which enables efficient targeted disruption of multiple genes of interest. We generated DJ-1-deficient DT40 cells and analyzed PD-related phenotypes. These cells exhibited vulnerability to oxidative stress, mitochondrial dysfunction and fragmentation. Importantly, we showed that mitochondrial membrane potential and morphology are available for the phenotype analysis in DT40. These results suggest that genetically engineered DT40 cells would serve as a relevant model of PD, and help understand the genetic and functional relationship among multiple causative genes. Furthermore, in line with the recent concept of PD as a systemic disorder, elucidating the pathomechanism of PD using DT40 would lead to the development of noninvasive diagnostic tools and drug screening assays using patient-derived lymphocytes. (c) 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 [Minakawa, Eiko N.; Yamakado, Hodaka; Uemura, Kengo; Takahashi, Ryosuke] Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, Kyoto 6068507, Japan. [Tanaka, Atsushi] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. RP Takahashi, R (reprint author), Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, 54 Kawahara Cho, Kyoto 6068507, Japan. EM minakawa@kuhp.kyoto-u.ac.jp; yamakado@kuhp.kyoto-u.ac.jp; atsushi.tanaka@med.id.yamagata-u.ac.jp; ueken@kuhp.kyoto-u.ac.jp; stakeda@rg.med.kyoto-u.ac.jp; ryosuket@kuhp.kyoto-u.ac.jp FU CREST program of JST (Japan Science and Technology Agency); NINDS FX This study was supported by CREST program of JST (Japan Science and Technology Agency) and the intramural research program of NINDS. We thank Dr. Richard J. Youle (NINDS, National Institutes of Health, USA) for helpful discussion and advice. We also thank Mr. Satoshi Horimoto (Department of Biophysics, Division of Biological Sciences, Kyoto University Graduate School of Science), Dr. Koji Hirota (Department of Radiation Genetics, Kyoto University Graduate School of Medicine), Dr. Takaaki Hirai (NINDS, National Institutes of Health, USA) and Dr. Keizo Tano (Research Reactor Institute, Kyoto University) for their technical advice. NR 33 TC 2 Z9 3 U1 0 U2 6 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 DEC PY 2013 VL 77 IS 4 BP 228 EP 233 DI 10.1016/j.neures.2013.09.006 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 278XJ UT WOS:000328922900006 PM 24064392 ER PT J AU Sciamanna, I Gualtieri, A Cossetti, C Osimo, EF Ferracin, M Macchia, G Arico, E Prosseda, G Vitullo, P Misteli, T Spadafora, C AF Sciamanna, Ilaria Gualtieri, Alberto Cossetti, Cristina Osimo, Emanuele Felice Ferracin, Manuela Macchia, Gianfranco Arico, Eleonora Prosseda, Gianni Vitullo, Patrizia Misteli, Tom Spadafora, Corrado TI A tumor-promoting mechanism mediated by retrotransposon-encoded reverse transcriptase is active in human transformed cell lines SO ONCOTARGET LA English DT Article DE LINE-1 retrotransposons; reverse transcriptase; transcriptome; miRNAs; DNA:RNA hybrids; cancer genome; reverse transcriptase inhibitor ID NONCODING RNAS; L1 RETROTRANSPOSITION; ULTRACONSERVED REGIONS; TRANSPOSABLE ELEMENTS; DNA METHYLATION; HUMAN MICRORNAS; BREAST-CANCER; HUMAN GENOME; STEM-CELLS; EXPRESSION AB LINE-1 elements make up the most abundant retrotransposon family in the human genome. Full-length LINE-1 elements encode a reverse transcriptase (RT) activity required for their own retrotranpsosition as well as that of non-autonomous Alu elements. LINE-1 are poorly expressed in normal cells and abundantly in cancer cells. Decreasing RT activity in cancer cells, by either LINE-1-specific RNA interference, or by RT inhibitory drugs, was previously found to reduce proliferation and promote differentiation and to antagonize tumor growth in animal models. Here we have investigated how RT exerts these global regulatory functions. We report that the RT inhibitor efavirenz (EFV) selectively downregulates proliferation of transformed cell lines, while exerting only mild effects on non-transformed cells; this differential sensitivity matches a differential RT abundance, which is high in the former and undetectable in the latter. Using CsCl density gradients, we selectively identify Alu and LINE-1 containing DNA: RNA hybrid molecules in cancer but not in normal cells. Remarkably, hybrid molecules fail to form in tumor cells treated with EFV under the same conditions that repress proliferation and induce the reprogramming of expression profiles of coding genes, microRNAs (miRNAs) and ultraconserved regions (UCRs). The RT-sensitive miRNAs and UCRs are significantly associated with Alu sequences. The results suggest that LINE-1-encoded RT governs the balance between single-stranded and double-stranded RNA production. In cancer cells the abundant RT reverse-transcribes retroelement-derived mRNAs forming RNA: DNA hybrids. We propose that this impairs the formation of double-stranded RNAs and the ensuing production of small regulatory RNAs, with a direct impact on gene expression. RT inhibition restores the 'normal' small RNA profile and the regulatory networks that depend on them. Thus, the retrotransposon-encoded RT drives a previously unrecognized mechanism crucial to the transformed state in tumor cells. C1 [Sciamanna, Ilaria; Gualtieri, Alberto; Cossetti, Cristina; Osimo, Emanuele Felice; Macchia, Gianfranco; Arico, Eleonora; Vitullo, Patrizia; Spadafora, Corrado] Ist Superiore Sanit, Rome, Italy. [Ferracin, Manuela] Univ Ferrara, LTTA, I-44100 Ferrara, Italy. [Ferracin, Manuela] Univ Ferrara, Dept Morphol Surg & Expt Med, I-44100 Ferrara, Italy. [Prosseda, Gianni] Univ Roma La Sapienza, Dept Biol & Biotechnol Charles Darwin, I-00185 Rome, Italy. [Misteli, Tom] NIH, Bethesda, MD 20892 USA. [Gualtieri, Alberto; Cossetti, Cristina] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy. RP Spadafora, C (reprint author), Ist Superiore Sanit, Viale Regina Elena 299, Rome, Italy. EM cspadaf@tin.it RI Ferracin, Manuela/K-2097-2016; Cossetti, Cristina/K-5034-2016 OI Ferracin, Manuela/0000-0002-1595-6887; Cossetti, Cristina/0000-0002-8809-4149 FU ISS-NIH; Italian Ministry of Health; Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research FX We are indebted with Massimo Negrini (University of Ferrara, Ferrara, Italy) for microarray analysis. We thank Giuseppe La Regina (Sapienza University, Rome, Italy) for purification of EFV, and Patrizia Lavia and Valeria de Turris (CNR, Rome, Italy) and Alessandro Rosa (Sapienza University, Rome, Italy), for suggestions and critical reading of the manuscript. We acknowledge the skillful assistance of Cosimo Curiano with drawing preparation. This work was supported by ISS-NIH cooperation grants ("Endogenous Reverse Transcriptase activity and chromatin remodeling in normal and transformed cells and early embryos"), Italian Ministry of Health grants "New therapeutic strategies based on studies of tumor microenvironment and new targets identified through genomic profile analysis", "Endogenous Reverse Transcriptase as tumour marker and causative agent of tumour onset and progression", "Endogenous Reverse Transcriptase in tumour onset and progression and in tumour therapy" to CS, and by the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research to TM. NR 68 TC 18 Z9 19 U1 1 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 DEC PY 2013 VL 4 IS 12 BP 2271 EP 2287 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 279CK UT WOS:000328936800012 PM 24345856 ER PT J AU Lee, P Linderman, J Smith, S Brychta, RJ Perron, R Idelson, C Werner, CD Chen, KY Celi, FS AF Lee, P. Linderman, J. Smith, S. Brychta, R. J. Perron, R. Idelson, C. Werner, C. D. Chen, K. Y. Celi, F. S. TI Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans? SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Beige adipose tissue; Bone mineral density; Brown adipose tissue; FGF21; Fibroblast growth factor-21 ID BROWN ADIPOSE-TISSUE; ADAPTIVE THERMOGENESIS; ADULT HUMANS; ADIPOCYTES AB In animals, high fibroblast growth factor 21 (FGF21) states improve insulin resistance but induce bone loss. Whether FGF21 relates to bone mineral density (BMD) is unknown in humans. Contrary to prediction from animal findings, we found higher FGF21 levels associating with greater BMD in women, independent of age and body composition. Introduction Recent laboratory studies suggest that FGF21 is involved in reciprocal regulation of bone and energy homeostasis. Systemic administration of FGF21 protects animals from obesity and diabetes but causes severe bone loss, smothering the enthusiasm over FGF21 as a potential antiobesity therapeutic. To date, there is no information on whether FGF21 relates to BMD in humans. We thus studied the relationship between plasma FGF21 levels and BMD in healthy adults. Methods Fasting plasma FGF21 levels were measured by enzyme-linked immunosorbent assay and body composition by dual-energy X-ray absorptiometry. Results Among 40 healthy volunteers (age 32 +/- 10 year, 16 women), men had significantly higher lean body mass (p<0.01) and total BMD (p<0.05), and lower percent body fat than women (p<0.01). Median plasma FGF21 levels were not different between the sexes. While therewas no association between FGF21 concentrations and body composition in men, FGF21 levels correlated positively with fat mass (p<0.01) in women. In men, no significant correlation between FGF21 with BMD was observed. However, in women, FGF21 correlated positively with total BMD(R-2=0.69, p=0.003) and spine BMD (R-2=0.76, p=0.001); the correlation remained significant after adjusting for age, ethnicity, and body composition. Conclusions This study reveals for the first time a strong positive association between plasma FGF21 levels and BMD in healthy women, suggesting the association between bone loss and high FGF21 states in animals may not be directly translated to humans in physiologic states. We hypothesize that FGF21 may increase bonemass particularly in women through paracrine mechanisms in the bone-adipose interface. C1 [Lee, P.; Linderman, J.; Smith, S.; Brychta, R. J.; Perron, R.; Idelson, C.; Werner, C. D.; Chen, K. Y.; Celi, F. S.] NIDDK, Obes Branch, NIH, CRC, Bethesda, MD 20892 USA. RP Lee, P (reprint author), NIDDK, Obes Branch, NIH, CRC, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM pcylee@gmail.com OI Chen, Kong/0000-0002-0306-1904 FU Australian National Health Medical Research Council (NHMRC); Royal Australasian College of Physicians (RACP) Foundations Diabetes Australia Fellowship; Bushell Travelling Fellowship; Intramural Research Program of NIDDK [Z01-DK047057-02, Z01-DK071044] FX Paul Lee was supported by an Australian National Health Medical Research Council (NHMRC) Early Career Fellowship, the Royal Australasian College of Physicians (RACP) Foundations Diabetes Australia Fellowship, and Bushell Travelling Fellowship. This study was supported by the Intramural Research Program of NIDDK: programs Z01-DK047057-02 and Z01-DK071044. NR 19 TC 15 Z9 15 U1 1 U2 18 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 DEC PY 2013 VL 24 IS 12 BP 3053 EP 3057 DI 10.1007/s00198-013-2464-9 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 281MK UT WOS:000329105500015 PM 23912560 ER PT J AU Pedone, C Napoli, N Pozzilli, P Lauretani, F Bandinelli, S Ferrucci, L Rossi, FF Antonelli-Incalzi, R AF Pedone, Claudio Napoli, Nicola Pozzilli, Paolo Lauretani, Fulvio Bandinelli, Stefania Ferrucci, Luigi Rossi, Francesca Flavia Antonelli-Incalzi, Raffaele TI Bone Health As a Function of Adipokines and Vitamin D Pattern in Elderly Patients SO REJUVENATION RESEARCH LA English DT Article ID MINERAL DENSITY; POSTMENOPAUSAL WOMEN; BIOCHEMICAL MARKERS; SERUM ADIPONECTIN; OLDER-ADULTS; BODY-COMPOSITION; VISFATIN LEVELS; D DEFICIENCY; FAT MASS; LEPTIN AB Background: Adiponectin, leptin, and resistin are involved in bone metabolism, but the evidence regarding their effects is not conclusive. We analyzed the relationship between these adipokines, vitamin D, and bone health using a cluster analysis approach. Methods: We used cross-sectional data coming from the InCHIANTI study, in which bone density and area were estimated using computed tomography. The sample size was 690 (women, 57.5%; mean age, 75.2 years; range, 65-102). Five clusters were generated on the basis of gender, age, adipokines, and vitamin D concentrations. The clusters were characterized, respectively, by higher resistin and older age (hR-O, n=134), higher vitamin D and younger age (hD-Y, n=152), higher adiponectin (hA, n=65), and higher leptin (hL, n=52). The last cluster had intermediate values of all the constituting variables (I, n=287). The clusters were compared with respect to bone parameters and clinical characteristics. Results: Cluster hR-O had the lowest total and cortical bone density. Cluster hD-Y had the lowest adiponectin (9.29g/mL) and leptin (7.9ng/mL) serum concentrations, the highest prevalence of men (71.1%), and total/cortical bone density and area. No statistically significant difference across clusters was observed for age- and sex-standardized measures of bone mineral density and bone area, but leptin was associated with these parameters in a linear model adjusted for age, gender, vitamin D, resistin, and leptin. Conclusions: In an elderly population, age and sex almost completely explain the variability in bone status across cluster characterized by different levels of circulating adipokines and vitamin D. The role of leptin, however, seems worthy of consideration. C1 [Pedone, Claudio; Rossi, Francesca Flavia; Antonelli-Incalzi, Raffaele] Univ Campus Biomed, Geriatr Unit, I-00128 Rome, Italy. [Pedone, Claudio] Alberto Sordi Fdn, Rome, Italy. [Napoli, Nicola; Pozzilli, Paolo] Univ Campus Biomed, Endocrinol Unit, I-00128 Rome, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Unit, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Lab Movement Anal, Geriatr & Rehabil Dept, Parma, Italy. [Bandinelli, Stefania] Florence Hlth Agcy, Geriatr Rehabil Unit, Florence, Italy. [Ferrucci, Luigi] NIH, Longitudinal Studies Sect, Baltimore, MD USA. [Antonelli-Incalzi, Raffaele] San Raffaele Cittadella Carita Fdn, Taranto, Italy. RP Pedone, C (reprint author), Univ Campus Biomed, Via Alvaro del Portillo 5, I-00128 Rome, Italy. EM c.pedone@unicampus.it RI Lauretani, Fulvio/K-5115-2016; OI Napoli, Nicola/0000-0002-3091-8205; Pedone, Claudio/0000-0003-1847-9032; Antonelli Incalzi, Raffaele/0000-0003-2100-2075; Lauretani, Fulvio/0000-0002-5287-9972; Pozzilli, Paolo/0000-0001-5090-636X NR 42 TC 2 Z9 2 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 EI 1557-8577 J9 REJUV RES JI Rejuv. Res. PD DEC 1 PY 2013 VL 16 IS 6 BP 467 EP 474 DI 10.1089/rej.2013.1436 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 273TD UT WOS:000328558300005 PM 23829612 ER PT J AU Niemann, CU Wiestner, A AF Niemann, Carsten U. Wiestner, Adrian TI B-cell receptor signaling as a driver of lymphoma development and evolution SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE Ibrutinib; Idelalisib; Lymphoma; B-cell receptor; Antigen ID CHRONIC-LYMPHOCYTIC-LEUKEMIA; NF-KAPPA-B; BRUTONS TYROSINE KINASE; NON-HODGKIN-LYMPHOMA; HELICOBACTER-PYLORI ERADICATION; LYN-DEFICIENT MICE; PHASE-II TRIAL; THERAPEUTIC TARGET; FOLLICULAR LYMPHOMA; AUTOIMMUNE-DISEASE AB The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway. Hepatitis C virus infection can lead to the development of splenic marginal zone lymphoma, while Helicobacter pylori infection is associated with the development of mucosa-associated lymphoid tissue lymphomas. In some of these cases, successful treatment of the infection removes the inciting antigen and results in resolution of the lymphoma. Chronic lymphocytic leukemia has been recognized for decades as a malignancy of auto-reactive B-cells and its clinical course is in part determined by the differential response of the malignant cells to BCR activation. In a number of B-cell malignancies, activating mutations in signal transduction components of the BCR pathway have been identified; prominent examples are activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCL) that carry mutations in CD79B and CARD11 and display chronic active BCR signaling resulting in constitutive activation of the NF-kappa B pathway. Despite considerable heterogeneity in biology and clinical course, many mature B-cell malignancies are highly sensitive to kinase inhibitors that disrupt BCR signaling. Thus, targeted therapy through inhibition of BCR signaling is emerging as a new treatment paradigm for many B-cell malignancies. Here, we review the role of the BCR in the pathogenesis of B-cell malignancies and summarize clinical results of the emerging class of kinase inhibitors that target this pathway. (C) 2013 Published by Elsevier Ltd. C1 [Niemann, Carsten U.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3E-5140, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov RI Niemann, Carsten/P-3497-2015 OI Niemann, Carsten/0000-0001-9880-5242 FU Danish Cancer Society; Heart, Lung, Blood Institute, National Institutes of Health FX CUN is supported by the Danish Cancer Society and AW is supported by the intramural research program of the Heart, Lung, Blood Institute, National Institutes of Health. NR 170 TC 50 Z9 53 U1 2 U2 38 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD DEC PY 2013 VL 23 IS 6 BP 410 EP 421 DI 10.1016/j.semcancer.2013.09.001 PG 12 WC Oncology SC Oncology GA 280EH UT WOS:000329011000003 PM 24060900 ER PT J AU Aufderheide, TP Nolan, JP Jacobs, IG van Belle, G Bobrow, BJ Marshall, J Finn, J Becker, LB Bottiger, B Cameron, P Drajer, S Jung, JJ Kloeck, W Koster, RW Ma, MHM Shin, SD Sopko, G Taira, BR Timerman, S Ong, MEH AF Aufderheide, Tom P. Nolan, Jerry P. Jacobs, Ian G. van Belle, Gerald Bobrow, Bentley J. Marshall, John Finn, Judith Becker, Lance B. Bottiger, Bernd Cameron, Peter Drajer, Saul Jung, Julianna J. Kloeck, Walter Koster, Rudolph W. Ma, Matthew Huei-Ming Shin, Sang Do Sopko, George Taira, Breena R. Timerman, Sergio Ong, Marcus Eng Hock TI Global Health and Emergency Care: A Resuscitation Research Agenda-Part 1 SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID HOSPITAL CARDIAC-ARREST; CARDIOPULMONARY-RESUSCITATION; LIFE-SUPPORT; TRAUMA CARE; SYSTEMATIC ANALYSIS; DEVELOPING-COUNTRY; SURGICAL CAPACITY; MORTALITY; DISEASE; BURDEN AB At the 2013 Academic Emergency Medicine global health consensus conference, a breakout session on a resuscitation research agenda was held. Two articles focusing on cardiac arrest and trauma resuscitation are the result of that discussion. This article describes the burden of disease and outcomes, issues in resuscitation research, and global trends in resuscitation research funding priorities. Globally, cardiovascular disease and trauma cause a high burden of disease that receives a disproportionately smaller research investment. International resuscitation research faces unique ethical challenges. It needs reliable baseline statistics regarding quality of care and outcomes; data linkages between providers; reliable and comparable national databases; and an effective, efficient, and sustainable resuscitation research infrastructure to advance the field. Research in resuscitation in low- and middle-income countries is needed to understand the epidemiology, infrastructure and systems context, level of training needed, and potential for cost-effective care to improve outcomes. Research is needed on low-cost models of population-based research, ways to disseminate information to the developing world, and finding the most cost-effective strategies to improve outcomes. (C) 2013 by the Society for Academic Emergency Medicine C1 [Aufderheide, Tom P.] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Nolan, Jerry P.] Royal United Hosp, Bath BA1 3NG, Avon, England. [Jacobs, Ian G.; Finn, Judith] Curtin Univ, Fac Hlth Sci, Prehosp Resuscitat & Emergency Care Res Unit, Perth, WA 6845, Australia. [van Belle, Gerald] Univ Washington, Dept Biostat, Clin Trial Ctr, Seattle, WA 98195 USA. [van Belle, Gerald] Univ Washington, Dept Environm & Occupat Hlth Sci, Clin Trial Ctr, Seattle, WA 98195 USA. [Bobrow, Bentley J.] Univ Arizona, Coll Med, Dept Emergency Med, Maricopa Med Ctr, Phoenix, AZ USA. [Bobrow, Bentley J.] Arizona Dept Hlth Serv, Bur EMS & Trauma Syst, Phoenix, AZ 85007 USA. [Marshall, John] St Michaels Hosp, Div Gen Surg, Toronto, ON M5B 1W8, Canada. [Finn, Judith] Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia. [Becker, Lance B.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Bottiger, Bernd] Univ Cologne, Univ Hosp, Dept Anaesthesiol & Intens Care Med, D-50931 Cologne, Germany. [Cameron, Peter] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Drajer, Saul] Univ Maimonides, Clin Esperanza, Buenos Aires, DF, Argentina. [Jung, Julianna J.] Johns Hopkins Univ, Sch Med Emergency Med Clin Programs, Baltimore, MD USA. [Kloeck, Walter] Univ Witwatersrand, Div Emergency Med, Johannesburg, South Africa. [Koster, Rudolph W.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Ma, Matthew Huei-Ming] Natl Taiwan Univ, Dept Emergency Med, Taipei 10764, Taiwan. [Shin, Sang Do] Seoul Natl Univ, Coll Med, Dept Emergency Med, Seoul, South Korea. [Sopko, George] NHLBI, NIH, Bethesda, MD 20892 USA. [Taira, Breena R.] Olive View Univ Calif, Los Angeles Med Ctr, Dept Emergency Med, Sylmar, CA USA. [Timerman, Sergio] Univ Sao Paulo, Sch Med, Inst Heart, Sao Paulo, Brazil. [Ong, Marcus Eng Hock] Singapore Gen Hosp, Dept Emergency Med, Singapore, Singapore. [Ong, Marcus Eng Hock] Duke NUS Grad Med Sch, Off Clin Sci, Singapore, Singapore. RP Aufderheide, TP (reprint author), Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. EM taufderh@mcw.edu RI Finn, Judith/B-2678-2010; OI Finn, Judith/0000-0002-7307-7944; MA, MATTHEW HUEI-MING/0000-0002-4388-9984; Nolan, Jerry/0000-0003-3141-3812 NR 58 TC 7 Z9 7 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2013 VL 20 IS 12 BP 1289 EP 1296 DI 10.1111/acem.12270 PG 8 WC Emergency Medicine SC Emergency Medicine GA 273WK UT WOS:000328566800012 PM 24341584 ER PT J AU Ong, MEH Aufderheide, TP Nichol, G Bobrow, BJ Bossaert, L Cameron, P Finn, J Jacobs, I Koster, RW McNally, B Ng, YY Shin, SD Sopko, G Tanaka, H Iwami, T Hauswald, M AF Ong, Marcus Eng Hock Aufderheide, Tom P. Nichol, Graham Bobrow, Bentley J. Bossaert, Leo Cameron, Peter Finn, Judith Jacobs, Ian Koster, Rudolph W. McNally, Bryan Ng, Yih Yng Shin, Sang Do Sopko, George Tanaka, Hideharu Iwami, Taku Hauswald, Mark TI Global Health and Emergency Care: A Resuscitation Research Agenda-Part 2 SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID HOSPITAL CARDIAC-ARREST; AMERICAN-HEART-ASSOCIATION; TRAUMA SYSTEM; POSTRESUSCITATION CARE; UNITED-STATES; MAJOR TRAUMA; CARDIOPULMONARY-RESUSCITATION; CLINICAL CARDIOLOGY; TRANSPORT INTERVAL; CONTROLLED-TRIALS AB At the 2013 Academic Emergency Medicine global health consensus conference, a breakout session to develop a research agenda for resuscitation was held. Two articles are the result of that discussion. This second article addresses data collection, management, and analysis and regionalization of postresuscitation care, resuscitation programs, and research examples around the world and proposes a strategy to strengthen resuscitation research globally. There is a need for reliable global statistics on resuscitation, international standardization of data, and development of an electronic standard for reporting data. Regionalization of postresuscitation care is a priority area for future research. Large resuscitation clinical research networks are feasible and can give valuable data for improvement of service and outcomes. Low-cost models of population-based research, and emphasis on interventional and implementation studies that assess the clinical effects of programs and interventions, are needed to determine the most cost-effective strategies to improve outcomes. The global challenge is how to adapt research findings to a developing world situation to have an effect internationally. (C) 2013 by the Society for Academic Emergency Medicine C1 [Ong, Marcus Eng Hock; Ng, Yih Yng] Singapore Gen Hosp, Dept Emergency Med, Singapore, Singapore. [Ong, Marcus Eng Hock] Duke NUS Grad Med Sch, Off Clin Sci, Singapore, Singapore. [Aufderheide, Tom P.] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Nichol, Graham] Univ Washington, Harborview Ctr Prehosp Emergency Care, Seattle, WA 98195 USA. [Bobrow, Bentley J.] Univ Arizona, Coll Med, Dept Emergency Med, Phoenix, AZ USA. [Bobrow, Bentley J.] Maricopa Cty Gen Hosp, Phoenix, AZ USA. [Bobrow, Bentley J.] Arizona Dept Hlth Serv, Bur EMS & Trauma Syst, Phoenix, AZ 85007 USA. [Bossaert, Leo] Univ Antwerp, Dept Intens Care, B-2020 Antwerp, Belgium. [Cameron, Peter] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Finn, Judith; Jacobs, Ian] Curtin Univ, Prehosp Resuscitat & Emergency Care Res Unit, Fac Hlth Sci, Perth, WA 6845, Australia. [Finn, Judith] Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia. [Koster, Rudolph W.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [McNally, Bryan] Emory Univ, Dept Emergency Med, Atlanta, GA 30322 USA. [Shin, Sang Do] Seoul Natl Univ, Coll Med, Dept Emergency Med, Seoul, South Korea. [Sopko, George] NHLBI, NIH, Bethesda, MD 20892 USA. [Tanaka, Hideharu] Kokushikan Univ, Dept Sport & Med Sci, Tokyo, Japan. [Iwami, Taku] Kyoto Univ Hlth Serv, Dept Prevent Serv, Kyoto, Japan. RP Ong, MEH (reprint author), Singapore Gen Hosp, Dept Emergency Med, Singapore, Singapore. EM marcus.ong.e.h@sgh.com.sg RI Finn, Judith/B-2678-2010 OI Finn, Judith/0000-0002-7307-7944 NR 61 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2013 VL 20 IS 12 BP 1297 EP 1303 DI 10.1111/acem.12272 PG 7 WC Emergency Medicine SC Emergency Medicine GA 273WK UT WOS:000328566800013 ER PT J AU Dawson, DA AF Dawson, Deborah A. TI Commentary on Tuithof et al. (2013): Implications of the DSM-5 revision for the analysis of persistence/remission of alcohol use disorder SO ADDICTION LA English DT Editorial Material ID 3-YEAR FOLLOW-UP; GENERAL-POPULATION; DEPENDENCE; REMISSION; IV; INDIVIDUALS; PREDICTORS; RECOVERY C1 NIAAA, NIH, Bethesda, MD 20816 USA. RP Dawson, DA (reprint author), NIAAA, NIH, Bethesda, MD 20816 USA. EM deborah.anne.dawson@gmail.com FU Intramural NIH HHS [Z99 AA999999] NR 15 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD DEC PY 2013 VL 108 IS 12 BP 2100 EP 2101 DI 10.1111/add.12351 PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 265LT UT WOS:000327954000012 PM 24237899 ER PT J AU Welzel, TM Graubard, BI Quraishi, S Zeuzem, S Davila, JA El-Serag, HB McGlynn, KA AF Welzel, Tania M. Graubard, Barry I. Quraishi, Sabah Zeuzem, Stefan Davila, Jessica A. El-Serag, Hashem B. McGlynn, Katherine A. TI Hepatocellular Carcinoma and Smoking: Oblivion or Contempt? Response SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Letter C1 [Welzel, Tania M.; Zeuzem, Stefan] Johann Wolfgang Goethe Univ Hosp, Frankfurt, Germany. [Graubard, Barry I.; Quraishi, Sabah; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Davila, Jessica A.; El-Serag, Hashem B.] Houston Vet Affairs Med Ctr, Houston, TX USA. [Davila, Jessica A.; El-Serag, Hashem B.] Baylor Coll Med, Houston, TX 77030 USA. RP McGlynn, KA (reprint author), NCI, DCEG, EPS 5022 6120 Execut Blvd, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov NR 5 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 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD DEC PY 2013 VL 108 IS 12 BP 1931 EP 1931 DI 10.1038/ajg.2013.342 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 272KM UT WOS:000328459300020 PM 24300871 ER PT J AU Das, S Seth, RK Kumar, A Kadiiska, MB Michelotti, G Diehl, AM Chatterjee, S AF Das, Suvarthi Seth, Ratanesh Kumar Kumar, Ashutosh Kadiiska, Maria B. Michelotti, Gregory Diehl, Anna Mae Chatterjee, Saurabh TI Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE 5,5-dimethyl-1-pyrroline N-oxide-nitrone adducts; lipid peroxidation; tyrosine nitration; cytokines; CYP2E1; light chain 3 isoform B; GABA-A receptor-associated protein ID FATTY LIVER-DISEASE; OBESE MICE; ACTIVATION; PROTEIN; STEATOSIS; FIBROSIS; CYP2E1; INJURY; DAMAGE AB Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH. C1 [Das, Suvarthi; Seth, Ratanesh Kumar; Chatterjee, Saurabh] Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Kumar, Ashutosh; Kadiiska, Maria B.] NIEHS, Free Radical Metab Grp, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Michelotti, Gregory; Diehl, Anna Mae] Duke Univ, Div Gastroenterol, Durham, NC USA. RP Chatterjee, S (reprint author), Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. EM schatt@mailbox.sc.edu RI Seth, Ratanesh/M-3700-2016; OI Seth, Ratanesh/0000-0002-7078-0052 FU NIH [4R00ES019875-02, R01DK053792]; National Institutes of Health; National Institute of Environmental Health Sciences FX This work has been supported by NIH pathway to Independence Award (4R00ES019875-02 to S. Chatterjee), NIH R01 (R01DK053792 to A. M. Diehl), and the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 36 TC 11 Z9 11 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD DEC PY 2013 VL 305 IS 12 BP G950 EP G963 DI 10.1152/ajpgi.00235.2013 PG 14 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 276OD UT WOS:000328758700008 PM 24157968 ER PT J AU Campbell, KM Lin, CD Iamsirithawom, S Scott, TW AF Campbell, Karen M. Lin, C. D. Iamsirithawom, Sopon Scott, Thomas W. TI The Complex Relationship between Weather and Dengue Virus Transmission in Thailand SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID AEDES-AEGYPTI DIPTERA; LIFE TABLE MODEL; TEMPERATURE-FLUCTUATIONS; PUERTO-RICO; HUMAN MOVEMENT; CULICIDAE; BANGKOK; DYNAMICS; DISEASE; VALIDATION AB Using a novel analytical approach, weather dynamics and seasonal dengue virus transmission cycles were profiled for each Thailand province, 1983-2001, using monthly assessments of cases, temperature, humidity, and rainfall. We observed systematic differences in the structure of seasonal transmission cycles of different magnitude, the role of weather in regulating seasonal cycles, necessary versus optimal transmission "weather-space," basis of large epidemics, and predictive indicators that estimate risk. Larger epidemics begin earlier, develop faster, and are predicted at Onset change-point when case counts are low. Temperature defines a viable range for transmission; humidity amplifies the potential within that range. This duality is central to transmission. Eighty percent of 1.2 million severe dengue cases occurred when mean temperature was 27-29.5 degrees C and mean humidity was > 75%. Interventions are most effective when applied early. Most cases occur near Peak, yet small reductions at Onset can substantially reduce epidemic magnitude. Monitoring the Quiet-Phase is fundamental in effectively targeting interventions pre-emptively. C1 [Campbell, Karen M.] San Diego State Univ, Computat Sci Res Ctr, San Diego, CA 92182 USA. San Diego State Univ, Dept Math & Stat, San Diego, CA 92182 USA. Off Dis Prevent & Control 1, Bangkok, Thailand. Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Campbell, KM (reprint author), San Diego State Univ, Computat Sci Res Ctr, 5500 Campanile Dr, San Diego, CA 92182 USA. EM kmca@roadrunner.com FU Bill & Melinda Gates Foundation [OPP52250]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was supported by the Bill & Melinda Gates Foundation (OPP52250). TWS acknowledges funding from Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. NR 43 TC 21 Z9 22 U1 1 U2 11 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2013 VL 89 IS 6 BP 1066 EP 1080 DI 10.4269/ajtmh.13-0321 PG 15 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 276CQ UT WOS:000328726100006 PM 23958906 ER PT J AU Yoon, IK Srikiatkhachorn, A Hermann, L Buddhari, D Scott, TW Jarman, RG Aldstadt, J Nisalak, A Thammapalo, S Bhoomiboonchoo, P Mammen, MP Green, S Gibbons, RV Endy, TP Rothman, AL AF Yoon, In-Kyu Srikiatkhachorn, Anon Hermann, Laura Buddhari, Darunee Scott, Thomas W. Jarman, Richard G. Aldstadt, Jared Nisalak, Ananda Thammapalo, Suwich Bhoomiboonchoo, Piraya Mammen, P. Mammen Green, Sharone Gibbons, Robert V. Endy, Timothy P. Rothman, Alan L. TI Characteristics of Mild Dengue Virus Infection in Thai Children SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PRIMARY-SCHOOL CHILDREN; DISEASE SEVERITY; LABORATORY INDICATORS; HEMORRHAGIC-FEVER; KAMPHAENG PHET; FEATURES; EPIDEMIOLOGY; VILLAGES; SAMPLES; BURDEN AB A four-year longitudinal cohort and geographic cluster study in rural Thailand was conducted to characterize the clinical spectrum of dengue virus (DENY) infection. Symptomatic DENV infections in the cohort were detected by active school absence-based surveillance that triggered cluster investigations around ill cohort children. Data from 189 cohort children with symptomatic DENV infection and 126 contact children in the clusters with DENY infection were analyzed. Of injected contacts, only 19% were asymptomatic; 81% were symptomatic, but only 65.9% reported fever. Symptom-based case definitions were unreliable for diagnosis. Symptomatic infections in contacts were milder with lower DENV RNA levels than the cohort. Infections in contacts with fever history were more likely to have detectable DENV RNA than infections without fever history. Mild infections identified by cluster investigations account for a major proportion of all DENY infections. These findings are relevant for disease burden assessments, transmission modeling, and determination of vaccine impact. C1 [Yoon, In-Kyu] Armed Forces Res Inst Med Sci, Dept Virol, Bangkok 10400, Thailand. Univ Massachusetts, Sch Med, Worcester, MA USA. Univ Toronto, Dept Med, Toronto, ON, Canada. Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. SUNY Buffalo, Dept Geog, Buffalo, NY 14260 USA. Minist Publ Hlth, Dept Med Sci, Bur Epidemiol, Nonthaburi, Thailand. SUNY Syracuse, Dept Infect Dis, Syracuse, NY USA. Univ Rhode Isl, Inst Immunol & Informat, Providence, RI 02908 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Yoon, IK (reprint author), Armed Forces Res Inst Med Sci, Dept Virol, Bangkok 10400, Thailand. EM yooni@afrims.org RI Aldstadt, Jared/A-8508-2009 OI Aldstadt, Jared/0000-0001-9162-7439 FU National Institutes of Health [P01 AI34533, R01 GM083224]; U.S. Military Infectious Diseases Research Program [S0016-04-AF]; Bill and Melinda Gates Foundation Global Health Program [OPP52250]; Canadian Institutes of Health Research Fellowship FX This research was supported, in part, by the National Institutes of Health (grants P01 AI34533 and R01 GM083224), the U.S. Military Infectious Diseases Research Program (grant S0016-04-AF), the Bill and Melinda Gates Foundation Global Health Program (grant OPP52250), and the Canadian Institutes of Health Research Fellowship (Laura Hermann). The funding source had no role in the study design, data collection, analysis and interpretation, manuscript writing, or manuscript submission for publication. NR 28 TC 6 Z9 6 U1 0 U2 9 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2013 VL 89 IS 6 BP 1081 EP 1087 DI 10.4269/ajtmh.13-0424 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 276CQ UT WOS:000328726100007 PM 24127167 ER PT J AU Joseph, L Thurm, A Farmer, C Shumway, S AF Joseph, Lisa Thurm, Audrey Farmer, Cristan Shumway, Stacy TI Repetitive Behavior and Restricted Interests in Young Children with Autism: Comparisons with Controls and Stability Over 2 Years SO AUTISM RESEARCH LA English DT Article DE autism spectrum disorders; repetitive behaviors; young children; trajectory ID SPECTRUM DISORDERS; ADOS SCORES; FOLLOW-UP; AGE; TRAJECTORIES; ASSOCIATION; SEVERITY; SYMPTOMS; TODDLERS; INFANTS AB Restricted, repetitive and stereotyped patterns of behavior, interests and activities [RRBs] are among the core symptoms of autism spectrum disorders (ASD). Previous studies have indicated that RRBs differentiate ASD from other developmental disorders and from typical development. This study examined the presentation of RRBs as reported on the Repetitive Behavior Scale-Revised, a caregiver report, in children with ASD [separated into autism and Pervasive Developmental Disorder-Not Otherwise Specified groups] compared with children with nonspectrum developmental delays or typical development. We examined the role of age, cognitive functioning, sex and social communication impairment as they relate to RRBs. The stability of RRBs in children with autism was also examined over the course of 2 years. Results of the study confirmed that the amount and type of RRBs differs by diagnosis. Age, cognitive functioning, sex and social-communication impairment were not significant correlates. Among children with autism, RRBs remained stable over time. Autism Res 2013, 6: 584-595. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc. C1 [Joseph, Lisa; Thurm, Audrey; Farmer, Cristan; Shumway, Stacy] NIH, Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. RP Joseph, L (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr,MSC 1255,Bldg 10,Room 1C250, Bethesda, MD 20892 USA. EM jlisa@mail.nih.gov OI Manwaring, Stacy/0000-0002-0835-9398 FU National Institute of Mental Health [NIMH] [NCT 00271622, 06-M-0065, NCT NCT00298246, 06-M-0102] FX This research was supported by the Intramural Program of the National Institute of Mental Health [NIMH], studies NCT 00271622, 06-M-0065 and NCT NCT00298246, 06-M-0102. The views expressed in this article do not necessarily represent the views of the NIMH, NIH, HHS, or the United Stated Government. The authors extend our gratitude for the children and their families who volunteered their time and efforts during this research. NR 40 TC 2 Z9 2 U1 4 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-3792 EI 1939-3806 J9 AUTISM RES JI Autism Res. PD DEC PY 2013 VL 6 IS 6 BP 584 EP 595 DI 10.1002/aur.1316 PG 12 WC Behavioral Sciences; Psychology, Developmental SC Behavioral Sciences; Psychology GA 274PG UT WOS:000328617900012 PM 23868881 ER PT J AU Fu, D Lippincott-Schwartz, J Arias, IM AF Fu, Dong Lippincott-Schwartz, Jennifer Arias, Irwin M. TI Increased mitochondrial fusion and autophagy help isolated hepatocytes repolarize in collagen sandwich cultures SO AUTOPHAGY LA English DT Editorial Material DE polarization; mitochondrial fusion; autophagy; oxidative phosphorylation; lipid droplets AB Freshly isolated, depolarized rat hepatocytes can repolarize into bile canalicular networks when plated in collagen sandwich cultures. We studied the events underlying this repolarization process, focusing on how hepatocytes restore ATP synthesis and resupply biosynthetic precursors after the stress of being isolated from liver. We found that soon after being plated in collagen sandwich cultures, hepatocytes converted their mitochondria into highly fused networks. This occurred through a combination of upregulation of mitochondrial fusion proteins and downregulation of a mitochondrial fission protein. Mitochondria also became more active for oxidative phosphorylation, leading to overall increased ATP levels within cells. We further observed that autophagy was upregulated in the repolarizing hepatocytes. Boosted autophagy levels likely served to recycle cellular precursors, supplying building blocks for repolarization. Repolarizing hepatocytes also extensively degraded lipid droplets, whose fatty acids provide precursors for -oxidation to fuel oxidative phosphorylation in mitochondria. Thus, through coordination of mitochondrial fusion, autophagy, and lipid droplet consumption, depolarized hepatocytes are able to boost ATP synthesis and biosynthetic precursors to efficiently repolarize in collagen sandwich cultures. C1 [Fu, Dong] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia. [Lippincott-Schwartz, Jennifer; Arias, Irwin M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM lippincj@mail.nih.gov; ariasi@cc.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD DEC 1 PY 2013 VL 9 IS 12 BP 2154 EP 2155 DI 10.4161/auto.26167 PG 2 WC Cell Biology SC Cell Biology GA 270DT UT WOS:000328299800018 PM 24212064 ER PT J AU Towner, RA Smith, N Saunders, D De Souza, PC Henry, L Lupu, F Silasi-Mansat, R Ehrenshaft, M Mason, RP Gomez-Mejiba, SE Ramirez, DC AF Towner, Rheal A. Smith, Nataliya Saunders, Debra De Souza, Patricia Coutinho Henry, Leah Lupu, Florea Silasi-Mansat, Robert Ehrenshaft, Marilyn Mason, Ronald P. Gomez-Mejiba, Sandra E. Ramirez, Dario C. TI Combined molecular MRI and immuno-spin-trapping for in vivo detection of free radicals in orthotopic mouse GL261 gliomas SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Molecular magnetic resonance imaging; Glioma; Free radical; Immuno-spin-trapping; In vivo; Mouse ID HYDROGEN-PEROXIDE; LIPID-PEROXIDATION; NITRIC-OXIDE; DETAILED CHARACTERIZATION; OXIDATIVE STRESS; GROWTH-FACTOR; MODEL; BRAIN; MICE; ASTROCYTOMAS AB Free radicals play a major role in gliomas. By combining immuno-spin-trapping (IST) arid molecular magnetic resonance imaging (mMRI), in vivo levels of free radicals were detected within mice bearing orthotopic GL261 gliomas. The nitrone spin trap DMPO (5,5-dimethyl pyrroline N-oxide) was administered prior to injection of an anti-DMPO probe (anti-DMPO antibody covalently bound to a bovine serum albumin (BSA)-Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-biotin MRI contrast agent) to trap tumor-associated free radicals. mMRI detected the presence of anti-DMPO adducts by either a significant sustained increase (p < 0.001) in MR signal intensity or a significant decrease (p < 0.001) in T-1 relaxation, measured as %T-1 change. In vitro assessment of the anti-DMPO probe indicated a significant decrease (p < 0.0001) in T-1 relaxation in GL261 cells that were oxidatively stressed with hydrogen peroxide, compared to controls. The biotin moiety of the anti-DMPO probe was targeted with fluorescently-labeled streptavidin to locate the anti-DMPO probe in excised brain tissues. As a negative control a non-specific IgG antibody covalently bound to the albumin-Gd-DTPA-biotin construct was used. DMPO adducts were also confirmed in tumor tissue from animals administered DMPO, compared to non-tumor brain tissue. GL261 gliomas were found to have significantly increased malondialdehyde (MDA) protein adducts (p < 0.001) and 3-nitrotyrosine (3-NT) (p < 0.05) compared to normal mouse brain tissue, indicating increased oxidized lipids and proteins, respectively. Co-localization of the anti-DMPO probe with either 3-NT or 4-hydroxynonenal was also observed. This is the first report regarding the detection of in vivo levels of free radicals from a glioma model. (C) 2013 Elsevier B.V. All rights reserved. C1 [Towner, Rheal A.; Smith, Nataliya; Saunders, Debra; De Souza, Patricia Coutinho; Henry, Leah] Oklahoma Hlth Sci Ctr, Adv Magnet Resonance Ctr, Oklahoma City, OK 73104 USA. [Lupu, Florea; Silasi-Mansat, Robert] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Ehrenshaft, Marilyn; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Gomez-Mejiba, Sandra E.; Ramirez, Dario C.] Natl Univ San Luis, Lab Expt Med & Therapeut, Inst Multidisciplinario Invest Biol San Luis, CONICET, RA-5700 San Luis, Argentina. RP Towner, RA (reprint author), Oklahoma Hlth Sci Ctr, Adv Magnet Resonance Ctr, Oklahoma City, OK 73104 USA. EM Rheal-Towner@omrf.org; leah-henry@ouhsc.edu RI RAMIREZ, DARIO/K-3312-2013; OI RAMIREZ, DARIO/0000-0001-6725-3326; Silasi, Robert/0000-0001-9590-6160 FU Oklahoma Medical Research Foundation; National Institute of Environmental Health Sciences (NIEHS) FX Funding was obtained by the Oklahoma Medical Research Foundation (RAT) and the National Institute of Environmental Health Sciences (NIEHS) (RPM). We would like to thank Dr. Ting He for assisting with the GL261 mouse glioma model. NR 37 TC 7 Z9 7 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD DEC PY 2013 VL 1832 IS 12 BP 2153 EP 2161 DI 10.1016/j.bbadis.2013.08.004 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 260AO UT WOS:000327567600026 PM 23959048 ER PT J AU Diao, GQ Zeng, DL Yang, S AF Diao, Guoqing Zeng, Donglin Yang, Song TI Efficient Semiparametric Estimation of Short-Term and Long-Term Hazard Ratios with Right-Censored Data SO BIOMETRICS LA English DT Article DE Non-parametric likelihood; Proportional hazards model; Proportional odds model; Semiparametric efficiency; Semiparametric hazards rate model ID MAXIMUM-LIKELIHOOD-ESTIMATION; TIME-DEPENDENT COEFFICIENTS; REGRESSION-MODELS; VARIANCE-COMPONENTS; SURVIVAL ANALYSIS; LINKAGE ANALYSIS; COX REGRESSION; MIXTURE-MODELS; ORDINAL TRAITS; ASSOCIATION AB The proportional hazards assumption in the commonly used Cox model for censored failure time data is often violated in scientific studies. Yang and Prentice (2005) proposed a novel semiparametric two-sample model that includes the proportional hazards model and the proportional odds model as sub-models, and accommodates crossing survival curves. The model leaves the baseline hazard unspecified and the two model parameters can be interpreted as the short-term and long-term hazard ratios. Inference procedures were developed based on a pseudo score approach. Although extension to accommodate covariates was mentioned, no formal procedures have been provided or proved. Furthermore, the pseudo score approach may not be asymptotically efficient. We study the extension of the short-term and long-term hazard ratio model of Yang and Prentice (2005) to accommodate potentially time-dependent covariates. We develop efficient likelihood-based estimation and inference procedures. The nonparametric maximum likelihood estimators are shown to be consistent, asymptotically normal, and asymptotically efficient. Extensive simulation studies demonstrate that the proposed methods perform well in practical settings. The proposed method successfully captured the phenomenon of crossing hazards in a cancer clinical trial and identified a genetic marker with significant long-term effect missed by using the proportional hazards model on age-at-onset of alcoholism in a genetic study. C1 [Diao, Guoqing] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Zeng, Donglin] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Yang, Song] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Diao, GQ (reprint author), George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. EM gdiao@gmu.edu FU NIH [GM31575, R15CA150698] FX The authors thank the editor, an associate editor and a referee for helpful comments. The authors are grateful to the COGA investigators and Jean W. MacCluer for providing the COGA data from GAW14, which was supported in part by the NIH Grant GM31575. The authors thank Dr. William Rosenberger for making valuable comments and suggestions, which lead to a considerable improvement in the presentation of this manuscript. The work of the first author was supported by the NIH Grant R15CA150698. NR 42 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD DEC PY 2013 VL 69 IS 4 BP 840 EP 849 DI 10.1111/biom.12097 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 271WT UT WOS:000328423000005 PM 24328712 ER PT J AU Davidov, O Peddada, S AF Davidov, Ori Peddada, Shyamal TI Testing for the Multivariate Stochastic Order among Ordered Experimental Groups with Application to Dose-Response Studies SO BIOMETRICS LA English DT Article DE Dose-response studies; Nonparametric tests; Ordered experimental conditions; Order restricted statistical inference; Stochastic order relations ID INFERENCE; DISTRIBUTIONS AB The comparison of two or more ordered experimental groups based on multivariate data is common in a variety of applications such as toxicology, clinical trials and drug development, to name just a few. In this article, we develop a nonparametric methodology for analyzing such data. In particular we propose a global K sample nonparametric test for order among vector valued outcomes. The testing procedure can also be used in a post-hoc fashion to answer questions about the ordering of subgroups and/or single outcomes within any subset of experimental groups. Such a methodology does not currently exist. In contrast with standard methodology such as multivariate analysis of variance (MANOVA), and its nonparametric analogues, we do not assume that the groups differ only by a location parameter or that the components of the response vector have the same marginal distributions between and across groups, that is, we allow for the shape of the distribution to change across groups. We emphasize that our test compares the outcome distributions, not just their mean tendencies, and explicitly incorporates and exploits the order constraints. Consequently it is more powerful than the existing unordered tests. The methodology is illustrated using genotoxicity data where the effect of hydrogen peroxide exposure on damage to DNA is evaluated using a comet assay. C1 [Davidov, Ori] Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. [Peddada, Shyamal] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Davidov, O (reprint author), Univ Haifa, Dept Stat, IL-31905 Haifa, Israel. EM davidov@stat.haifa.ac.il FU Israeli Science Foundation [875/09]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX The research of O.D. was partially supported by the Israeli Science Foundation Grant No. 875/09. This research [in part] was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101744-04). We also thank Jack Taylor, Epidemiology Branch, NIEHS, NIH, and David Dunson, Duke University, for providing the data that were analyzed in this paper. We also thank the Editor, the AE and referee for their comment which improved the paper. NR 27 TC 2 Z9 2 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD DEC PY 2013 VL 69 IS 4 BP 982 EP 990 DI 10.1111/biom.12070 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 271WT UT WOS:000328423000018 PM 24125397 ER PT J AU Baker, SG AF Baker, Stuart G. TI Comment on Hubbard and Miglioretti (2013), Consider Also a Selection Model for the Cumulative Risk of False Positive Screening Tests SO BIOMETRICS LA English DT Letter C1 NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 9 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD DEC PY 2013 VL 69 IS 4 BP 1084 EP 1084 DI 10.1111/biom.12116 PG 1 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 271WT UT WOS:000328423000028 PM 24328716 ER PT J AU Cunningham, BK Hadley, DW Hannoush, H Meltzer, AC Niforatos, N Pineda-Alvarez, D Sachdev, V Warren-Mora, N Solomon, BD AF Cunningham, Bridget K. Hadley, Donald W. Hannoush, Hwaida Meltzer, Andrew C. Niforatos, Nickie Pineda-Alvarez, Daniel Sachdev, Vandana Warren-Mora, Nicole Solomon, Benjamin D. TI Analysis of Cardiac Anomalies in VACTERL Association SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE VACTERL; VACTERL association; VATER; VATER association; congenital heart defects ID CONGENITAL HEART-DEFECTS; SUPERIOR VENA-CAVA; VATER ASSOCIATION; MALFORMATIONS; SPECTRUM; DISEASE; BIRTH AB BACKGROUNDCongenital heart disease (CHD) is estimated to affect between 3 and 5% of all newborns. Extra-cardiac malformations are observed in 7 to 50% of patients with CHD. One relatively well-known association that can occur in the context of CHD is VACTERL. Controversy still remains regarding the definition of VATER association and its expansion to VACTERL, the appropriate diagnostic criteria and the overall incidence. METHODSWe conducted a description of a case series to characterize the cardiac findings present in a cohort of patients meeting the criteria for VACTERL association. RESULTSForty-six of 220 were eligible for inclusion into the study, 67% (31 of 46) had CHD. The most common CHD was ventricular septal defect, present in 18 of 31 patients (58%). There was no statistically significant association between CHD severity and the presence or absence of other VACTERL component features, specifically anorectal malformation (p=0.18) or tracheo-esophageal fistula (p=0.72). CHD presence also did not correlate with the presence of tracheo-esophageal fistula or anorectal malformation. CONCLUSIONAlthough this study does not, by design, provide further evidence toward the questions of whether CHD is a defining feature of VACTERL association, the frequency of CHD in our cohort does lend support to it being an important medical consideration in patients with VACTERL association. Based on our experience, we strongly recommend a screening echocardiogram to evaluate for CHD in individuals with a potential diagnosis of VACTERL association. Birth Defects Research (Part A) 97:792-797, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Cunningham, Bridget K.] Walter Reed Natl Mil Med Ctr Bethesda, Dept Pediat, Bethesda, MD USA. [Cunningham, Bridget K.; Hadley, Donald W.; Pineda-Alvarez, Daniel; Warren-Mora, Nicole; Solomon, Benjamin D.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Hannoush, Hwaida; Sachdev, Vandana] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Meltzer, Andrew C.] George Washington Univ, Dept Emergency Med, Washington, DC USA. [Niforatos, Nickie] Childrens Natl Med Ctr, Dept Neonatol, Washington, DC 20010 USA. [Solomon, Benjamin D.] Inova Hlth Syst, Inova Translat Med Inst, Div Med Genom, Falls Church, VA USA. [Solomon, Benjamin D.] Inova Hlth Syst, Inova Childrens Hosp, Dept Pediat, Falls Church, VA USA. RP Solomon, BD (reprint author), Inova Translat Med Inst, Claude Moore Bldg,3300 Gallows Rd, Falls Church, VA 22042 USA. EM benjamin.solomon@inova.org FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported (in part) by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Pertaining to Dr. Cunningham, the views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, nor the U.S. Government. Dr. Solomon thanks Dr. Max Muenke for his support and mentorship. All of the authors express their deepest gratitude to the patients and families who participate in their research on VACTERL association and related disorders. NR 24 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD DEC PY 2013 VL 97 IS 12 BP 792 EP 797 DI 10.1002/bdra.23211 PG 6 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 272RK UT WOS:000328477700007 PM 24343877 ER PT J AU Foley, AR Quijano-Roy, S Collins, J Straub, V McCallum, M Deconinck, N Mercuri, E Pane, M D'Amico, A Bertini, E North, K Ryan, MM Richard, P Allamand, V Hicks, D Lamande, S Hu, Y Gualandi, F Auh, S Muntoni, F Bonnemann, CG AF Foley, A. Reghan Quijano-Roy, Susana Collins, James Straub, Volker McCallum, Michelle Deconinck, Nicolas Mercuri, Eugenio Pane, Marika D'Amico, Adele Bertini, Enrico North, Kathryn Ryan, Monique M. Richard, Pascale Allamand, Valerie Hicks, Debbie Lamande, Shireen Hu, Ying Gualandi, Francesca Auh, Sungyoung Muntoni, Francesco Boennemann, Carsten G. TI Natural history of pulmonary function in collagen VI-related myopathies SO BRAIN LA English DT Article DE collagen VI-related myopathies; natural history; forced vital capacity; optimization of care; outcome measure ID CONGENITAL MUSCULAR-DYSTROPHY; CONSENSUS STATEMENT; RESPIRATORY CARE; BETHLEM MYOPATHY; MUSCLE; MYOSCLEROSIS; DISORDERS; MUTATIONS; PHENOTYPE; MECHANISM AB The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed 'collagen VI-related myopathies' and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (+/- 4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (+/- 1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials. C1 [Foley, A. Reghan; Muntoni, Francesco] UCL, Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England. [Foley, A. Reghan; Muntoni, Francesco] Great Ormond St Hosp Sick Children, London WC1N 1EH, England. [Quijano-Roy, Susana] Raymond Poincare Univ Hosp UVSQ, Garches Neuromuscular Ctr GNMH, F-92380 Garches, France. [Collins, James] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA. [Straub, Volker; McCallum, Michelle; Hicks, Debbie] Univ Newcastle, Int Ctr Life, Inst Med Genet, Newcastle NE1 3BZ, England. [Deconinck, Nicolas] Univ Libre Brussels, Queen Fabiola Univ Childrens Hosp, Dept Neurol, ULB, B-1000 Brussels, Belgium. [Deconinck, Nicolas] Ghent Univ Hosp, Neuromuscular Reference Ctr, B-9000 Ghent, Belgium. [Mercuri, Eugenio; Pane, Marika] Univ Cattolica Sacro Cuore, Dept Paediat Neurol, I-00168 Rome, Italy. [D'Amico, Adele; Bertini, Enrico] Bambino Gesu Pediat Hosp, Mol Med Lab, I-00165 Rome, Italy. [North, Kathryn] Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Westmead, NSW 2145, Australia. [Ryan, Monique M.] Univ Melbourne, Murdoch Childrens Res Inst, Royal Childrens Hosp, Dept Neurol, Parkville, Vic 3052, Australia. [Richard, Pascale] Pitie Salpetriere Hosp Grp, AP HP, Cardiogenet & Myogenet Funct Unit, Metab Biochem Div, F-75013 Paris, France. [Richard, Pascale; Allamand, Valerie] Univ Paris 06, IFR14, Inst Myol, F-75013 Paris, France. [Allamand, Valerie] CNRS, UMR7215, F-75013 Paris, France. [Allamand, Valerie] Univ Paris 06, INSERM, U974, F-75013 Paris, France. [Lamande, Shireen] Univ Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Hu, Ying; Boennemann, Carsten G.] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Gualandi, Francesca] Univ Ferrara, Dept Med Sci, Med Genet Sect, I-44100 Ferrara, Italy. [Auh, Sungyoung] NINDS, Biostat Unit, NIH, Bethesda, MD 20892 USA. RP Bonnemann, CG (reprint author), NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. EM carsten.bonnemann@nih.gov RI d'amico, adele/J-9203-2016; Gualandi, Francesca/K-7513-2016; OI d'amico, adele/0000-0003-2438-2624; Gualandi, Francesca/0000-0001-9551-057X; Bertini, Enrico/0000-0001-9276-4590; Ryan, Monique/0000-0001-6397-1910 FU National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR051999]; Muscular Dystrophy Association USA [MDA3896]; National Institute of Neurological Disorders and Stroke/National Institutes of Health; Muscular Dystrophy Campaign Centre; Great Ormond Street Children's Charity; NHS National Specialist Commissioning Team; NMD-CHIP Consortium; European Commission [HEALTH-F5-2008-223026] FX This work was supported, in part, by grants from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR051999 to C.G.B.]; the Muscular Dystrophy Association USA [MDA3896 to C.G.B]; intramural funds of the National Institute of Neurological Disorders and Stroke/National Institutes of Health (C.G.B.); the Muscular Dystrophy Campaign Centre Grant (F.M.). F.M. is supported by the Great Ormond Street Children's Charity. A.R.F. is a Muscular Dystrophy Campaign Fellow. The support of the NHS National Specialist Commissioning Team to the Dubowitz Neuromuscular is also gratefully acknowledged. This work was partly funded by the NMD-CHIP Consortium, a FP7 HEALTH project of the European Commission (Development of Targeted DNA Chips for High Throughput Diagnosis of Neuromuscular Disorders - Collaborative Project - FP7 Grant Agreement Number: HEALTH-F5-2008-223026; to V.A.). NR 35 TC 16 Z9 16 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD DEC PY 2013 VL 136 BP 3625 EP 3633 DI 10.1093/brain/awt284 PN 12 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 271BR UT WOS:000328366000014 PM 24271325 ER PT J AU Berman, BD Hallett, M Herscovitch, P Simonyan, K AF Berman, Brian D. Hallett, Mark Herscovitch, Peter Simonyan, Kristina TI Striatal dopaminergic dysfunction at rest and during task performance in writer's cramp SO BRAIN LA English DT Article DE dystonia; dopamine; PET; raclopride; striatum ID FOCAL HAND DYSTONIA; POSITRON EMISSION TOMOGRAPHY; IDIOPATHIC CERVICAL DYSTONIA; VOLUNTARY MUSCLE-RELAXATION; DOPA-RESPONSIVE DYSTONIA; TRANSGENIC MOUSE MODEL; PRIMARY MOTOR CORTEX; GRAY-MATTER CHANGES; DELTA-E-TORSINA; KNOCK-IN MOUSE AB Writer's cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer's cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously investigated in writer's cramp. Using positron emission tomography imaging with the D-2/D-3 antagonist C-11-raclopride, we analysed striatal D-2/D-3 availability at rest and endogenous dopamine release during sequential finger tapping and speech production tasks in 15 patients with writer's cramp and 15 matched healthy control subjects. Compared with control subjects, patients had reduced C-11-raclopride binding to D-2/D-3 receptors at rest in the bilateral striatum, consistent with findings in previous studies. During the tapping task, patients had decreased dopamine release in the left striatum as assessed by reduced change in C-11-raclopride binding compared with control subjects. One cluster of reduced dopamine release in the left putamen during tapping overlapped with a region of reduced C-11-raclopride binding to D-2/D-3 receptors at rest. During the sentence production task, patients showed increased dopamine release in the left striatum. No overlap between altered dopamine release during speech production and reduced C-11-raclopride binding to D-2/D-3 receptors at rest was seen. Striatal regions where D-2/D-3 availability at rest positively correlated with disease duration were lateral and non-overlapping with striatal regions showing reduced D-2/D-3 receptor availability, except for a cluster in the left nucleus accumbens, which showed a negative correlation with disease duration and overlapped with striatal regions showing reduced D-2/D-3 availability. Our findings suggest that patients with writer's cramp may have divergent responses in striatal dopamine release during an asymptomatic motor task involving the dystonic hand and an unrelated asymptomatic task, sentence production. Our voxel-based results also suggest that writer's cramp may be associated with reduced striatal dopamine release occuring in the setting of reduced D-2/D-3 receptor availability and raise the possibility that basal ganglia circuits associated with premotor cortices and those associated with primary motor cortex are differentially affected in primary focal dystonias. C1 [Berman, Brian D.] Univ Colorado, Dept Neurol, Denver, CO 80202 USA. [Berman, Brian D.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Herscovitch, Peter] NIH, Positron Emiss Tomog Dept, Bethesda, MD 20892 USA. [Simonyan, Kristina] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY USA. [Simonyan, Kristina] Icahn Sch Med Mt Sinai, Dept Otolaryngol, New York, NY USA. RP Berman, BD (reprint author), Univ Colorado Denver, Dept Neurol, 12631 E 17th Ave,Mail Stop B-185, Aurora, CO 80045 USA. EM brian.berman@ucdenver.edu OI Simonyan, Kristina/0000-0001-7444-0437 FU National Institute on Deafness and Other Communication Disorders, NIH [DC009629]; National Institute of Neurological Disorders and Stroke, NIH FX This work was supported by the National Institute on Deafness and Other Communication Disorders, NIH [DC009629 to K.S.]; and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. NR 93 TC 11 Z9 11 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD DEC PY 2013 VL 136 BP 3645 EP 3658 DI 10.1093/brain/awt282 PN 12 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 271BR UT WOS:000328366000016 PM 24148273 ER PT J AU Kraemer, KH Tamura, D Khan, SG DiGiovanna, JJ AF Kraemer, K. H. Tamura, D. Khan, S. G. DiGiovanna, J. J. TI Burning issues in the diagnosis of xeroderma pigmentosum SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Editorial Material C1 [Kraemer, K. H.; Tamura, D.; Khan, S. G.; DiGiovanna, J. J.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kraemer, KH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM kraemerk@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD DEC PY 2013 VL 169 IS 6 BP 1176 EP 1176 DI 10.1111/bjd.12707 PG 1 WC Dermatology SC Dermatology GA 259ZG UT WOS:000327564200003 PM 24299525 ER PT J AU Kim, SYH AF Kim, Scott Y. H. TI Varieties of decisional incapacity: theory and practice SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID CAPACITY; CONSENT; COMPETENCE AB Evaluation of decision-making capacity (DMC) for treatment is challenging. Owen et al, in this issue of the Journal, compare the abilities (understanding, appreciation and reasoning) relevant to DMC in medical and psychiatric patients. Here I discuss three key issues their article raises and that are relevant to the direction of future research. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,1C118, Bethesda, MD 20892 USA. EM scott.kim@nih.gov NR 10 TC 2 Z9 2 U1 0 U2 0 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 EI 1472-1465 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD DEC PY 2013 VL 203 IS 6 BP 403 EP 405 DI 10.1192/bjp.bp.113.128256 PG 3 WC Psychiatry SC Psychiatry GA 274HK UT WOS:000328597200004 PM 24297786 ER PT J AU Truong, H Logan, J Turkbey, B Siddiqui, MM Rais-Bahrami, S Hoang, AN Pusateri, C Shuch, B Walton-Diaz, A Vourganti, S Nix, J Stamatakis, L Harris, C Chua, C Choyke, PL Wood, BJ Pinto, PA AF Hong Truong Logan, Jennifer Turkbey, Baris Siddiqui, M. Minhaj Rais-Bahrami, Soroush Hoang, Anthony N. Pusateri, Chad Shuch, Brian Walton-Diaz, Annerleim Vourganti, Srinivas Nix, Jeffrey Stamatakis, Lambros Harris, Colette Chua, Celene Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI MRI characterization of the dynamic effects of 5 alpha-reductase inhibitors on prostate zonal volumes SO CANADIAN JOURNAL OF UROLOGY LA English DT Article DE prostate volume; MRI; BPH; 5 alpha-reductase; inhibitors ID TRANSRECTAL ULTRASOUND; CLINICAL PROGRESSION; TISSUE COMPOSITION; ENLARGED PROSTATE; CANCER-DETECTION; FINASTERIDE; HYPERPLASIA; DUTASTERIDE; MEN; THERAPY AB Introduction: Prior studies of volumetric effects of 5 alpha-reductase inhibitors (5ARIs) on the prostate have used transrectal ultrasound which provides poor differentiation of prostatic zones. We utilized high-resolution prostate MRI to evaluate the true dynamic effects of 5ARI in men who underwent multiple MRIs. Materials and methods: A retrospective study of patients who underwent serial 3.0 Tesla prostate MRI from 2007 to 2012 and were treated with 5ARI were studied. Nineteen patients who had a baseline MRI prior to 5ARI initiation and subsequent MRI follow up were selected. A randomly selected group of 40 patients who had not received any form of therapy was selected as the control cohort. Total prostate volume (TPV), transition zone volume (TZV), and peripheral zone volume (PZV) were calculated using 3D reconstructions and prostate segmentation from T2-weighted MRI. Changes in volumes were correlated with the duration of treatment using linear regression analysis. Results: Following over 2 years of treatment, 5ARI decreased TPV significantly (16.7%, p < 0.0001). There were similar decreases in TZV (7.5%, p < 0.001) and PZV (27.4%, p = 0.0002) from baseline. In the control group, TPV and TZV increased (p < 0.0001) while PZV remained stable. When adjusted for the natural growth of prostate zonal volume dynamics seen in the control cohort, approximately 60% of the reduction of the TPV from 5ARI resulted from changes in the TZV and 40% of the reduction from changes in the PZV. Conclusions: 3.0 Tesla MRI characterizations of the dynamic effects of 5ARI on prostate zonal volumes demonstrate significant decreases in TPV, TZV, and PZV. SARI blocks the natural growth of TZV as men age and decreases both TZV and PZV below their baselines. As imaging technology improves, prostate MRI allows for more accurate assessment of drug effects on dynamic prostate volumes. C1 [Hong Truong; Logan, Jennifer; Siddiqui, M. Minhaj; Rais-Bahrami, Soroush; Hoang, Anthony N.; Pusateri, Chad; Shuch, Brian; Walton-Diaz, Annerleim; Vourganti, Srinivas; Nix, Jeffrey; Stamatakis, Lambros; Harris, Colette; Chua, Celene] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. OI Siddiqui, Mohummad/0000-0002-4484-6820 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This research was also made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at hap://www.fnih.org/work/programs-development/medical-research-scholars- program. We also thank the administrative support staff of the Urologic Oncology Branch, Center for Cancer Research for assisting with the manuscript review and submission processes. NR 21 TC 2 Z9 2 U1 0 U2 0 PU CANADIAN J UROLOGY PI ST LAURENT PA 2330 WARD ST, STE 604, ST LAURENT, QUEBEC H4M 2V6, CANADA SN 1195-9479 J9 CAN J UROL JI Can. J. Urol. PD DEC PY 2013 VL 20 IS 6 BP 7002 EP 7007 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 275ZG UT WOS:000328717300002 PM 24331340 ER PT J AU Sasaki, T Miller, CF Hansford, R Zipunnikov, V Zviman, MM Marine, JE Spragg, D Cheng, A Tandri, H Sinha, S Kolandaivelu, A Zimmerman, SL Bluemke, DA Tomaselli, GF Berger, RD Halperin, HR Calkins, H Nazarian, S AF Sasaki, Takeshi Miller, Christopher F. Hansford, Rozann Zipunnikov, Vadim Zviman, Menekhem M. Marine, Joseph E. Spragg, David Cheng, Alan Tandri, Harikrishna Sinha, Sunil Kolandaivelu, Aravindan Zimmerman, Stefan L. Bluemke, David A. Tomaselli, Gordon F. Berger, Ronald D. Halperin, Henry R. Calkins, Hugh Nazarian, Saman TI Impact of Nonischemic Scar Features on Local Ventricular Electrograms and Scar-Related Ventricular Tachycardia Circuits in Patients With Nonischemic Cardiomyopathy SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE tachycardia; ventricular ID CATHETER ABLATION; INFARCT SCARS; SUBSTRATE; IDENTIFICATION; ENHANCEMENT; ARRHYTHMIA; DISEASE AB Background The association of local electrogram features with scar morphology and distribution in nonischemic cardiomyopathy has not been investigated. We aimed to quantify the association of scar on late gadolinium-enhanced cardiac magnetic resonance with local electrograms and ventricular tachycardia circuit sites in patients with nonischemic cardiomyopathy. Methods and Results Fifteen patients with nonischemic cardiomyopathy underwent late gadolinium-enhanced cardiac magnetic resonance before ventricular tachycardia ablation. The transmural extent and intramural types (endocardial, midwall, epicardial, patchy, transmural) of scar were measured in late gadolinium-enhanced cardiac magnetic resonance short-axis planes. Electroanatomic map points were registered to late gadolinium-enhanced cardiac magnetic resonance images. Myocardial wall thickness, scar transmurality, and intramural scar types were independently associated with electrogram amplitude, duration, and deflections in linear mixed-effects multivariable models, clustered by patient. Fractionated and isolated potentials were more likely to be observed in regions with higher scar transmurality (P<0.0001 by ANOVA) and in regions with patchy scar (versus endocardial, midwall, epicardial scar; P<0.05 by ANOVA). Most ventricular tachycardia circuit sites were located in scar with >25% scar transmurality. Conclusions Electrogram features are associated with scar morphology and distribution in patients with nonischemic cardiomyopathy. Previous knowledge of electrogram image associations may optimize procedural strategies including the decision to obtain epicardial access. C1 [Sasaki, Takeshi; Miller, Christopher F.; Hansford, Rozann; Zviman, Menekhem M.; Marine, Joseph E.; Spragg, David; Cheng, Alan; Tandri, Harikrishna; Sinha, Sunil; Kolandaivelu, Aravindan; Tomaselli, Gordon F.; Berger, Ronald D.; Halperin, Henry R.; Calkins, Hugh; Nazarian, Saman] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD 21287 USA. [Zipunnikov, Vadim] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21287 USA. [Zimmerman, Stefan L.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Div Radiol & Imaging Sci, NIH Clin Ctr, Bethesda, MD USA. RP Sasaki, T (reprint author), Johns Hopkins Univ, Div Cardiol, Carnegie 592A,600 N Wolfe St, Baltimore, MD 21287 USA. EM tsasaki.cvm@tmd.ac.jp OI Bluemke, David/0000-0002-8323-8086 FU Francis Chiaramonte MD Private Foundation; National Institutes of Health [K23HL089333, R01HL116280, R01-HL094610] FX The study was supported by grants from the Francis Chiaramonte MD Private Foundation to T. S. and from the National Institutes of Health (K23HL089333 and R01HL116280 to S.N. and R01-HL094610 to H.R.H.). NR 26 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 EI 1941-3084 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD DEC PY 2013 VL 6 IS 6 BP 1139 EP 1147 DI 10.1161/CIRCEP.113.000159 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 273HN UT WOS:000328526000024 PM 24235267 ER PT J AU He, J Kelly, TN Zhao, Q Li, HF Huang, JF Wang, LY Jaquish, CE Sung, YJ Shimmin, LC Lu, FH Mu, JJ Hu, DS Ji, X Shen, C Guo, DS Ma, JX Wang, RP Shen, JJ Li, SX Chen, J Mei, H Chen, CS Chen, SF Chen, JC Li, JX Cao, J Lu, XF Wu, XG Rice, TK Gu, CC Schwander, K Hamm, LL Liu, DP Rao, DC Hixson, JE Gu, DF AF He, Jiang Kelly, Tanika N. Zhao, Qi Li, Hongfan Huang, Jianfeng Wang, Laiyuan Jaquish, Cashell E. Sung, Yun Ju Shimmin, Lawrence C. Lu, Fanghong Mu, Jianjun Hu, Dongsheng Ji, Xu Shen, Chong Guo, Dongshuang Ma, Jixiang Wang, Renping Shen, Jinjin Li, Shengxu Chen, Jing Mei, Hao Chen, Chung-Shiuan Chen, Shufeng Chen, Jichun Li, Jianxin Cao, Jie Lu, Xiangfeng Wu, Xigui Rice, Treva K. Gu, C. Charles Schwander, Karen Hamm, L. Lee Liu, Depei Rao, Dabeeru C. Hixson, James E. Gu, Dongfeng TI Genome-Wide Association Study Identifies 8 Novel Loci Associated With Blood Pressure Responses to Interventions in Han Chinese SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE blood pressure; genomics; potassium; sodium ID DIETARY-SODIUM INTERVENTION; QT INTERVAL DURATION; SALT-SENSITIVITY; COMMON VARIANTS; SUSCEPTIBILITY LOCI; PULSE PRESSURE; FOLLOW-UP; HYPERTENSION; POPULATION; DISEASE AB Background Blood pressure (BP) responses to dietary sodium and potassium intervention and cold pressor test vary considerably among individuals. We aimed to identify novel genetic variants influencing individuals' BP responses to dietary intervention and cold pressor test. Methods and Results We conducted a genome-wide association study of BP responses in 1881 Han Chinese and de novo genotyped top findings in 698 Han Chinese. Diet-feeding study included a 7-day low-sodium (51.3 mmol/d), a 7-day high-sodium (307.8 mmol/d), and a 7-day high-sodium plus potassium supplementation (60 mmol/d). Nine BP measurements were obtained during baseline observation and each intervention period. The meta-analyses identified 8 novel loci for BP phenotypes, which physically mapped in or near PRMT6 (P=7.29x10(-9)), CDCA7 (P=3.57x10(-8)), PIBF1 (P=1.78x10(-9)), ARL4C (P=1.86x10(-8)), IRAK1BP1 (P=1.44x10(-10)), SALL1 (P=7.01x10(-13)), TRPM8 (P=2.68x10(-8)), and FBXL13 (P=3.74x10(-9)). There was a strong dose-response relationship between the number of risk alleles of these independent single-nucleotide polymorphisms and the risk of developing hypertension during the 7.5-year follow-up in the study participants. Compared with those in the lowest quartile of risk alleles, odds ratios (95% confidence intervals) for those in the second, third, and fourth quartiles were 1.39 (0.97, 1.99), 1.72 (1.19, 2.47), and 1.84 (1.29, 2.62), respectively (P=0.0003 for trend). Conclusions Our study identified 8 novel loci for BP responses to dietary sodium and potassium intervention and cold pressor test. The effect size of these novel loci on BP phenotypes is much larger than those reported by the previously published studies. Furthermore, these variants predict the risk of developing hypertension among individuals with normal BP at baseline. C1 [He, Jiang; Kelly, Tanika N.; Zhao, Qi; Li, Shengxu; Chen, Jing; Mei, Hao; Chen, Chung-Shiuan; Hamm, L. Lee] Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. [He, Jiang; Chen, Jing; Hamm, L. Lee] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Li, Hongfan; Huang, Jianfeng; Chen, Shufeng; Chen, Jichun; Li, Jianxin; Cao, Jie; Lu, Xiangfeng; Wu, Xigui; Gu, Dongfeng] Fuwai Hosp, State Key Lab Cardiovasc Dis, Dept Epidemiol & Populat Genet, Natl Ctr Cardiovasc Dis, Beijing, Peoples R China. [Liu, Depei] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Peking Union Med Coll, Beijing 100730, Peoples R China. [Li, Hongfan; Wang, Laiyuan] Natl Human Genome Ctr Beijing, Beijing, Peoples R China. [Jaquish, Cashell E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Sung, Yun Ju; Rice, Treva K.; Gu, C. Charles; Schwander, Karen; Rao, Dabeeru C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Shimmin, Lawrence C.; Hixson, James E.] Univ Texas Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Lu, Fanghong] Shandong Acad Med Sci, Inst Basic Med, Shandong, Peoples R China. [Ma, Jixiang] Ctr Dis Control & Prevent Shandong, Jinan, Shandong, Peoples R China. [Mu, Jianjun] Xi An Jiao Tong Univ, Coll Med, Affiliated Hosp 1, Xian, Shaanxi, Peoples R China. [Hu, Dongsheng] Shenzhen Univ Med Ctr, Shenzhen, Guangdong, Peoples R China. [Ji, Xu] Xinle Tradit Med Hosp, Xinle, Hebei, Peoples R China. [Shen, Chong] Nanjing Med Univ Sch Publ Hlth, Dept Epidemiol & Biostat, Nanjing, Peoples R China. [Guo, Dongshuang] Yuxian Peoples Hosp, Yangquan, Shanxi, Peoples R China. [Wang, Renping] Hebei Changcheng Hosp, Shijiazhuang, Hebei, Peoples R China. [Shen, Jinjin] Ctr Dis Control & Prevent Yancheng, Yancheng, Jiangsu, Peoples R China. RP He, J (reprint author), Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, 1440 Canal St,Suite 2000, New Orleans, LA 70118 USA. EM jhe@tulane.edu; gudf@yahoo.com FU National Heart, Lung, and Blood Institute, National Institutes of Health [U01HL072507, R01HL087263, R01HL090682]; Collins C. Diboll Private Foundation, New Orleans, LA; High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China [2012AA02A516] FX GenSalt is supported by research grants (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, and partially supported by the Collins C. Diboll Private Foundation, New Orleans, LA. This study is also partially funded by research grant (2012AA02A516) of the High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China. NR 48 TC 16 Z9 16 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2013 VL 6 IS 6 BP 598 EP 607 DI 10.1161/CIRCGENETICS.113.000307 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 274TR UT WOS:000328629600011 PM 24165912 ER PT J AU Puggal, MA Schully, SD Srinivas, PR Papanicolaou, GJ Jaquish, CE Fabsitz, RR AF Puggal, Mona A. Schully, Sheri D. Srinivas, Pothur R. Papanicolaou, George J. Jaquish, Cashell E. Fabsitz, Richard R. TI Translation of Genetics Research to Clinical Medicine The National Heart, Lung, and Blood Institute Perspective SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE genetics; humans; National Heart; Lung; and Blood Institute (U; S; ); National Institutes of Health (U; S; ); translational medical research ID PERSONALIZED MEDICINE; INTEGRATION; GENOMICS; CARE; NIH C1 [Puggal, Mona A.; Srinivas, Pothur R.; Papanicolaou, George J.; Jaquish, Cashell E.; Fabsitz, Richard R.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Schully, Sheri D.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Puggal, MA (reprint author), NHLBI DCVS PPSP EB, Rockledge 2,6701 Rockledge Dr,Room 10199,MSC 7936, Bethesda, MD 20892 USA. EM mona.puggal@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 35 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2013 VL 6 IS 6 BP 634 EP 639 DI 10.1161/CIRCGENETICS.113.000227 PG 6 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 274TR UT WOS:000328629600015 PM 24347619 ER PT J AU Wilson, JLL Miranda, CA Knepper, MA AF Wilson, Justin L. L. Miranda, Carlos A. Knepper, Mark A. TI Vasopressin and the regulation of aquaporin-2 SO CLINICAL AND EXPERIMENTAL NEPHROLOGY LA English DT Review DE Vasopressin; Trafficking; Transcription; Polyuria; Hyponatremia; SIADH ID MEDULLARY COLLECTING DUCT; NEPHROGENIC DIABETES-INSIPIDUS; WATER CHANNEL EXPRESSION; LONG-TERM REGULATION; PROTEIN-KINASE-A; URINARY CONCENTRATING DEFECT; ADENYLATE-CYCLASE ACTIVITY; ENHANCER-BINDING PROTEIN; INDUCED DOWN-REGULATION; RENAL EPITHELIAL-CELLS AB Water excretion is regulated in large part through the regulation of osmotic water permeability of the renal collecting duct epithelium. Water permeability is controlled by vasopressin through regulation of the water channel, aquaporin-2 (AQP2). Two processes contribute: (1) regulation of AQP2 trafficking to the apical plasma membrane; and (2) regulation of the total amount of the AQP2 protein in the cells. Regulation of AQP2 abundance is defective in several water-balance disorders, including many polyuric disorders and the syndrome of inappropriate antidiuresis. Here we review vasopressin signaling in the renal collecting duct that is relevant to the two modes of water permeability regulation. C1 [Wilson, Justin L. L.; Miranda, Carlos A.; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Intramural NIH HHS [ZIA HL001285-26, Z01 HL001285-21, Z01 HL001285-22, Z99 HL999999, ZIA HL001285-23, ZIA HL001285-24, ZIA HL006128-02, ZIA HL006129-02] NR 157 TC 28 Z9 31 U1 3 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1342-1751 EI 1437-7799 J9 CLIN EXP NEPHROL JI Clin. Exp. Nephrol. PD DEC PY 2013 VL 17 IS 6 BP 751 EP 764 DI 10.1007/s10157-013-0789-5 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 272VR UT WOS:000328490900001 PM 23584881 ER PT J AU Follmann, D Brittain, E Powers, JH AF Follmann, Dean Brittain, Erica Powers, John H. TI Discordant minimum inhibitory concentration analysis: A new path to licensure for anti-infective drugs SO CLINICAL TRIALS LA English DT Article ID STAPHYLOCOCCUS-AUREUS BACTEREMIA; PNEUMONIA; TRIALS; RISK AB Background Evaluation of anti-infective drugs for licensure often relies on a noninferiority (NI) design where new drug B is noninferior to comparator drug A if the difference in success rates is reliably not worse than some fixed margin. The margin must be based on historical studies that estimate the magnitude of the benefit of drug A over placebo. This approach hampers drug development because the obligatory evidence for margin determination is often nonexistent. Purpose To develop a new method for licensure of anti-infective drugs when there is no historical evidence for reliable construction of the NI margin. Methods The minimum inhibitory concentration (MIC) measures the minimum amount of drug that it takes to inhibit growth of bacteria in vitro. Patients who are infected with bacteria that have a low MIC to a given drug are expected to have good outcomes when treated with that drug. Thus, a differential effect of drug B versus drug A, if it exists, is likely to occur in patients whose pathogens have discordant MICs (e.g., low MIC for drug B, high MIC for drug A, or vice versa). A new paradigm for licensure of anti-infective drugs is proposed where a clinically acceptable NI margin is selected and licensure supported if the NI margin is met and B is reliably demonstrated superior to A in a subset of patients whose paired MICs favor B. The requirement for some evidence of superiority encourages a study that is carefully designed and executed. Results Simulations indicate that the approach shows promise in realistic settings, provided adequate data are available. A simulated example illustrates use of the methods. Limitations If the data have small sample size, weak MIC/success relationship, or high correlation between MIC-A, MIC-B, this procedure will have poor power. Conclusion Discordant MIC analysis may offer a novel path to licensure for certain anti-infective drugs. C1 [Follmann, Dean; Brittain, Erica] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Powers, John H.] NIAID, SAIC Support, Div Clin Res, Bethesda, MD 20892 USA. RP Follmann, D (reprint author), NIAID, Biostat Res Branch, 6700A Rockledge Dr Room 5138, Bethesda, MD 20892 USA. EM dean.follmann@nih.gov FU National Institutes of Health (NIH) FX This work was supported by the National Institutes of Health (NIH). The authors are either employees or contractors of the National Institute of Allergy and Infectious Diseases (NIAID). NR 14 TC 2 Z9 2 U1 0 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2013 VL 10 IS 6 BP 876 EP 885 DI 10.1177/1740774513507503 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 275LB UT WOS:000328676700006 PM 24287133 ER PT J AU Shmueli-Blumberg, D Hu, L Allen, C Frasketi, M Wu, LT VanVeldhuisen, P AF Shmueli-Blumberg, Dikla Hu, Lian Allen, Colleen Frasketi, Michael Wu, Li-Tzy VanVeldhuisen, Paul TI The National Drug Abuse Treatment Clinical Trials Network Data Share project: Website design, usage, challenges, and future directions SO CLINICAL TRIALS LA English DT Article ID SUBSTANCE USE DISORDERS; ITEM RESPONSE THEORY; BRIEF SCREENERS; HIV RISK; DEPENDENCE; ALCOHOL; GENDER; RATES AB Background There are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the gold standard' for establishing treatment effectiveness, but clinical trial research is very costly, and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. Purpose We describe the goals, developments, and usage of the Data Share website (http://www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the United States, including lessons learned, limitations, and major revisions, and considerations for future directions to improve data sharing. Methods Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. Results Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. Limitations Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. Conclusions The Data Share website offers researchers easy access to de-identified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, ongoing collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses. C1 [Shmueli-Blumberg, Dikla; Hu, Lian; Allen, Colleen; Frasketi, Michael; VanVeldhuisen, Paul] EMMES Corp, NIDA CTN Clin Coordinating Ctr, Rockville, MD 20850 USA. [Wu, Li-Tzy] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. RP Shmueli-Blumberg, D (reprint author), EMMES Corp, NIDA CTN Clin Coordinating Ctr, 401 N Washington St,Suite 700, Rockville, MD 20850 USA. EM dblumberg@emmes.com FU US National Institute on Drug Abuse (NIDA) of the National Institutes of Health [HHSN271200900034C, HSN271200522071C]; NIDA [R33DA027503, R01DA019623] FX The work for the National Drug Abuse Treatment Clinical Trials Network (CTN) Data Share website is made possible by the US National Institute on Drug Abuse (NIDA) of the National Institutes of Health (grant number HHSN271200900034C to The EMMES Corporation, and grant number HSN271200522071C to Duke University). Li-Tzy Wu has received research funding from NIDA (R33DA027503, R01DA019623). NR 31 TC 2 Z9 2 U1 1 U2 8 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2013 VL 10 IS 6 BP 977 EP 986 DI 10.1177/1740774513503522 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 275LB UT WOS:000328676700016 PM 24085772 ER PT J AU Fay, MP AF Fay, Michael P. TI An alternative property for evaluating sample size for normal data using preliminary data SO CLINICAL TRIALS LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NIAID, 6700-B Rockledge Dr MSC 7630, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 NR 2 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2013 VL 10 IS 6 BP 990 EP 991 DI 10.1177/1740774513506965 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 275LB UT WOS:000328676700018 PM 24287134 ER PT J AU Crampton, SP Bolland, S AF Crampton, Steve P. Bolland, Silvia TI Spontaneous activation of RNA-sensing pathways in autoimmune disease SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TOLL-LIKE RECEPTORS; AICARDI-GOUTIERES-SYNDROME; B-CELL RESPONSES; I INTERFERON; MURINE LUPUS; NUCLEIC-ACID; IMMUNE-RESPONSES; DENDRITIC CELLS; SELF-RNA AB Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid-specific antibodies and induces an inflammatory program. In contrast, spontaneous activation of cytoplasmic RNA sensing pathways targets mostly non-hematopoietic tissues and their effect on autoimmune disease is secondary to the release of interferon in the circulation. The fact that pathologies result from spontaneous activation of innate pathways implies that endogenous RNA ligands that might be sensed as pathogenic are commonly found in both immune and non-immune cells. C1 [Crampton, Steve P.; Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM sbolland@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [Z108015] FX The authors' work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (Z108015). NR 67 TC 4 Z9 4 U1 2 U2 8 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD DEC PY 2013 VL 25 IS 6 BP 712 EP 719 DI 10.1016/j.coi.2013.09.011 PG 8 WC Immunology SC Immunology GA 276AG UT WOS:000328719900008 PM 24455767 ER PT J AU Wu, Y Christensen, R Colon-Ramos, D Shroff, H AF Wu, Yicong Christensen, Ryan Colon-Ramos, Daniel Shroff, Hari TI Advanced optical imaging techniques for neurodevelopment SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID LIGHT-SHEET MICROSCOPY; STRUCTURED-ILLUMINATION MICROSCOPY; MOUSE-BRAIN; FLUORESCENCE MICROSCOPY; GENERATION MICROSCOPY; PLANE ILLUMINATION; LIVE; ZEBRAFISH; TOMOGRAPHY; RESOLUTION AB Over the past decade, developmental neuroscience has been transformed by the widespread application of confocal and two-photon fluorescence microscopy. Even greater progress is imminent, as recent innovations in microscopy now enable imaging with increased depth, speed, and spatial resolution; reduced phototoxicity; and in some cases without external fluorescent probes. We discuss these new techniques and emphasize their dramatic impact on neurobiology, including the ability to image neurons at depths exceeding 1 mm, to observe neurodevelopment noninvasively throughout embryogenesis, and to visualize neuronal processes or structures that were previously too small or too difficult to target with conventional microscopy. C1 [Wu, Yicong; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. [Christensen, Ryan; Colon-Ramos, Daniel] Yale Univ, Sch Med, Dept Cell Biol, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06536 USA. RP Wu, Y (reprint author), Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, 13 South Dr, Bethesda, MD 20892 USA. EM yicong.wu@nih.gov; hari.shroff@nih.gov RI Shroff, Hari/E-7247-2016 OI Shroff, Hari/0000-0003-3613-8215 FU Intramural NIH HHS [ZIA EB000074-01]; NINDS NIH HHS [R01 NS076558] NR 52 TC 9 Z9 9 U1 0 U2 21 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 EI 1873-6882 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD DEC PY 2013 VL 23 IS 6 BP 1090 EP 1097 DI 10.1016/j.conb.2013.06.008 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 273EN UT WOS:000328517800026 PM 23831260 ER PT J AU Kozak, CA AF Kozak, Christine A. TI Evolution of different antiviral strategies in wild mouse populations exposed to different gammaretroviruses SO CURRENT OPINION IN VIROLOGY LA English DT Article ID MURINE LEUKEMIA VIRUSES; CELL-SURFACE RECEPTOR; FOCUS-INDUCING VIRUSES; HOST-RANGE VARIANTS; XENOTROPIC GAMMARETROVIRUSES; CYTIDINE DEAMINASE; LABORATORY MOUSE; RETROVIRUS XMRV; ENVELOPE GENES; XPR1 RECEPTOR AB Laboratory mice carry three host range groups of gammaretroviruses all of which are linked to leukemia induction. Although polytropic mouse leukemia viruses (PMLVs) are generally recognized as the proximate cause of MLV-induced leukemias in laboratory mice, wild mice that carry only endogenous P-MLVs do not produce infectious virus and are not prone to disease; these mice carry the permissive XPR1 retroviral receptor and an attenuated variant of the retroviral restriction factor, APOBEC3. In contrast, Eurasian mice carrying ecotropic and xenotropic MLVs have evolved multiple restrictive XPR1 variants, other factors that interfere with MLV entry, and more effectively antiviral variants of APOBEC3. These different antiviral restrictions in Mus muscu/us subspecies suggest that the different virus types found in these natural populations may pose different but largely uncharacterized survival risks in their host subspecies. C1 NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov FU Intramural Program of the NIAID, NIH, Bethesda, MD FX This work was supported by the Intramural Program of the NIAID, NIH, Bethesda, MD. NR 59 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD DEC PY 2013 VL 3 IS 6 BP 657 EP 663 DI 10.1016/j.coviro.2013.08.001 PG 7 WC Virology SC Virology GA 275YR UT WOS:000328715800008 PM 23992668 ER PT J AU Strebel, K AF Strebel, Klaus TI HIV accessory proteins versus host restriction factors SO CURRENT OPINION IN VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; AICARDI-GOUTIERES SYNDROME; CYCLIN-DEPENDENT KINASES; E3 UBIQUITIN LIGASE; CD4(+) T-CELLS; SAMHD1 RESTRICTS; CBF-BETA; PARTICLE RELEASE; DOWN-MODULATION; DENDRITIC CELLS AB Primate immunodeficiency viruses, including HIV-1, are characterized by the presence of accessory genes such as vif, vpr, vpx, vpu, and nef. Current knowledge indicates that none of the primate lentiviral accessory proteins has enzymatic activity. Instead, these proteins interact with cellular ligands to either act as adapter molecules to redirect the normal function of host factors for virus-specific purposes or to inhibit a normal host function by mediating degradation or causing intracellular mislocalization/sequestration of the factors involved. This review aims at providing an update of our current understanding of how Vif, Vpu, and Vpx control the cellular restriction factors APOBEC3G, BST-2, and SAMHD1 respectively. C1 NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [1 Z01 AI000669] FX K Strebel is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (1 Z01 AI000669). NR 82 TC 42 Z9 42 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD DEC PY 2013 VL 3 IS 6 BP 692 EP 699 DI 10.1016/j.coviro.2013.08.004 PG 8 WC Virology SC Virology GA 275YR UT WOS:000328715800013 PM 24246762 ER PT J AU Gabel, SA DeRose, EF London, RE AF Gabel, Scott A. DeRose, Eugene F. London, Robert E. TI XRCC1 interaction with the REV1 C-terminal domain suggests a role in post replication repair SO DNA REPAIR LA English DT Article DE XRCC1; REV1 C-terminal domain; Post replication repair; REV1 interacting region; NMR spectroscopy ID BASE EXCISION-REPAIR; DNA-LIGASE-III; NUCLEAR OVERHAUSER ENHANCEMENT; SINGLE-STRAND BREAKS; TRANSLESION POLYMERASES; DAMAGE TOLERANCE; STRUCTURAL BASIS; CANCER RISK; HUMAN-CELLS; PROTEIN AB The function of X-ray cross complementing group 1 protein (XRCC1), a scaffold that binds to DNA repair enzymes involved in single-strand break and base excision repair, requires that it be recruited to sites of damaged DNA. However, structural insights into this recruitment are currently limited. Sequence analysis of the first unstructured linker domain of XRCC1 identifies a segment consistent with a possible REV1 interacting region (X1RIR) motif. The X1RIR motif is present in translesion polymerases that can be recruited to the pol zeta/REV1 DNA repair complex via a specific interaction with the REV1 C-terminal domain. NMR and fluorescence titration studies were performed on XRCC1-derived peptides containing this putative RIR motif in order to evaluate the binding affinity for the REV1 C-terminal domain. These studies demonstrate an interaction of the XRCC1-derived peptide with the human REV1 C-terminal domain characterized by dissociation constants in the low micromolar range. Ligand competition studies comparing the XRCC1 RIR peptide with previously studied RIR peptides were found to be inconsistent with the NMR based K-d values. These discrepancies were resolved using a fluorescence assay for which the RIR-REV1 system is particularly well suited. The structure of a REV1-XRCC1 peptide complex was determined by using NOE restraints to dock the unlabeled XRCC1 peptide with a labeled REV1 C-terminal domain. The structure is generally homologous with previously determined complexes with the pol kappa and pol eta RIR peptides, although the helical segment in XRCC1 is shorter than was observed in these cases. These studies suggest the possible involvement of XRCC1 and its associated repair factors in post replication repair. Published by Elsevier B.V. C1 [Gabel, Scott A.; DeRose, Eugene F.; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, MR-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01 ES050111]; National Institutes of Health, NIEHS [HHSN273200700046U] FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, project numbers Z01 ES050111. E.F.D. is supported by National Institutes of Health, NIEHS, under Delivery Order HHSN273200700046U. NR 53 TC 7 Z9 7 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD DEC PY 2013 VL 12 IS 12 BP 1105 EP 1113 DI 10.1016/j.dnarep.2013.08.015 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 274GO UT WOS:000328595000012 PM 24409475 ER PT J AU Wolf, L Gao, CS Gueta, K Xie, Q Chevallier, T Podduturi, NR Sun, J Conte, I Zelenka, PS Ashery-Padan, R Zavadil, J Cvekl, A AF Wolf, Louise Gao, Chun S. Gueta, Karen Xie, Qing Chevallier, Tiphaine Podduturi, Nikhil R. Sun, Jian Conte, Ivan Zelenka, Peggy S. Ashery-Padan, Ruth Zavadil, Jiri Cvekl, Ales TI Identification and Characterization of FGF2-Dependent mRNA: microRNA Networks During Lens Fiber Cell Differentiation SO G3-GENES GENOMES GENETICS LA English DT Article DE c-Maf; Dicer1; differentiation; FGF2; lens; microRNAs; signaling ID FIBROBLAST-GROWTH-FACTOR; BONE MORPHOGENETIC PROTEIN; ALPHA-A-CRYSTALLIN; EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTORS; OCULAR LENS; TERMINAL DIFFERENTIATION; ORGANELLE DEGRADATION; EPITHELIAL-CELLS; PROGENITOR CELLS AB MicroRNAs (miRNAs) and fibroblast growth factor (FGF) signaling regulate a wide range of cellular functions, including cell specification, proliferation, migration, differentiation, and survival. In lens, both these systems control lens fiber cell differentiation; however, a possible link between these processes remains to be examined. Herein, the functional requirement for miRNAs in differentiating lens fiber cells was demonstrated via conditional inactivation of Dicer1 in mouse (Mus musculus) lens. To dissect the miRNA-dependent pathways during lens differentiation, we used a rat (Rattus norvegicus) lens epithelial explant system, induced by FGF2 to differentiate, followed by mRNA and miRNA expression profiling. Transcriptome and miRNome analysis identified extensive FGF2-regulated cellular responses that were both independent and dependent on miRNAs. We identified 131 FGF2-regulated miRNAs. Seventy-six of these miRNAs had at least two in silico predicted and inversely regulated target mRNAs. Genes modulated by the greatest number of FGF-regulated miRNAs include DNA-binding transcription factors Nfib, Nfat5/OREBP, c-Maf, Ets1, and N-Myc. Activated FGF signaling influenced bone morphogenetic factor/transforming growth factor-, Notch, and Wnt signaling cascades implicated earlier in lens differentiation. Specific miRNA:mRNA interaction networks were predicted for c-Maf, N-Myc, and Nfib (DNA-binding transcription factors); Cnot6, Cpsf6, Dicer1, and Tnrc6b (RNA to miRNA processing); and Ash1l, Med1/PBP, and Kdm5b/Jarid1b/Plu1 (chromatin remodeling). Three miRNAs, including miR-143, miR-155, and miR-301a, down-regulated expression of c-Maf in the 3-UTR luciferase reporter assays. These present studies demonstrate for the first time global impact of activated FGF signaling in lens cell culture system and predicted novel gene regulatory networks connected by multiple miRNAs that regulate lens differentiation. C1 [Wolf, Louise; Xie, Qing; Cvekl, Ales] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. [Wolf, Louise; Xie, Qing; Chevallier, Tiphaine; Sun, Jian; Cvekl, Ales] Albert Einstein Coll Med, Dept Ophthalmol & Visual Sci, Bronx, NY 10461 USA. [Gao, Chun S.; Zelenka, Peggy S.] NEI, Lab Mol & Dev Biol, Bethesda, MD 20892 USA. [Gueta, Karen; Ashery-Padan, Ruth] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Gueta, Karen; Ashery-Padan, Ruth] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Podduturi, Nikhil R.; Zavadil, Jiri] NYU, Dept Pathol, Langone Med Ctr, New York, NY 10000 USA. [Podduturi, Nikhil R.; Zavadil, Jiri] NYU, Langone Med Ctr, Ctr Hlth Informat & Bioinformat, New York, NY 10000 USA. [Conte, Ivan] Telethon Inst Genet & Med, I-80131 Naples, Italy. RP Cvekl, A (reprint author), Albert Einstein Coll Med, Ullmann 123,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM ZavadilJ@iarc.fr; ales.cvekl@einstein.yu.edu OI Podduturi, Nikhil Reddy/0000-0002-2592-2090; Zavadil, Jiri/0000-0003-0640-5562 FU National Institutes of Health/National Cancer Institute [P30 CA016087-30]; NEI [Z01-EY000238]; Research to Prevent Blindness, Inc.; Israel Science Foundation [610/10]; Israel Ministry of Science [36494]; Ziegler Foundation; Binational Science Foundation; [R01 EY014237]; [EY014237-7S1] FX We thank M. T. Pizzo at the TIGEM institute for excellent technical help. We are grateful to Drs. Eran Hornstein (Weizman Institute of Science, Haifa, Israel) and Michael L. Robinson (Miami University, Miami, OH) for providing us the Dicer1flox/flox and the MLR10-cre mouse, respectively. We also thank Drs. Antony Rodriguez (Baylor College of Medicine) for the reference c-Maf 3'-UTR-luc plasmids, and Robert Farris and Slava Tomarev (National Eye Institute) for support. T. C. is a student in the Magistere de Genetique Graduate Program at Universite Paris Diderot, Sorbonne Paris Cite. Core facilities: AECOM Genomics and NYU Genome Technology Center supported in part by the National Institutes of Health/National Cancer Institute P30 CA016087-30 grant. Grant support: R01 EY014237 and EY014237-7S1 (A. C.), NEI intramural support Z01-EY000238 (P.S.Z.), and Research to Prevent Blindness, Inc. unrestricted grant to the Department of Ophthalmology and Visual Sciences. R.A.-P.'s research is supported by the Israel Science Foundation 610/10, the Israel Ministry of Science 36494, the Ziegler Foundation, and the Binational Science Foundation. NR 124 TC 10 Z9 12 U1 1 U2 12 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD DEC PY 2013 VL 3 IS 12 BP 2239 EP 2255 DI 10.1534/g3.113.008698 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 270QV UT WOS:000328334500014 PM 24142921 ER PT J AU Koroshetz, WJ Brown, J AF Koroshetz, Walter J. Brown, Jeremy TI NIH: Developing And Funding Research In Emergency Care And Training The Next Generation Of Emergency Care Researchers SO HEALTH AFFAIRS LA English DT Article ID ROUND-TABLE; INFORMED-CONSENT; TRIAL; CHALLENGES; HEMORRHAGE; EXCEPTION; OUTCOMES AB For the best health care to be provided in emergency settings, it must be based on the best available science. There are about 136 million visits to emergency departments (EDs) in the United States annually. Many of the nation's most critically ill patients are first stabilized and treated in EDs-the point of origin for nearly half of all medical intensive care unit admissions and a fourth of all surgical intensive care unit admissions. This article explores the role of the National Institutes of Health (NIH) in developing and funding research in emergency care and in training the next generation of emergency care researchers. Recognizing that effective emergency care research spans multiple organ systems and disciplines, the NIH established the Office of Emergency Care Research in December 2011 to facilitate and coordinate funding opportunities relevant to research and research training in emergency settings. Because the NIH funds education, basic research, and large clinical trials, it plays a key role in improving emergency care. C1 [Koroshetz, Walter J.] NINDS, NIH, Bethesda, MD 20892 USA. [Brown, Jeremy] NIGMS, Off Emergency Care Res, NIH, Bethesda, MD USA. RP Koroshetz, WJ (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM koroshetzw@ninds.nih.gov NR 30 TC 3 Z9 3 U1 0 U2 1 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD DEC PY 2013 VL 32 IS 12 BP 2186 EP 2192 DI 10.1377/hlthaff.2013.0833 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 275QC UT WOS:000328690900019 PM 24301404 ER PT J AU Ganmaa, D Rich-Edwards, JW Frazier, LA Davaalkham, D Oyunbileg, G Janes, C Potischman, N Hoover, R Troisi, R AF Ganmaa, Davaasambuu Rich-Edwards, Janet W. Frazier, Lindsay A. Davaalkham, Dambadarjaa Oyunbileg, Gankhuyag Janes, Craig Potischman, Nancy Hoover, Robert Troisi, Rebecca TI A comparison of migrants to, and women born in, urban Mongolia: demographic, reproductive, anthropometric and lifestyle characteristics SO INTERNATIONAL HEALTH LA English DT Article DE Lifestyle; Reproductive factors; Diet; Non-communicable diseases; Mongolia; Asia ID CONSUMPTION; POPULATION; DISEASES; CHINA; RISK; DIET AB Mongolia has experienced vast migration from rural to urban areas since the 1950s. We hypothesized that women migrating to Ulaanbaatar, the capital, would differ in factors related to future chronic disease risk compared with women who were born in Ulaanbaatar. Premenopausal mothers (aged 44 years) of children attending two schools (one in the city centre and one in the outskirts) in Ulaanbaatar were recruited for the study. During April and May 2009, 420 women were interviewed about migration, reproductive history and lifestyle factors and anthropometric measurements were taken. Women born in (n178) and outside (n242) Ulaanbaatar were similar in education and marital status, but the latter appeared to have a more traditional lifestyle including being more likely to have lived as a nomadic herder (22.3 vs 5.6; p0.001) and to currently live in a traditional yurt or ger (40.1 vs 29.2). Ever-use of hormonal contraception was more common in women born outside Ulaanbaatar (52.1 vs 38.2; p0.005) and their age at first live birth was older (26.0 vs 20.8 for 25 vs 25 years). Although the number of pregnancies was similar, the number of live births was greater for those born outside Ulaanbaatar (p0.002). Women born in Ulaanbaatar were more likely to have smoked cigarettes (24.7 vs 11.2; p0.001). Women born outside Ulaanbaatar were more likely to consume the traditional meat and dairy diet. Rural migrants to Mongolias capital have retained a traditional lifestyle in some, but not all, respects. Internal migrant populations may provide the opportunity to assess the effect of changes in isolated risk factors for subsequent chronic disease. C1 [Ganmaa, Davaasambuu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ganmaa, Davaasambuu; Rich-Edwards, Janet W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. [Ganmaa, Davaasambuu; Rich-Edwards, Janet W.; Frazier, Lindsay A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Frazier, Lindsay A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Frazier, Lindsay A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Davaalkham, Dambadarjaa; Oyunbileg, Gankhuyag] Univ Mongolia, Ulaanbaatar, Mongol Peo Rep. [Janes, Craig] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Potischman, Nancy] NCI, Div Canc Control & Populat Sci, US Dept HHS, Bethesda, MD 20892 USA. [Hoover, Robert; Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. RP Ganmaa, D (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,Room 341B, Boston, MA 02115 USA. EM gdavaasa@hsph.harvard.edu FU National Cancer Institute, National Institutes of Health, Bethesda, MD, USA FX This work was supported by a contract from the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. NR 17 TC 3 Z9 3 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1876-3413 EI 1876-3405 J9 INT HEALTH JI Int. Health PD DEC PY 2013 VL 5 IS 4 BP 244 EP 250 DI 10.1093/inthealth/iht020 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 271BH UT WOS:000328364800002 PM 24021762 ER PT J AU McCaffery, JM Papandonatos, GD Huggins, GS Peter, I Kahn, SE Knowler, WC Hudnall, GE Lipkin, EW Kitabchi, AE Wagenknecht, LE Wing, RR AF McCaffery, J. M. Papandonatos, G. D. Huggins, G. S. Peter, I. Kahn, S. E. Knowler, W. C. Hudnall, G. E. Lipkin, E. W. Kitabchi, A. E. Wagenknecht, L. E. Wing, R. R. CA Genetic Subgrp Look AHEAD Look AHEAD Res Grp TI FTO predicts weight regain in the Look AHEAD clinical trial SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE type 2 diabetes; weight loss; diet; genetics ID GENOME-WIDE ASSOCIATION; DIABETES PREVENTION PROGRAM; LIFE-STYLE INTERVENTION; OBESITY-RELATED TRAITS; REDUCES ENERGY-INTAKE; BODY-MASS INDEX; NEUROTROPHIC FACTOR; ADULT OBESITY; CHILDHOOD OBESITY; RISK-FACTORS AB BACKGROUND: Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. METHODS: Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. RESULTS: No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene (FTO) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P = 0.005), but not ILI (P = 0.761), resulting in SNP x treatment arm interaction (P = 0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (P = 0.051). CONCLUSIONS: Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss. C1 [McCaffery, J. M.; Wing, R. R.] Miriam Hosp, Dept Psychiat & Human Behav, Weight Control & Diabet Res Ctr, Providence, RI 02903 USA. [McCaffery, J. M.; Wing, R. R.] Brown Med Sch, Providence, RI USA. [Papandonatos, G. D.] Brown Univ, Ctr Stat Sci, Providence, RI 02912 USA. [Huggins, G. S.] Tufts Med Ctr, Mol Cardiol Res Inst, MCRI Ctr Translat Genom, Boston, MA USA. [Peter, I.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Kahn, S. E.; Kitabchi, A. E.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Knowler, W. C.] Natl Inst Diabet & Digest & Kidney Dis, Phoenix, AZ USA. [Hudnall, G. E.] Baylor Coll Med, Houston, TX 77030 USA. [Hudnall, G. E.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Lipkin, E. W.] Univ Tennessee, Ctr Hlth Sci, Div Endocrinol Diabet & Metab, Memphis, TN 38163 USA. [Wagenknecht, L. E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. RP McCaffery, JM (reprint author), Miriam Hosp, Dept Psychiat & Human Behav, Weight Control & Diabet Res Ctr, 196 Richmond St, Providence, RI 02903 USA. EM jeanne_mccaffery@brown.edu RI Papandonatos, George/J-2328-2014; OI Papandonatos, George/0000-0001-6770-932X; Kahn, Steven/0000-0001-7307-9002 FU Department of Health and Human Services through National Institutes of Health [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; Centers for Disease Control and Prevention; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical and Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center [M01RR000056 44]; NIH [DK 046204, DK072497]; VA Puget Sound Health Care System and Department of Veterans Affairs; Frederic C Bartter General Clinical Research Center [M01RR01346]; Training Program in Cardiovascular Research (NIH) [5T32HL069770] FX We acknowledge the Look AHEAD sites that participated in this ancillary study. This study is supported by the Department of Health and Human Services through the following cooperative agreements from the National Institutes of Health: DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135 and DK56992. The following federal agencies have contributed support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; and the Centers for Disease Control and Prevention. Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) Clinical and Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (M01RR000056 44) and NIH grants (DK 046204 and DK072497); and VA Puget Sound Health Care System and Department of Veterans Affairs; Frederic C Bartter General Clinical Research Center (M01RR01346). AKH was supported by the Training Program in Cardiovascular Research (NIH, 5T32HL069770). The following organizations have committed to make major contributions to Look AHEAD: Federal Express; Health Management Resources; Johnson & Johnson, LifeScan Inc.; Optifast-Novartis Nutrition; Roche Pharmaceuticals; Ross Product Division of Abbott Laboratories; Slim-Fast Foods Company; and Unilever. NR 38 TC 12 Z9 12 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD DEC PY 2013 VL 37 IS 12 BP 1545 EP 1552 DI 10.1038/ijo.2013.54 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 272JJ UT WOS:000328456200005 PM 23628854 ER PT J AU Leon, B Jenkins, S Pepin, K Chaudhry, H Smith, K Zalos, G Miller, BV Chen, KY Remaley, AT Waclawiw, MA Sumner, AE Cannon, RO AF Leon, B. Jenkins, S. Pepin, K. Chaudhry, H. Smith, K. Zalos, G. Miller, B. V., III Chen, K. Y. Remaley, A. T. Waclawiw, M. A. Sumner, A. E. Cannon, R. O., III TI Insulin and extremity muscle mass in overweight and obese women SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE insulin; skeletal muscle; weight loss; women's health ID INTERMUSCULAR ADIPOSE-TISSUE; SKELETAL-MUSCLE; WEIGHT-LOSS; INDUCED HYPERTROPHY; PROTEIN-SYNTHESIS; BODY-COMPOSITION; OLDER-ADULTS; AMINO-ACIDS; HYPERINSULINEMIA; RESISTANCE AB BACKGROUND: Obesity disproportionately affects women, especially those of African descent, and is associated with increases in both fat and muscle masses. OBJECTIVE: Although increased extremity muscle mass may be compensatory to fat mass load, we propose that elevated insulin levels resulting from diminished insulin sensitivity may additionally contribute to extremity muscle mass in overweight or obese women. METHODS: The following measurements were performed in 197 non-diabetic women (57% black, 35% white; age 46 +/- 11 years (mean +/- s.d.), body mass index (BMI) range 25.0-57.7 kg m(-2)): dual-energy X-ray absorptiometry for fat and extremity muscle masses; exercise performance by duration and peak oxygen consumption (VO2 peak) during graded treadmill exercise; fasting insulin and, in 183 subjects, insulin sensitivity index (SI) calculated from the minimal model. RESULTS: SI (range 0.5-14.1 lmU(-1) min(-1)) was negatively, and fasting insulin (range 1.9-35.6 mu Uml(-1)) positively associated with extremity muscle mass (both P<0.001), independent of age and height. Sixty-seven percent of women completed 6 months of participation in a weight loss and exercise program: we found a significant association between reduction in fasting insulin and a decrease in extremity muscle mass (P = 0.038), independent of reduction in fat mass or improvement in exercise performance by VO2 peak and exercise duration, and without association with change in SI or interaction by race. CONCLUSIONS: Hyperinsulinemia in overweight or obese women is associated with increased extremity muscle mass, which is partially reversible with reduction in fasting insulin concentration, consistent with the stimulatory effects of insulin on skeletal muscle. C1 [Leon, B.; Jenkins, S.; Pepin, K.; Chaudhry, H.; Smith, K.; Zalos, G.; Remaley, A. T.; Cannon, R. O., III] Natl Inst Diabet Digest Dis & Kidney Dis, Cardiovasc & Pulm Branch, Bethesda, MD USA. [Leon, B.; Jenkins, S.; Pepin, K.; Chaudhry, H.; Smith, K.; Zalos, G.; Miller, B. V., III; Chen, K. Y.; Remaley, A. T.; Waclawiw, M. A.; Sumner, A. E.; Cannon, R. O., III] NIH, Bethesda, MD 20892 USA. [Miller, B. V., III; Chen, K. Y.; Sumner, A. E.] NHLBI, Bethesda, MD 20892 USA. [Miller, B. V., III; Chen, K. Y.; Sumner, A. E.] Natl Inst Diabet Digest Dis & Kidney Dis, Diabet Endocrinol & Obes Branch, Bethesda, MD USA. [Waclawiw, M. A.] Natl Inst Diabet Digest Dis & Kidney Dis, Off Biostat Res, Bethesda, MD USA. RP Cannon, RO (reprint author), NHLBI, NIH, Bldg 10 CRC Room 5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM cannonr@nih.gov OI Chen, Kong/0000-0002-0306-1904 FU National Heart, Lung, and Blood Institute; National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health FX We gratefully acknowledge the contributions of Janet Dejesus, Rachel Permuth-Levine, Nancy Sebring, Amber Courville, Rita Lapointe, Diane Dellavalle, Greg McMahon, Catherine Marinac, Rachel Perron, Chris Idelson and Megan Sabo to this study. This research was supported by the intramural research programs of the National Heart, Lung, and Blood Institute and the National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health. NR 32 TC 2 Z9 2 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD DEC PY 2013 VL 37 IS 12 BP 1560 EP 1564 DI 10.1038/ijo.2013.45 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 272JJ UT WOS:000328456200007 PM 23609936 ER PT J AU Hall, KD Chow, CC AF Hall, K. D. Chow, C. C. TI Why is the 3500 kcal per pound weight loss rule wrong? SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Letter C1 [Hall, K. D.; Chow, C. C.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. RP Hall, KD (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. EM kevinh@niddk.nih.gov FU Intramural NIH HHS [ZIA DK013022-09] NR 6 TC 6 Z9 6 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD DEC PY 2013 VL 37 IS 12 BP 1614 EP 1614 DI 10.1038/ijo.2013.112 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 272JJ UT WOS:000328456200017 PM 23774459 ER PT J AU Agarwal, N AF Agarwal, Neeraj TI RGC-5 Cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Letter ID RETINAL GANGLION-CELLS; LINE; DEATH; DIFFERENTIATION; EXPRESSION; MICE C1 NEI, NIH, Div Extramural Res, Rockville, MD USA. RP Agarwal, N (reprint author), NEI, NIH, Div Extramural Res, Rockville, MD USA. EM agarwalnee@nei.nih.gov NR 21 TC 5 Z9 5 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2013 VL 54 IS 13 BP 7884 EP 7884 DI 10.1167/iovs.13-13292 PG 1 WC Ophthalmology SC Ophthalmology GA 267YH UT WOS:000328133800007 ER PT J AU Pogue-Geile, KL Kim, C Jeong, JH Tanaka, N Bandos, H Gavin, PG Fumagalli, D Goldstein, LC Sneige, N Burandt, E Taniyama, Y Bohn, OL Lee, A Kim, SI Reilly, ML Remillard, MY Blackmon, NL Kim, SR Horne, ZD Rastogi, P Fehrenbacher, L Romond, EH Swain, SM Mamounas, EP Wickerham, DL Geyer, CE Costantino, JP Wolmark, N Paik, S AF Pogue-Geile, Katherine L. Kim, Chungyeul Jeong, Jong-Hyeon Tanaka, Noriko Bandos, Hanna Gavin, Patrick G. Fumagalli, Debora Goldstein, Lynn C. Sneige, Nour Burandt, Eike Taniyama, Yusuke Bohn, Olga L. Lee, Ahwon Kim, Seung-Il Reilly, Megan L. Remillard, Matthew Y. Blackmon, Nicole L. Kim, Seong-Rim Horne, Zachary D. Rastogi, Priya Fehrenbacher, Louis Romond, Edward H. Swain, Sandra M. Mamounas, Eleftherios P. Wickerham, D. Lawrence Geyer, Charles E., Jr. Costantino, Joseph P. Wolmark, Norman Paik, Soonmyung TI Predicting Degree of Benefit From Adjuvant Trastuzumab in NSABP Trial B-31 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HER2-POSITIVE BREAST-CANCER; FACTOR-I RECEPTOR; CHEMOTHERAPY; EXPRESSION; RESISTANCE; PLUS; HER2; HERCEPTIN; TAMOXIFEN; ANTIBODY AB National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Case subjects with tumor blocks were randomly divided into discovery (n 588) and confirmation cohorts (n 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] 0.67 to 3.69; P .29; n 100), 0.60 (95% CI 0.41 to 0.89; P .01; n 449), and 0.28 (95% CI 0.20 to 0.41; P < .001; n 442; P-interaction between the model and trastuzumab < .001). We developed a gene expressionbased predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47). C1 [Jeong, Jong-Hyeon; Bandos, Hanna; Rastogi, Priya; Fehrenbacher, Louis; Romond, Edward H.; Swain, Sandra M.; Mamounas, Eleftherios P.; Wickerham, D. Lawrence; Geyer, Charles E., Jr.; Costantino, Joseph P.; Wolmark, Norman; Paik, Soonmyung] Natl Surg Adjuvant Breast & Bowel Project Operat, Pittsburgh, PA USA. [Jeong, Jong-Hyeon; Bandos, Hanna; Rastogi, Priya; Fehrenbacher, Louis; Romond, Edward H.; Swain, Sandra M.; Mamounas, Eleftherios P.; Wickerham, D. Lawrence; Geyer, Charles E., Jr.; Costantino, Joseph P.; Wolmark, Norman; Paik, Soonmyung] Natl Surg Adjuvant Breast & Bowel Project Biostat, Pittsburgh, PA USA. [Pogue-Geile, Katherine L.; Kim, Chungyeul; Tanaka, Noriko; Gavin, Patrick G.; Fumagalli, Debora; Taniyama, Yusuke; Bohn, Olga L.; Lee, Ahwon; Kim, Seung-Il; Reilly, Megan L.; Remillard, Matthew Y.; Blackmon, Nicole L.; Kim, Seong-Rim; Horne, Zachary D.] NSABP, Div Pathol, Pittsburgh, PA 15212 USA. [Jeong, Jong-Hyeon; Bandos, Hanna; Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Goldstein, Lynn C.] PLLC, PhenoPath Labs, Seattle, WA USA. [Sneige, Nour] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Burandt, Eike] Univ Canc Ctr, Univ Med Ctr Hamburg Eppendorf, Dept Pathol, Hamburg, Germany. [Lee, Ahwon] Catholic Univ Korea, Dept Pathol, Seoul, South Korea. [Rastogi, Priya] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Fehrenbacher, Louis] Kaiser Permanente No Calif, Dept Oncol, Vallejo, CA USA. [Romond, Edward H.] Univ Kentucky, Markey Canc Ctr, Dept Internal Med, Lexington, KY USA. [Swain, Sandra M.] MedStar Washington Hosp Ctr, Washington Canc Inst, Dept Med, Washington, DC USA. [Mamounas, Eleftherios P.] MD Anderson Canc Ctr, Dept Surg, Orlando, FL USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA. [Wickerham, D. Lawrence; Wolmark, Norman] Allegheny Gen Hosp, Dept Surg, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [Paik, Soonmyung] Yonsei Univ, Coll Med, Severance Biomed Sci Inst, Dept Biomed Sci, Seoul, South Korea. [Paik, Soonmyung] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Dept Oncol, Seoul, South Korea. RP Paik, S (reprint author), NSABP, Div Pathol, 1307 Fed St,Ste 303, Pittsburgh, PA 15212 USA. EM soon.paik@nsabp.org OI kim, chungyeul/0000-0002-9636-5228; Jeong, Jong/0000-0003-0596-2201 FU National Cancer Institute, Department of Health and Human Services, Public Health Service [U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974]; Pennsylvania Department of Health FX This work was supported by the National Cancer Institute, Department of Health and Human Services, Public Health Service (grants U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974) and by a grant from the Pennsylvania Department of Health. The latter Department specifically disclaims responsibility for any analysis, interpretations, or conclusions. NR 22 TC 37 Z9 39 U1 1 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD DEC PY 2013 VL 105 IS 23 BP 1782 EP 1788 DI 10.1093/jnci/djt321 PG 7 WC Oncology SC Oncology GA 271DE UT WOS:000328370000007 PM 24262440 ER PT J AU Rutter, CM Johnson, EA Feuer, EJ Knudsen, AB Kuntz, KM Schrag, D AF Rutter, Carolyn M. Johnson, Eric A. Feuer, Eric J. Knudsen, Amy B. Kuntz, Karen M. Schrag, Deborah TI Secular Trends in Colon and Rectal Cancer Relative Survival SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID METASTATIC COLORECTAL-CANCER; FECAL-OCCULT-BLOOD; RANDOMIZED CONTROLLED-TRIAL; ADJUVANT THERAPY; UNITED-STATES; MORTALITY; METAANALYSIS; FLUOROURACIL; CHEMOTHERAPY; POPULATIONS AB Treatment options for colorectal cancer (CRC) have improved substantially over the past 25 years. Measuring the impact of these improvements on survival outcomes is challenging, however, against the background of overall survival gains from advancements in the prevention, screening, and treatment of other conditions. Relative survival is a metric that accounts for these concurrent changes, allowing assessment of changes in CRC survival. We describe stage- and location-specific trends in relative survival after CRC diagnosis. We analyzed survival outcomes for 233965 people in the Surveillance Epidemiology and End Results (SEER) program who were diagnosed with CRC between January 1, 1975, and December 31, 2003. All models were adjusted for sex, race (black vs white), age at diagnosis, time since diagnosis, and diagnosis year. We estimated the proportional difference in survival for CRC patients compared with overall survival for age-, sex-, race-, and period-matched controls to account for concurrent changes in overall survival using two-sided Wald tests. We found statistically significant reductions in excess hazard of mortality from CRC in 2003 relative to 1975, with excess hazard ratios ranging from 0.75 (stage IV colon cancer; P < .001) to 0.32 (stage I rectal cancer; P < .001), indicating improvements in relative survival for all stages and cancer locations. These improvements occurred in earlier years for patients diagnosed with stage I cancers, with smaller but continuing improvements for later-stage cancers. Our results demonstrate a steady trend toward improved relative survival for CRC, indicating that treatment and surveillance improvements have had an impact at the population level. C1 [Rutter, Carolyn M.; Johnson, Eric A.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Dept Radiol, Boston, MA 02114 USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. [Schrag, Deborah] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. RP Rutter, CM (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Ste 1600, Seattle, WA 98101 USA. EM rutter.c@ghc.org FU National Cancer Institute of the National Institutes of Health [U01CA52959] FX Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award No. U01CA52959. NR 44 TC 17 Z9 17 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD DEC PY 2013 VL 105 IS 23 BP 1806 EP 1813 DI 10.1093/jnci/djt299 PG 8 WC Oncology SC Oncology GA 271DE UT WOS:000328370000010 PM 24174654 ER PT J AU Brown, DA Lamb, ME Lewis, C Pipe, ME Orbach, Y Wolfman, M AF Brown, Deirdre A. Lamb, Michael E. Lewis, Charlie Pipe, Margaret-Ellen Orbach, Yael Wolfman, Missy TI The NICHD Investigative Interview Protocol: An Analogue Study SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-APPLIED LA English DT Article DE children's memory; eyewitness testimony; forensic interviews; interviewing protocols; suggestibility ID CHILD SEXUAL-ABUSE; NARRATIVE ELABORATION; FORENSIC INTERVIEWS; COGNITIVE INTERVIEW; ALLEGED VICTIMS; QUESTION FORMAT; EVENT MEMORY; RECALL; PRESCHOOLERS; WITNESSES AB One hundred twenty-eight 5-to 7-year-old children were interviewed using the National Institute of Child Health and Human Development (NICHD) Investigative Interview Protocol about an event staged 4 to 6 weeks earlier. Children were prepared for talking about the investigated event using either an invitational or directive style of prompting, with or without additional practice describing experienced events. The open invitation prompts (including those using children's words to encourage further reporting) elicited more detailed responses than the more focused directive prompts without reducing accuracy. Children were most responsive when they had received preparation that included practice describing experienced events in response to invitation prompts. Overall, children were highly accurate regardless of prompt type. Errors mostly related to peripheral rather than central information and were more likely to be elicited by directive or yes/no questions than by invitations. Children who provided accounts when asked about a false event were less accurate when describing the true event. Children who received preparation that included practice recalling a recent event in response to directive and yes/no questions were least accurate when questioned about the false event first. The data provide the first direct evaluation of the accuracy of information elicited using different prompt types in the course of NICHD Protocol interviews, and underscore the importance of how children are prepared for subsequent reporting. C1 [Brown, Deirdre A.; Lewis, Charlie] Univ Lancaster, Dept Psychol, Lancaster LA1 4YF, Lancs, England. [Lamb, Michael E.] Univ Cambridge, Dept Psychol, Cambridge, England. [Pipe, Margaret-Ellen] CUNY Brooklyn Coll, Dept Psychol, Brooklyn, NY 11210 USA. [Orbach, Yael] NICHHD, Bethesda, MD 20892 USA. [Brown, Deirdre A.; Wolfman, Missy] Victoria Univ Wellington, Sch Psychol, Wellington 6012, New Zealand. RP Brown, DA (reprint author), Victoria Univ Wellington, Sch Psychol, POB 600, Wellington 6012, New Zealand. EM Deirdre.Brown@vuw.ac.nz NR 78 TC 16 Z9 16 U1 2 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1076-898X EI 1939-2192 J9 J EXP PSYCHOL-APPL JI J. Exp. Psychol.-Appl. PD DEC PY 2013 VL 19 IS 4 BP 367 EP 382 DI 10.1037/a0035143 PG 16 WC Psychology, Applied SC Psychology GA 277KH UT WOS:000328817200008 PM 24341318 ER PT J AU Ghedin, E Rogers, MB Widen, SG Guzman, H da Rosa, APAT Wood, TG Fitch, A Popov, V Holmes, EC Walker, PJ Vasilakis, N Tesh, RB AF Ghedin, Elodie Rogers, Matthew B. Widen, Steven G. Guzman, Hilda da Rosa, Amelia P. A. Travassos Wood, Thomas G. Fitch, Adam Popov, Vsevolod Holmes, Edward C. Walker, Peter J. Vasilakis, Nikos Tesh, Robert B. TI Kolente virus, a rhabdovirus species isolated from Communication ticks and bats in the Republic of Guinea SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; PHYLOGENETIC-RELATIONSHIPS; GENOMIC CHARACTERIZATION; PHLEBOTOMINE SANDFLIES; BORNE VIRUSES; SEQUENCE; GENE; PROTEIN; VERTEBRATES; LYSSAVIRUS AB Kolente virus (KOLEV) is a rhabdovirus originally isolated from ticks and a bat in Guinea, West Africa, in 1985. Although tests at the time of isolation suggested that KOLEV is a novel rhabdovirus, it has remained largely uncharacterized. We assembled the complete genome sequence of the prototype strain DakAr K7292, which was found to encode the five canonical rhabdovirus structural proteins (N, P, M, G and L) with alternative ORFs (>180 nt) in the P and L genes. Serologically, KOLEV exhibited a weak antigenic relationship with Barur and Fukuoka viruses in the Kern Canyon group. Phylogenetic analysis revealed that KOLEV represents a distinct and divergent lineage that shows no clear relationship to any rhabdovirus except Oita virus, although with limited phylogenetic resolution. In summary, KOLEV represents a novel species in the family Rhabdoyiridae. C1 [Ghedin, Elodie; Rogers, Matthew B.; Fitch, Adam] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Ctr Vaccine Res, Pittsburgh, PA USA. [Widen, Steven G.; Wood, Thomas G.] Univ Texas Med Branch, Dept Biochem, Galveston, TX 77555 USA. [Guzman, Hilda; da Rosa, Amelia P. A. Travassos; Popov, Vsevolod; Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [Guzman, Hilda; da Rosa, Amelia P. A. Travassos; Popov, Vsevolod; Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Popov, Vsevolod; Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Ctr Trop Dis, Galveston, TX 77555 USA. [Popov, Vsevolod; Vasilakis, Nikos; Tesh, Robert B.] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Walker, Peter J.] CSIRO Anim Food & Hlth Sci, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. RP Vasilakis, N (reprint author), Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. EM nivasila@utmb.edu RI Walker, Peter/H-6059-2013 OI Walker, Peter/0000-0003-1851-642X FU Department of Pathology; Institute for Human Infections and Immunity, University of Texas Medical Branch, NIH [HHSN272201000040I/HHSN27200004/D04]; NHMRC Australia Fellowship FX This work was supported in part by the Department of Pathology start-up funds and a grant from the Institute for Human Infections and Immunity, University of Texas Medical Branch (NV), NIH contract HHSN272201000040I/HHSN27200004/D04 (R. B. T.). E. C. H. is supported by an NHMRC Australia Fellowship. NR 40 TC 10 Z9 10 U1 0 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD DEC PY 2013 VL 94 BP 2609 EP 2615 DI 10.1099/vir.0.055939-0 PN 12 PG 7 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 277GW UT WOS:000328808000003 PM 24062532 ER PT J AU Koscso, B Csoka, B Kokai, E Nemeth, ZH Pacher, P Virag, L Leibovich, SJ Hasko, G AF Koscso, Balazs Csoka, Balazs Kokai, Endre Nemeth, Zoltan H. Pacher, Pal Virag, Laszlo Leibovich, S. Joseph Hasko, Gyoergy TI Adenosine augments IL-10-induced STAT3 signaling in M2c macrophages SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE arginase; TIMP-1; alternative activation ID NECROSIS-FACTOR-ALPHA; IL-10 PRODUCTION; RECEPTOR AGONISTS; TIMP-1 PRODUCTION; TNF-ALPHA; A(2B); INFLAMMATION; ACTIVATION; CELLS; EXPRESSION AB Adenosine signaling augments IL-10-induced STAT-3 dependent gene expression in macrophages, suggesting its role in M2c polarization. The alternatively activated macrophage phenotype induced by IL-10 is called M2c. Adenosine is an endogenous purine nucleoside that accumulates in the extracellular space in response to metabolic disturbances, hypoxia, inflammation, physical damage, or apoptosis. As adenosine is known to regulate classically activated M1 and IL4- and IL-13-activated M2a macrophages, the goal of the present study was to explore its effects on M2c macrophages. We found that adenosine augmented the IL-10-induced expression of TIMP-1 and arginase-1 by the mouse macrophage cell line RAW 264.7 and by mouse BMDMs. The effects of AR stimulation on IL-10-induced TIMP-1 or arginase-1 expression were lacking in A(2B)AR KO macrophages. The role of A(2B)AR on TIMP-1 production of RAW 264.7 cells was confirmed with specific agonist BAY606583 and antagonist PSB0788. AR stimulation augmented IL-10-induced STAT3 phosphorylation in macrophages, and pharmacological inhibition or silencing of STAT3 using siRNA reduced the stimulatory effect of AR stimulation on TIMP-1 production. In contrast to its stimulatory effect on IL-10-induced STAT3 activation, adenosine inhibited IL-6-induced STAT3 phosphorylation and SAA3 expression. In conclusion, adenosine enhances IL-10-induced STAT3 signaling and M2c macrophage activation. C1 [Koscso, Balazs; Csoka, Balazs; Kokai, Endre; Hasko, Gyoergy] Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Leibovich, S. Joseph] Rutgers New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. [Hasko, Gyoergy] Rutgers New Jersey Med Sch, Ctr Immun & Inflammat, Newark, NJ 07103 USA. [Nemeth, Zoltan H.] Morristown Med Ctr, Dept Surg, Morristown, NJ USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, Bethesda, MD USA. [Kokai, Endre; Virag, Laszlo; Hasko, Gyoergy] Univ Debrecen, Dept Med Chem, Debrecen, Hungary. [Kokai, Endre; Virag, Laszlo; Hasko, Gyoergy] Univ Debrecen, Med & Hlth Sci Ctr, Debrecen, Hungary. RP Hasko, G (reprint author), Rutgers New Jersey Med Sch, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@njms.rutgers.edu RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU U.S. National Institutes of Health [R01GM66189, R01GM068636]; U.S. Army Medical Research and Materiel Command [09065004]; Hungarian Scientific Research Fund (OTKA) [K 109178]; Hungarian Scientific Research Fund grant [Human MB08-1-2011-0015, OTKA 84685] FX This work was supported by the U.S. National Institutes of Health grants R01GM66189 and R01GM068636, U.S. Army Medical Research and Materiel Command Grant 09065004, and Hungarian Scientific Research Fund (OTKA) grant K 109178 to G. H. and by a Hungarian Scientific Research Fund grant (Human MB08-1-2011-0015; OTKA 84685) to E.K. NR 53 TC 22 Z9 25 U1 1 U2 13 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD DEC PY 2013 VL 94 IS 6 BP 1309 EP 1315 DI 10.1189/jlb.0113043 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 275NH UT WOS:000328683600022 PM 23922379 ER PT J AU Tae, HJ Kim, JM Park, S Tomiya, N Li, G Wei, W Petrashevskaya, N Ahmet, I Pang, J Cruschwitz, S Riebe, RA Zhang, YH Morrell, CH Browe, D Lee, YC Xiao, RP Talan, MI Lakatta, EG Lin, L AF Tae, Hyun-Jin Kim, Ji Min Park, Sungha Tomiya, Noboru Li, Geng Wei, Wen Petrashevskaya, Natalia Ahmet, Ismayil Pang, John Cruschwitz, Stefanie Riebe, Rebecca A. Zhang, Yinghua Morrell, Christopher H. Browe, David Lee, Yuan Chuan Xiao, Rui-ping Talan, Mark I. Lakatta, Edward G. Lin, Li TI The N-glycoform of sRAGE is the key determinant for its therapeutic efficacy to attenuate injury-elicited arterial inflammation and neointimal growth SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Article DE sRAGE; N-glycoform; Arterial injury; Arterial inflammation; Neointimal hyperplasia; Therapeutic window ID GLYCATION END-PRODUCTS; VASCULAR ENDOTHELIAL-CELLS; SMOOTH-MUSCLE-CELLS; MYOCARDIAL-INFARCTION; RECEPTOR; RAGE; PROTEINS; BINDING; GLYCOSYLATION; EXPRESSION AB Signaling of the receptor for advanced glycation end products (RAGE) has been implicated in the development of injury-elicited vascular complications. Soluble RAGE (sRAGE) acts as a decoy of RAGE and has been used to treat pathological vascular conditions in animal models. However, previous studies used a high dose of sRAGE produced in insect Sf9 cells (sRAGE(Sf9))and multiple injections to achieve the therapeutic outcome. Here, we explore whether modulation of sRAGE N-glycoform impacts its bioactivity and augments its therapeutic efficacy. We first profiled carbohydrate components of sRAGE produced in Chinese hamster Ovary cells (sRAGE(CHO)) to show that a majority of its N-glycans belong to sialylated complex types that are not shared by sRAGE(Sf9). In cell-based NF-kappa B activation and vascular smooth muscle cell (VSMC) migration assays, sRAGE(CHO) exhibited a significantly higher bioactivity relative to sRAGE(Sf9) to inhibit RAGE alarmin ligand-induced NF-kappa B activation and VSMC migration. We next studied whether this N-glycoform-associated bioactivity of sRAGE(CHO) is translated to higher in vivo therapeutic efficacy in a rat carotid artery balloon injury model. Consistent with the observed higher bioactivity in cell assays, sRAGE(CHO) significantly reduced injury-induced neointimal growth and the expression of inflammatory markers in injured vasculature. Specifically, a single dose of 3 ng/g of sRAGE(CHO) reduced neointimal hyperplasia by over 70 %, whereas the same dose of sRAGE(Sf9) showed no effect. The administered sRAGE(CHO) is rapidly and specifically recruited to the injured arterial locus, suggesting that early intervention of arterial injury with sRAGE(CHO) may offset an inflammatory circuit and reduce the ensuing tissue remodeling. Our findings showed that the N-glycoform of sRAGE is the key determinant underlying its bioactivity and thus is an important glycobioengineering target to develop a highly potent therapeutic sRAGE for future clinical applications. Key message The specific N-glycoform modification is the key underlying sRAGE bioactivity Markedly reduced sRAGE dose to attenuate neointimal hyperplasia and inflammation Provide a molecular target for glycobioengineering of sRAGE as a therapeutic protein Blocking RAGE alarmin ligands during acute injury phase offsets neointimal growth. C1 [Tae, Hyun-Jin; Kim, Ji Min; Park, Sungha; Wei, Wen; Petrashevskaya, Natalia; Ahmet, Ismayil; Pang, John; Cruschwitz, Stefanie; Riebe, Rebecca A.; Morrell, Christopher H.; Browe, David; Xiao, Rui-ping; Talan, Mark I.; Lakatta, Edward G.; Lin, Li] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Tae, Hyun-Jin] Hallym Univ, Dept Biomed Sci, Chunchon, South Korea. [Tae, Hyun-Jin] Hallym Univ, Res Inst Biosci & Biotechnol, Chunchon, South Korea. [Park, Sungha] Yonsei Univ, Coll Med, Ctr Cardiovasc, Div Cardiol, Seoul 120749, South Korea. [Tomiya, Noboru; Lee, Yuan Chuan] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Li, Geng; Xiao, Rui-ping] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Zhang, Yinghua] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Morrell, Christopher H.] Loyola Univ, Dept Math & Stat, Baltimore, MD USA. RP Lin, L (reprint author), NIA, Cardiovasc Sci Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM linli@mail.nih.gov FU NIH, National Institute on Aging; Korea Research Foundation [KRF-2009-013-E00008]; Oak Ridge Institute for Science and Education's Research Associates Program at NIH; Johns Hopkins "Excellent in Medical Student Research Award"; NIH FX We thank Robert Monticone for rat VSMCs and advice on cell migration assays. We also thank reviewers of this manuscript for their inputs that improve our work. The work was supported by the intramural research program of the NIH, National Institute on Aging (LL, MIT, RPX, and EGL), and the Korea Research Foundation grant KRF-2009-013-E00008 (SP). WW was supported in part by the Oak Ridge Institute for Science and Education's Research Associates Program at NIH; JP was a recipient of the 2011 Johns Hopkins "Excellent in Medical Student Research Award"; and RAR and DB were supported by intramural research training awards from NIH. NR 42 TC 7 Z9 8 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 EI 1432-1440 J9 J MOL MED JI J. Mol. Med. PD DEC PY 2013 VL 91 IS 12 BP 1369 EP 1381 DI 10.1007/s00109-013-1091-4 PG 13 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 255NL UT WOS:000327246700005 PM 24132651 ER PT J AU Liang, JR Ito, Y Zhang, XX He, J Sun, WJ AF Liang, Jinru Ito, Yoichiro Zhang, Xinxin He, Jiao Sun, Wenji TI Rapid preparative separation of six bioactive compounds from Gentiana crassicaulis Duthie ex Burk. using microwave-assisted extraction coupled with high-speed counter-current chromatography SO JOURNAL OF SEPARATION SCIENCE LA English DT Article DE Gentiana crassicaulis Duthie ex Burk; High-speed counter-current chromatography; Microwave-assisted extraction; Quadrupole TOF MS; Response surface methodology ID RESPONSE-SURFACE METHODOLOGY; OPTIMIZATION; GLYCOSIDES; PURIFICATION AB A rapid method combining microwave-assisted extraction (MAE) and high-speed counter-current chromatography (HSCCC) was applied for preparative separation of six bioactive compounds including loganic acid (I), isoorientin-4-O-glucoside (II), 6-O--d-glucopyranosyl gentiopicroside (III), swertiamarin (IV), gentiopicroside (V), sweroside (VI) from traditional Tibetan medicine Gentiana crassicaulisDuthie ex Burk. MAE parameters were predicted by central composite design response surface methodology. That is, 5.0 g dried roots of G. crassicaulis were extracted with 50 mL 57.5% aqueous ethanol under 630 W for 3.39 min. The extract (gentian total glycosides) was separated by HSCCC with n-butanol/ethyl acetate/methanol/1% acetic acid water (7.5:0.5:0.5:3.5, v/v/v/v) using upper phase mobile in tail-to-head elution mode. 16.3, 8.8, 12., 25.1, 40.7, and 21.8 mg of compounds I-VI were obtained with high purities in one run from 500 mg of original sample. The purities and identities of separated components were confirmed using HPLC with photo diode array detection and quadrupole TOF-MS and NMR spectroscopy. The study reveals that response surface methodology is convenient and highly predictive for optimizing extraction process, MAE coupled with HSCCC could be an expeditious method for extraction and separation of phytochemicals from ethnomedicine. C1 [Liang, Jinru; Zhang, Xinxin; He, Jiao; Sun, Wenji] NW Univ Xian, Biomed Key Lab Shaanxi Prov, Xian 710069, Peoples R China. [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Sun, WJ (reprint author), NW Univ Xian, Biomed Key Lab Shaanxi Prov, 229 Taibai North Rd, Xian 710069, Peoples R China. EM cxbml@nwu.edu.cn FU Northwest University [PR12079] FX Financial support from Funds of scientific research launched project of Northwest University (PR12079) is gratefully acknowledged. NR 28 TC 10 Z9 10 U1 4 U2 58 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1615-9306 EI 1615-9314 J9 J SEP SCI JI J. Sep. Sci. PD DEC PY 2013 VL 36 IS 24 BP 3934 EP 3940 DI 10.1002/jssc.201300897 PG 7 WC Chemistry, Analytical SC Chemistry GA 267ZW UT WOS:000328138200017 PM 24151213 ER PT J AU Dy, SM Pfoh, ER Salive, ME Boyd, CM AF Dy, Sydney M. Pfoh, Elizabeth R. Salive, Marcel E. Boyd, Cynthia M. TI Health-Related Quality of Life and Functional Status Quality Indicators for Older Persons with Multiple Chronic Conditions SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE multiple chronic conditions; quality indicators; quality measurement; functional status; health-related quality of life ID PRIMARY-CARE; MULTIMORBIDITY AB ObjectivesTo explore central challenges with translating self-reported measurement tools for functional status and health-related quality of life (HRQOL) into ambulatory quality indicators for older people with multiple chronic conditions (MCCs). DesignReview. SettingSources including the National Quality Measures Clearinghouse and National Quality Forum were reviewed for existing ambulatory quality indicators relevant to functional status, HRQOL, and people with MCCs. ParticipantsSeven informants with expertise in indicators using functional status and HRQOL. MeasurementsInformant interviews were conducted to explore knowledge about these types of indicators, particularly usability and feasibility. ResultsNine important existing indicators were identified in the review. For process, identified indicators addressed whether providers assessed functional status; outcome indicators addressed quality of life. In interviews, informants agreed that indicators using self-reported data were important in this population. Challenges identified included concerns about usability due to inability to discriminate quality of care adequately between organizations and feasibility concerns regarding high data collection burden, with a correspondingly low response rate. Validity was also a concern because evidence is mixed that healthcare interventions can improve HRQOL or functional status for this population. As a possible first step, a structural standard could be systematic collection of these measures in a specific setting. ConclusionAlthough functional status and HRQOL are important outcomes for older people with MCCs, few relevant ambulatory quality indicators exist, and there are concerns with usability, feasibility, and validity. Further research is needed on how best to incorporate these outcomes into quality indicators for people with MCCs. C1 [Dy, Sydney M.; Pfoh, Elizabeth R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Salive, Marcel E.] NIA, Div Geriatr & Clin Gerontol, Bethesda, MD 20892 USA. [Boyd, Cynthia M.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21205 USA. RP Dy, SM (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Room 609,624 N Broadway, Baltimore, MD 21205 USA. EM sdy@jhsph.edu FU National Institute on Aging (NIA); Paul Beeson K23 Program; NIA; AFAR; Atlantic Philanthropies; Hartford Foundation; Starr Foundation FX This work was funded by the National Institute on Aging (NIA). Dr. Boyd was supported by the Paul Beeson K23 Program (NIA/AFAR/Atlantic Philanthropies/Hartford Foundation/Starr Foundation/Anonymous Donor). Dr. Dy and Ms Pfoh received contract funding from the NIA, Dr. Boyd received an honorarium and has grant funding from NIA, and Dr. Salive is an employee of NIA. NR 19 TC 5 Z9 7 U1 1 U2 7 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 DEC PY 2013 VL 61 IS 12 BP 2120 EP 2127 DI 10.1111/jgs.12555 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 271UB UT WOS:000328416000008 PM 24320819 ER PT J AU Parsa, A Fuchsberger, C Kottgen, A O'Seaghdha, CM Pattaro, C de Andrade, M Chasman, DI Teumer, A Endlich, K Olden, M Chen, MH Tin, A Kim, YJ Taliun, D Li, M Feitosa, M Gorski, M Yang, Q Hundertmark, C Foster, MC Glazer, N Isaacs, A Rao, M Smith, AV O'Connell, JR Struchalin, M Tanaka, T Li, G Hwang, SJ Atkinson, EJ Lohman, K Cornelis, MC Johansson, A Toenjes, A Dehghan, A Couraki, V Holliday, EG Sorice, R Kutalik, Z Lehtimaeki, T Esko, T Deshmukh, H Ulivi, S Chu, AY Murgia, F Trompet, S Imboden, M Kollerits, B Pistis, G Harris, TB Launer, LJ Aspelund, T Eiriksdottir, G Mitchell, BD Boerwinkle, E Schmidt, H Hofer, E Hu, F Demirkan, A Oostra, BA Turner, ST Ding, J Andrews, JS Freedman, BI Giulianini, F Koenig, W Illig, T Doering, A Wichmann, HE Zgaga, L Zemunik, T Boban, M Minelli, C Wheeler, HE Igl, W Zaboli, G Wild, SH Wright, AF Campbell, H Ellinghaus, D Noethlings, U Jacobs, G Biffar, R Ernst, F Homuth, G Kroemer, HK Nauck, M Stracke, S Voelker, U Voelzke, H Kovacs, P Stumvoll, M Maegi, R Hofman, A Uitterlinden, AG Rivadeneira, F Aulchenko, YS Polasek, O Hastie, N Vitart, V Helmer, C Wang, JJ Stengel, B Ruggiero, D Bergmann, S Kaehoenen, M Viikari, J Nikopensius, T Province, M Colhoun, H Doney, A Robino, A Kraemer, BK Portas, L Ford, I Buckley, BM Adam, M Thun, GA Paulweber, B Haun, M Sala, C Mitchell, P Ciullo, M Vollenweider, P Raitakari, O Metspalu, A Palmer, C Gasparini, P Pirastu, M Jukema, JW Probst-Hensch, NM Kronenberg, F Toniolo, D Gudnason, V Shuldiner, AR Coresh, J Schmidt, R Ferrucci, L Van Duijn, CM Borecki, I Kardia, SLR Liu, Y Curhan, GC Rudan, I Gyllensten, U Wilson, JF Franke, A Pramstaller, PP Rettig, R Prokopenko, I Witteman, J Hayward, C Ridker, PM Bochud, M Heid, IM Siscovick, DS Fox, CS Kao, WL Boeger, CA AF Parsa, Afshin Fuchsberger, Christian Koettgen, Anna O'Seaghdha, Conall M. Pattaro, Cristian de Andrade, Mariza Chasman, Daniel I. Teumer, Alexander Endlich, Karlhans Olden, Matthias Chen, Ming-Huei Tin, Adrienne Kim, Young J. Taliun, Daniel Li, Man Feitosa, Mary Gorski, Mathias Yang, Qiong Hundertmark, Claudia Foster, Meredith C. Glazer, Nicole Isaacs, Aaron Rao, Madhumathi Smith, Albert V. O'Connell, Jeffrey R. Struchalin, Maksim Tanaka, Toshiko Li, Guo Hwang, Shih-Jen Atkinson, Elizabeth J. Lohman, Kurt Cornelis, Marilyn C. Johansson, Asa Toenjes, Anke Dehghan, Abbas Couraki, Vincent Holliday, Elizabeth G. Sorice, Rossella Kutalik, Zoltan Lehtimaeki, Terho Esko, Tonu Deshmukh, Harshal Ulivi, Sheila Chu, Audrey Y. Murgia, Federico Trompet, Stella Imboden, Medea Kollerits, Barbara Pistis, Giorgio Harris, Tamara B. Launer, Lenore J. Aspelund, Thor Eiriksdottir, Gudny Mitchell, Braxton D. Boerwinkle, Eric Schmidt, Helena Hofer, Edith Hu, Frank Demirkan, Ayse Oostra, Ben A. Turner, Stephen T. Ding, Jingzhong Andrews, Jeanette S. Freedman, Barry I. Giulianini, Franco Koenig, Wolfgang Illig, Thomas Doering, Angela Wichmann, H. -Erich Zgaga, Lina Zemunik, Tatijana Boban, Mladen Minelli, Cosetta Wheeler, Heather E. Igl, Wilmar Zaboli, Ghazal Wild, Sarah H. Wright, Alan F. Campbell, Harry Ellinghaus, David Noethlings, Ute Jacobs, Gunnar Biffar, Reiner Ernst, Florian Homuth, Georg Kroemer, Heyo K. Nauck, Matthias Stracke, Sylvia Voelker, Uwe Voelzke, Henry Kovacs, Peter Stumvoll, Michael Maegi, Reedik Hofman, Albert Uitterlinden, Andre G. Rivadeneira, Fernando Aulchenko, Yurii S. Polasek, Ozren Hastie, Nick Vitart, Veronique Helmer, Catherine Wang, Jie Jin Stengel, Benedicte Ruggiero, Daniela Bergmann, Sven Kaehoenen, Mika Viikari, Jorma Nikopensius, Tiit Province, Michael Colhoun, Helen Doney, Alex Robino, Antonietta Kraemer, Bernhard K. Portas, Laura Ford, Ian Buckley, Brendan M. Adam, Martin Thun, Gian-Andri Paulweber, Bernhard Haun, Margot Sala, Cinzia Mitchell, Paul Ciullo, Marina Vollenweider, Peter Raitakari, Olli Metspalu, Andres Palmer, Colin Gasparini, Paolo Pirastu, Mario Jukema, J. Wouter Probst-Hensch, Nicole M. Kronenberg, Florian Toniolo, Daniela Gudnason, Vilmundur Shuldiner, Alan R. Coresh, Josef Schmidt, Reinhold Ferrucci, Luigi Van Duijn, Cornelia M. Borecki, Ingrid Kardia, Sharon L. R. Liu, Yongmei Curhan, Gary C. Rudan, Igor Gyllensten, Ulf Wilson, James F. Franke, Andre Pramstaller, Peter P. Rettig, Rainer Prokopenko, Inga Witteman, Jacqueline Hayward, Caroline Ridker, Paul M. Bochud, Murielle Heid, Iris M. Siscovick, David S. Fox, Caroline S. Kao, W. Linda Boeger, Carsten A. TI Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID COMMUNITY-BASED POPULATION; BLOOD-PRESSURE; METAANALYSIS; LOCI; HYPERTENSION; NEPHROPATHY; PROTEINURIA; PROGRESSION; PREDICTORS; ADJUSTMENT AB Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research. C1 [Parsa, Afshin] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. [Fuchsberger, Christian] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Koettgen, Anna; Hundertmark, Claudia] Freiburg Univ Clin, Div Renal, Freiburg, Germany. [Koettgen, Anna; Tin, Adrienne; Li, Man; Coresh, Josef; Kao, W. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [O'Seaghdha, Conall M.; Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Seaghdha, Conall M.; Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Nephrol, Boston, MA 02115 USA. [Pattaro, Cristian; Taliun, Daniel; Minelli, Cosetta; Pramstaller, Peter P.] European Acad Bozen Bolzano, Biomed Ctr, Bolzano, Italy. [de Andrade, Mariza; Atkinson, Elizabeth J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. 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[Kollerits, Barbara; Haun, Margot; Kronenberg, Florian] Med Univ Innsbruck, Div Genet Epidemiol, A-6020 Innsbruck, Austria. [Pistis, Giorgio; Sala, Cinzia; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Dept Neurol, Austrian Stroke Prevent Study, Graz, Austria. [Hofer, Edith; Schmidt, Reinhold] Med Univ Graz, Univ Clin Neurol, Dept Neurol, Austrian Stroke Prevent Study,Clin Div Neurogeria, Graz, Austria. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Ding, Jingzhong] Wake Forest Univ, Wake Forest Sch Med, Dept Internal Med, Div Geriatr, Winston Salem, NC 27109 USA. [Andrews, Jeanette S.] Wake Forest Univ, Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Freedman, Barry I.] Wake Forest Univ, Wake Forest Sch Med, Dept Internal Med, Div Nephrol, Winston Salem, NC 27109 USA. [Koenig, Wolfgang] Univ Ulm, Ulm Univ Clin, Dept Internal Med 2, D-89069 Ulm, Germany. [Illig, Thomas] Hanover Med Sch, Hanover Unified Biobank, Hanover, NH USA. [Illig, Thomas] German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Doering, Angela; Wichmann, H. -Erich] German Res Ctr Environm Hlth, Inst Epidemiol 1 & 2, Neuherberg, Germany. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. -Erich] Grosshadern Clin, Neuherberg, Germany. [Zgaga, Lina; Rudan, Igor; Wilson, James F.] Univ Edinburgh Med Sch, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Zemunik, Tatijana; Boban, Mladen; Polasek, Ozren] Univ Split Med Sch, Croatian Ctr Global Hlth, Split, Croatia. [Wheeler, Heather E.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Wheeler, Heather E.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Hastie, Nick; Vitart, Veronique; Hayward, Caroline] Western Gen Hosp, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Franke, Andre] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Zaboli, Ghazal; Wild, Sarah H.] Schleswig Holstein Univ Hosp, PopGen Biobank, Kiel, Germany. [Zaboli, Ghazal; Wild, Sarah H.] Univ Kiel, Inst Epidemiol, Kiel, Germany. [Zaboli, Ghazal] Univ Bonn, Dept Nutr & Food Sci, Bonn, Germany. [Wright, Alan F.] Ernst Moritz Arndt Univ Greifswald, Clin Prosthodont Dent Gerostomatol & Mat Sci, Greifswald, Germany. [Noethlings, Ute; Kroemer, Heyo K.] Ernst Moritz Arndt Univ Greifswald, Dept Pharmacol, Greifswald, Germany. [Jacobs, Gunnar; Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Biffar, Reiner; Stracke, Sylvia] Ernst Moritz Arndt Univ Greifswald, Clin Internal Med A, Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Maegi, Reedik; Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Helmer, Catherine] Univ Bordeaux 2, Inst Publ Hlth, INSERM, U897, F-33076 Bordeaux, France. [Helmer, Catherine] Univ Bordeaux 2, F-33076 Bordeaux, France. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Vis Res, Sydney, NSW 2006, Australia. [Wang, Jie Jin] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Australia. [Stengel, Benedicte] INSERM, UMRS 1018, Villejuif, France. [Stengel, Benedicte] Univ Paris Sud, UMRS 1018, Paris, France. [Kaehoenen, Mika] Univ Tampere, Sch Med, Tampere Univ Hosp, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Viikari, Jorma] Univ Turku, Turku Univ Hosp, Dept Med, Turku, Finland. [Doney, Alex] Ninewells Hosp, Clin Res Ctr, Wellcome Trust Ctr Mol Med, Natl Hlth Serv Tayside, Dundee DD1 9SY, Scotland. [Kraemer, Bernhard K.] Mannheim Univ Med Ctr, Dept Med 5, Mannheim, Germany. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Paulweber, Bernhard] Paracelsus Med Univ, Dept Internal Med 1, Salzburg, Austria. [Vollenweider, Peter] Univ Lausanne, Vaudois Univ Hosp Ctr, Dept Internal Med, Lausanne, Switzerland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Palmer, Colin] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Jukema, J. Wouter] Einthoven Lab Expt Vasc Med, Leiden, Netherlands. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Toniolo, Daniela] CNR Inst Mol Genet, Pavia, Italy. [Shuldiner, Alan R.] Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD USA. [Coresh, Josef; Kao, W. Linda] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Van Duijn, Cornelia M.] Netherlands Genom Initiat, Netherlands Consortium Healthy Aging, Leiden, Netherlands. [Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Curhan, Gary C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Karlsburg, Germany. [Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Bochud, Murielle] Univ Lausanne, Vaudois Univ Hosp Ctr, Univ Inst Social & Prevent Med, Lausanne, Switzerland. [Heid, Iris M.] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol, Boston, MA 02115 USA. RP Parsa, A (reprint author), Univ Maryland, Sch Med, Div Nephrol, 685 W Baltimore St,MSTF 314, Baltimore, MD 21201 USA. EM aparsa@medicine.umaryland.edu RI Kronenberg, Florian/B-1736-2008; Aulchenko, Yurii/M-8270-2013; Stengel, Benedicte/G-5730-2015; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; ruggiero, daniela/K-5638-2016; Bochud, Murielle/A-3981-2010; Hayward, Caroline/M-8818-2016; Ellinghaus, David/G-4467-2012; Franke, Andre/B-2151-2010; Boban, Mladen/E-2777-2017; Feitosa, Mary/K-8044-2012; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Colaus, PsyColaus/K-6607-2013; Nothlings, Ute/B-2713-2010; Yang, Qiong/G-5438-2014; Aspelund, Thor/C-5983-2008; Pramstaller, Peter/C-2357-2008; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; HELMER, Catherine/I-6581-2015; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011 OI Mitchell, Braxton/0000-0003-4920-4744; Johansson, Asa/0000-0002-2915-4498; Bergmann, Sven/0000-0002-6785-9034; Dehghan, Abbas/0000-0001-6403-016X; Magi, Reedik/0000-0002-2964-6011; Fuchsberger, Christian/0000-0002-5918-8947; Zgaga, Lina/0000-0003-4089-9703; Wheeler, Heather/0000-0003-1365-9667; Palmer, Colin/0000-0002-6415-6560; Colhoun, Helen/0000-0002-8345-3288; Kronenberg, Florian/0000-0003-2229-1120; Aulchenko, Yurii/0000-0002-7899-1575; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; ruggiero, daniela/0000-0003-3898-7827; Bochud, Murielle/0000-0002-5727-0218; Hayward, Caroline/0000-0002-9405-9550; Franke, Andre/0000-0003-1530-5811; Feitosa, Mary/0000-0002-0933-2410; Thun, Gian Andri/0000-0003-4436-3455; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Aspelund, Thor/0000-0002-7998-5433; Wang, Jie Jin/0000-0001-9491-4898; HELMER, Catherine/0000-0002-5169-7421; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862 FU National Institutes of Health (NIH) [N01AG12100]; National Institute on Aging (NIA) Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NIH [R01AG18728, R01HL088119, U01GM07451804, U01HL072515-06, U01-HL084756, K12RR023250, HHSN268200625226C, HHSN268200782096C]; University of Maryland (MCRDP); University of Maryland General Clinical Research Center [M01RR16500]; Baltimore Veterans Affairs Medical Center Geriatrics Research and Education Clinical Center; Paul Beeson Physician Faculty Scholars in Aging Program; Austrian Science Fund [P20545P05, P13180]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute (NHGRI) [U01HG004402]; NIH Roadmap for Medical Research [UL1RR025005]; NIH; Emmy Noether programme of the German Research Foundation [K03598/2-1]; NIH NIA; NHLBI [N01HC85079, N01HC85086, N01HC35129, N01HC15103, N01HC55222, N01HC75150, N01HC45133, U01HL080295, R01HL087652, 5R01HL08770003, 5R01HL08821502, N01HC25195, R01HL87660, HL043851, HL69757]; National Center for Research Resources grant [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK063491]; Netherlands Organization for Scientific Research; Erasmus Medical Center; Centre for Medical Systems Biology; Netherlands Kidney Foundation; NIDDK [5R01DK07568102, 5R01DK06833603, R01DK058845, DK66574]; Affymetrix contract for genotyping services [N02HL64278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; NIA; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; NIH from Children's Hospital Boston [1 R01DK07578701A1]; German National Genome Research Net NGFN2 and NGFNplus [01GS0823, A3, 01GS0834]; Munich Center of Health Sciences as part of LMUinnovativ; Else Kroner-Fresenius-Stiftung [P48/08//All/08, 2012_A147]; Else Krdner-Fresenius-Stiftung; Regensburg University Medical Center, Germany; University of Ulm, Germany; Else Kroner-Fresenius-Stiftung; KfH Stiftung Praventivmedizin; Doktor Robert Pfleger-Stiftung; German Research Center for Enviromnental Health; German Research Center for Environmental Health; German Federal Ministry of Education and Research; State of Bavaria; University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center; NHGRI [U01HG004402, U01HG004738, U01HG004422, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033]; National Institute of Dental and Craniofacial Research [U01DE018993]; Gene Environment-Association Studies (GENEVA) under the NTH Genes, Environment, and Health Initiative (GEI); NIH GET [U01HG04424]; Johns Hopkins University Center for Inherited Disease Research; NIH GEI [U01HG004438]; National Cancer Institute (NCI) [P01CA087969, P01CA055075]; Medical Research Council UK; Ministry of Science, Education, and Sport of the Republic of Croatia [108-1080315-0302]; Ministry of Health and Department of Educational Assistance; Universities and Research of the Autonomous Province of Bolzano; South Tyrolean Sparkasse Foundation; European Union framework program 6 EUROSPAN project [LSHG-CT-2006018947, LSHG-CT-2006-018947]; Swedish Natural Sciences Research Council; European Union through the EUROSPAN project [LSHG-CT-2006018947]; Foundation for Strategic Research (SSF); Linneaus Centre for Bioinformatics; NCI [P01CA087969, P01CA055075, CA047988]; Chief Scientist Office of the Scottish Government; Royal Society; German Ministry of Education and Research through the National Genome Research Network; Ministry of Science, Commerce, and Transportation of the State of Schleswig-Holstein; DFG "Inflammation at Interfaces" excellence cluster; German Research Council [KFO152]; Adiposity Diseases Integrated Research and Treatment Center [K7-37]; European Community's Seventh Framework Programme, ENGAGE project [HEALTH-F4-2007-201413]; European Commission under Marie Curie Intra-European Fellowship; Netherlands Organization of Scientific Research (NWO) [175-010-2005-011, 911-03-012]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project [050-060-810]; Erasmus Medical Center, Erasmus University; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission (DG XI); Municipality of Rotterdam; German Bundesministerium fuer Forschung und Technology [01-AK803A-H, 01-IG07015G]; NWO (vici) [918-76-619]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare (Erlangen, Germany); Federal State of Mecklenburg-West Pomerania; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; National Foundation for Alzheimer's Disease and Related Disorders; Institut Pasteur de Lille; Centre National de Genotypage; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; MGEN; Institut de la Longevite; Agence Francaise de Securite Sanitaire des Produits de Sante; Aquitaine and Bourgogne Regional Councils; Fondation de France; French Ministry of Research/INSERM "Cohortes et collections de donnees biologiques" programme; Eisai; Australian Research and Development Grants Advisory Committee [1992-94]; Australian National Health and Medical Research Council, Canberra Australia [974159, 211069, 991407, 457349]; Australian National Health and Medical Research Council [512423, 475604, 529912]; Wellcome Trust UK; Wellcome Trust Case Control Consortium 2 [085475/B/08/Z, 085475/08/Z]; Australian National Health and Medical Research Council; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099]; Swiss School of Public Health Plus; Academy of Finland [117797, 121584, 126925]; Social Insurance Institution of Finland; University Hospital Medical funds; Finnish Foundation of Cardiovascular Research; Emil Aaaltonen Foundation; FP7 grants [201413 ENGAGE, 212111 BBMRI, 205419 ECOGENE, 245536 OPENGENE]; Estonian Government [SF0180142s08]; European Union through the European Regional Development Fund, Centre of Excellence in Genomics; NHLBI Family Heart Study; NIH grant [5R01HL08770002]; Wellcome Trust; Telethon; FVG region; Fondo Trieste; European Union [Vasoplus-037254]; Italian Ministry of Universities [FIRB -RBIN064YAT]; Assessorato Ricerca Regione Campania; Ente Parco Nazionale del Cilento e Vallo di Diano; Fondazione Banco di Napoli to M Ciullo; Compagnia di San Paolo (Torino, Italy); Cariplo Fundation (Milano, Italy); Italian Ministry of Health Progetto Finalizzato; AstraZeneca; Italian Ministry of Education, University, and Research [5571/DSPAR/2002, 718/Ric/2005]; Bristol-Myers Squibb; European Union's Seventh Framework Programme [HEALTH-F2-2009-223004]; Netherlands Consortium of Healthy Aging [NGI 05060810]; Federal Office for Forest, Environment, and Landscape; Federal Office of Public Health; Federal Office of Roads and Transport; canton government of Aargau; canton government of Basel-Stadt; canton government of Basel-Land; canton government of Geneva; canton government of Luzern; canton government of Ticino; canton government of Zurich; Swiss Lung League; canton Lung League government of Basel Stadt/Basel Landschaft; canton Lung League government of Geneva; canton Lung League government of Ticino; canton Lung League government of Zurich; Kamillo Eisner Stiftung; Genomics of Lipid-Associated Disorders of the Austrian Genome Research Programme GEN-AU; Ellison Medical Foundation/American Federation for Aging Research postdoctoral fellowship; Stanford Dean's postdoctoral fellowship; NHGRI; NIGMS FX AGES. The Age, Gene/Environment Susceptibility (AGES) study was funded by the National Institutes of Health (NIH) (contract N01AG12100), the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).; Amish Study. The Amish study was supported by NIH grants and contracts (R01AG18728, Amish Longevity Study; R01HL088119, Amish Calcification Study; U01GM07451804, Pharmacogenomics of Anti-Platelet Intervention [PAPI] Study; U01HL072515-06, Heredity and Phenotype Interaction [HAPI] Study; and U01-HL084756 and K12RR023250), as well as grants from the University of Maryland (MCRDP grant), University of Maryland General Clinical Research Center (M01RR16500), Baltimore Veterans Affairs Medical Center Geriatrics Research and Education Clinical Center, and the Paul Beeson Physician Faculty Scholars in Aging Program.; ASPS. The Austrian Stroke Prevention Study (ASPS) research reported in this article was funded by grants from the Austrian Science Fund (P20545P05 and P13180). The Medical University of Graz supported the databank of the ASPS.; ARIC. The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) (contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, and R01HL086694), the National Human Genome Research Institute (NHGRI) (U01HG004402), and the NIH (HHSN268200625226C). Infrastructure was partly supported by a component of the NIH and NIH Roadmap for Medical Research (Grant UL1RR025005). A. K. and C. H. were supported by the Emmy Noether programme of the German Research Foundation (K03598/2-1). The authors thank the staff and participants of the ARIC study for their important contributions.; BLSA. The Baltimore Longitudinal Study of Aging (BLSA) was supported in part by the Intramural Research Program of the NIH NIA.; CHS. The Cardiovascular Health Study (CHS) research reported in this article was supported by the NHLBI (contracts N01HC85079 through N01HC85086, N01HC35129, N01HC15103, N01HC55222, N01HC75150, and N01HC45133; grants U01HL080295 and R01HL087652), with additional contributions from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions is available at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by a National Center for Research Resources grant (M01RR00425) to the Cedars-Sinai General Clinical Research Center genotyping core and a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant (DK063491) to the Southern California Diabetes Endocrinology Research Center.; ERE The Erasmus Rucphen Family (ERF) study was supported by grants from the Netherlands Organization for Scientific Research (Pioneer grant), Erasmus Medical Center, Centre for Medical Systems Biology, and Netherlands Kidney Foundation.; FHS. The Family Heart Study (FHS) work was supported in part by the NHLBI (grants 5R01HL08770003 and 5R01HL08821502 to M. P.) and the NIDDK (5R01DK07568102 and 5R01DK06833603 to I.B.).; Framingham Heart Study. The Framingham Heart Study research reported in this paper was conducted in part using data and resources from the Framingham Heart Study of the NIH NHLBI and the Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by NHLBI Framingham Heart Study contracts (N01HC25195) as well as an Affymetrix contract for genotyping services (N02HL64278). A portion of this research utilized the Linux Cluster for Genetic Analysis funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.; GENOA. The Genetic Epidemiology Network of Arteriopathy (GENOA) research was partially supported by the NHLBI (R01HL87660).; Health ABC. The Health Aging and Body Composition Study (Health ABC) was funded by the NIA. This research was supported by the NIA (contracts N01AG62101, N01AG62103, and N01AG62106). The GWAS was funded by a NIA grant (1R01AG032098-01A1) to Wake Forest University Health Sciences. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to Johns Hopkins University (HHSN268200782096C). This research was supported in part by the Intramural Research Program of the NIH NIA.; KORA. For the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) F3 and F4 studies, the genetic epidemiological work was funded by an NIH subcontract from the Children's Hospital Boston (prime grant 1 R01DK07578701A1 to H. E. W. and I. M. H.), the German National Genome Research Net NGFN2 and NGFNplus (01GS0823 to H. E. W.; WK project A3, 01GS0834), the Munich Center of Health Sciences as part of LMUinnovativ, and by Else Kroner-Fresenius-Stiftung (P48/08//All/08 to C. A. B. and B. K. K. and 2012_A147 to C. A. B. and I. M. H.). The F3 kidney parameter measurements were funded by Else Krdner-Fresenius-Stiftung (to C. A. B. and B. K. K.) and the Regensburg University Medical Center, Germany, and the F4 measurements were funded by the University of Ulm, Germany (to W. K.). Genome-wide genotyping costs in F3 and F4 were funded in part by Else Kroner-Fresenius-Stiftung (to C. A. B. and B. K. K.). De novo genotyping in F3 and F4 was funded by the Else Kroner-Fresenius-Stiftung (C. A. B. and B. K. K.). C. A. B. has received research funding from Else Kroner-Fresenius-Stiftung, KfH Stiftung Praventivmedizin, and Doktor Robert Pfleger-Stiftung. The KORA research platform and the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg studies were initiated and financed by the German Research Center for Enviromnental Health, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, and the State of Bavaria. Genotyping was performed in the Genome Analysis Center of the German Research Center for Environmental Health. The LINUX platform for computation was funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center.; NHS/HPFS. The Nurses' Health Study (NHS)/Health Professionals' Follow-Up Study (HPFS) type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; U01DE018993, all funded by the NHGRI; U01DE018903 from the National Institute of Dental and Craniofacial Research). The study is also funded as part of the Gene Environment-Association Studies (GENEVA) under the NTH Genes, Environment, and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of the Massachusetts Institute of Technology and Harvard University, with funding support from the NIH GET (U01HG04424), as well as the Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH (contract HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (NCI) (P01CA087969 and P01CA055075) and the NIDDK (R01DK058845). The authors thank the staff and participants of the NHS and HPFS for their dedication and commitment.; Korcula. The Korcula study was supported through grants from the Medical Research Council UK (to H. C., A.F.W., and I. R.) and by the Ministry of Science, Education, and Sport of the Republic of Croatia (108-1080315-0302 to I.R.).; MICROS. The MICROS study was supported by the Ministry of Health and Department of Educational Assistance, the Universities and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union framework program 6 EUROSPAN project (contract LSHG-CT-2006018947).; Northern Swedish Population Health Study. The Northern Swedish Population Health Study was supported by grants from the Swedish Natural Sciences Research Council, the European Union through the EUROSPAN project (contract LSHG-CT-2006018947), the Foundation for Strategic Research (SSF), and the Linneaus Centre for Bioinformatics.; NHS. The Nurses' Health Study (NHS) renal function and albuminuria work was supported by a NIDDK grant (DK66574). Additional funding for the current research was provided by the NCI (P01CA087969 and P01CA055075) and the NIDDK (R01DK058845).; ORCADES. The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, and the European Union framework program 6 EUROSPAN project (contract LSHG-CT-2006018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh.; PopGen. The PopGen study was supported by the German Ministry of Education and Research through the National Genome Research Network, and the Ministry of Science, Commerce, and Transportation of the State of Schleswig-Holstein. The project has also received infrastructure support through the DFG "Inflammation at Interfaces" excellence cluster.; SORBS. The SORBS study was funded by grants from the German Research Council (KFO152 to M. S.) and the Adiposity Diseases Integrated Research and Treatment Center (K7-37 to M. S. and A. T.). The authors also thank Dr. Knut Krohn (Microarray Core Facility of the Interdisciplinary Centre for Clinical Research, University of Leipzig, Germany) for providing the genotyping platform. I. P. is funded in part through the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project (grant agreement HEALTH-F4-2007-201413). R. M. acknowledges financial support from the European Commission under a Marie Curie Intra-European Fellowship.; Rotterdam Study-I and Rotterdam Study-II. For the Rotterdam Study-I and Rotterdam Study-II, the GWAS was funded by the Netherlands Organization of Scientific Research (NWO) (175-010-2005-011 and 911-03-012), the Research Institute for Diseases in the Elderly (RIDE2; 014-93-015,), and the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project (050-060-810). The Rotterdam Study is funded by Erasmus Medical Center, Erasmus University, Netherlands Organization for Health Research and Development, 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 XI), and the Municipality of Rotterdam. The Erasmus Computing Grid (Rotterdam, The Netherlands) and the national German MediGRID and Services@MediGRID part of the German D-Grid were both funded by grants from the German Bundesministerium fuer Forschung und Technology (01-AK803A-H and 01-IG07015G) for access to their grid resources. A. D. is supported by an NWO grant (vici, 918-76-619).; SHIP. The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, funded by grants from the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by a grant from the Federal Ministry of Education and Research (03ZIK012) as well as a joint grant from Siemens Healthcare (Erlangen, Germany) and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of Siemens AG.; Vis. The Vis study was supported through grants from the Medical Research Council UK (to H. C., A. F. W., and I. R.), the Ministry of Science, Education, and Sport of the Republic of Croatia (108-1080315-0302 to I. R.), and the European Union framework program 6 EUROSPAN project (contract LSHG-CT-2006-018947).; WGHS. The Women's Genome Health Study (WGHS) is supported by the NHLBI (HL043851 and HL69757) and the NCI (CA047988), the Donald W. Reynolds Foundation, and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen.; 3 City Study. The 3 City Study was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille, and the Centre National de Genotypage. The 3 City Study was performed as part of a collaboration between the Institut National de la Sante et de la Recherche Medicale (INSERM), the Victor Segalen Bordeaux II University, and Sanofi-Synthelabo. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3 City Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise de Securite Sanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM "Cohortes et collections de donnees biologiques" programme. L. G. received an unconditional grant from Eisai.; BMES. The Blue Mountains Eye Study (BMES) has been supported by grants from the Australian Research and Development Grants Advisory Committee (1992-94) and the Australian National Health and Medical Research Council, Canberra Australia (974159, 211069, 991407, and 457349). The GWAS studies of he BMES population are supported by grants from the Australian National Health and Medical Research Council (512423, 475604, 529912) and the Wellcome Trust UK (2008), as part of Wellcome Trust Case Control Consortium 2 (085475/B/08/Z and 085475/08/Z to A. V., P.Mc., P.Mi., ET., P. RE). E. G. H. and J.J.W. are funded by the Australian National Health and Medical Research Council Fellowship Schemes.; CoLaus. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (33CSCO-122661). M.Bo. is supported by the Swiss School of Public Health Plus.; YFS. The Cardiovascular Risk in Young Finns study (YFS) is supported by grants from the Academy of Finland (117797, 121584, and 126925), the Social Insurance Institution of Finland, University Hospital Medical funds to Tampere and Turku University Hospitals, the Finnish Foundation of Cardiovascular Research, and the Emil Aaaltonen Foundation (to T.L.).; University of Tartu Estonian Gene Project. The Estonian Genome Center of the University of Tartu (EGCUT) received support from FP7 grants (201413 ENGAGE, 212111 BBMRI, 205419 ECOGENE, 245536 OPENGENE) and also received targeted financing from Estonian Government (SF0180142s08) and from the European Union through the European Regional Development Fund, in the frame of the Centre of Excellence in Genomics.; FPanHS-II. The research of the FamHS-II was conducted in part using data and resources from the NHLBI Family Heart Study supported in part by an NIH grant (5R01HL08770002).; GoDARTS. For the Genetics of Diabetes Audit and Research Tayside (GoDARTS) study, the Wellcome Trust provides support for the Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection and the informatics support is provided by the Chief Scientist Office, and the Wellcome Trust funded Scottish Health Informatics Programme.; INGI-Carlantino and INGI-FVG. The INGI-Carlantino and INGI-FVG studies were supported by grants from Telethon, FVG region, and Fondo Trieste. The INGI-Cilento study was supported by grants from the European Union (Vasoplus-037254), the Italian Ministry of Universities (FIRB -RBIN064YAT), the Assessorato Ricerca Regione Campania, the Ente Parco Nazionale del Cilento e Vallo di Diano, and the Fondazione Banco di Napoli to M Ciullo. The INGI-Val Borbera Study was supported from Compagnia di San Paolo (Torino, Italy), Cariplo Fundation (Milano, Italy), and Italian Ministry of Health Progetto Finalizzato 2007 and 2009.; JUPITER. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial and the genotyping were supported by AstraZeneca. The Ogliastra Genetic Park (OGP) Replication Study and the OGP Talana study were supported by grants from the Italian Ministry of Education, University (5571/DSPAR/2002), and Research (718/Ric/2005).; PROSPER. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was supported by an investigator-initiated grant from Bristol-Myers Squibb. The study was conducted, analyzed, and reported independently of the company. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013, under Grant Agreement HEALTH-F2-2009-223004). For a part of the genotyping, we received funding from the Netherlands Consortium of Healthy Aging (NGI 05060810).; SAPALDIA. The Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) was supported by grants from the Swiss National Science Foundation (33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, and 4026-028099), the Federal Office for Forest, Environment, and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Zurich, the Swiss Lung League and the canton's Lung League government of Basel Stadt/Basel Landschaft, Geneva, Ticino, and Zurich.; SAPHIR. The Salzburg Atherosclerosis Prevention program in subjects at High Individual Risk (SAPHIR) study was partially supported by a grant from the Kamillo Eisner Stiftung (to B. P.) and by grants from the Genomics of Lipid-Associated Disorders of the Austrian Genome Research Programme GEN-AU (to EK.). For eQTL analysis, H.J.G received support from a Ellison Medical Foundation/American Federation for Aging Research postdoctoral fellowship and a Stanford Dean's postdoctoral fellowship. H. E. W. and S. K. K. were supported by grants from the NIA, NHGRI, and NIGMS. NR 32 TC 9 Z9 9 U1 1 U2 23 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 DEC PY 2013 VL 24 IS 12 BP 2105 EP 2117 DI 10.1681/ASN.2012100983 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 277KI UT WOS:000328817300021 PM 24029420 ER PT J AU Mizurini, D Calvo, E Francischetti, I Monteiro, R AF Mizurini, D. Calvo, E. Francischetti, I Monteiro, R. TI Molecular mechanisms involved in the antithrobotic activity of aegyptin, a novel mosquito-derived collagen-binding protein SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Mizurini, D.; Monteiro, R.] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Calvo, E.; Francischetti, I] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD DEC PY 2013 VL 11 SU 3 SI SI BP 67 EP 68 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 265BL UT WOS:000327924600175 ER PT J AU Herman, SEM Sun, X McAuley, EM Hsieh, MM Pittaluga, S Raffeld, M Liu, D Keyvanfar, K Chapman, CM Chen, J Buggy, JJ Aue, G Tisdale, JF Perez-Galan, P Wiestner, A AF Herman, S. E. M. Sun, X. McAuley, E. M. Hsieh, M. M. Pittaluga, S. Raffeld, M. Liu, D. Keyvanfar, K. Chapman, C. M. Chen, J. Buggy, J. J. Aue, G. Tisdale, J. F. Perez-Galan, P. Wiestner, A. TI Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy SO LEUKEMIA LA English DT Article DE ibrutinib; BCR; CLL; xenograft; NF-kappaB; kinase inhibitor ID B-CELL RECEPTOR; FOSTAMATINIB DISODIUM; ANTIGEN RECEPTORS; IN-VIVO; PROLIFERATION; PCI-32765; CLL; ACTIVATION; SURVIVAL; MICROENVIRONMENT AB Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, the B-cell receptor (BCR) and nuclear factor-kappa B (NF-kappa B) pathways are activated in the lymph node (LN) microenvironment. Thus, model systems mimicking tumor-host interactions are important tools to study CLL biology and pathogenesis. We investigated whether the recently established NOD/scid/gamma c(null) (NSG) mouse xenograft model can recapitulate the effects of the human microenvironment. We assessed, therefore, tumor characteristics previously defined in LN-resident CLL cells, including proliferation, and activation of the BCR and NF-kappa B pathways. We found that the murine spleen (SP) microenvironment supported CLL cell proliferation and activation to a similar degree than the human LN, including induction of BCR and NF-kappa B signaling in the xenografted cells. Next, we used this model to study ibrutinib, a Bruton's tyrosine kinase inhibitor in clinical development. Ibrutinib inhibited BCR and NF-kappa B signaling induced by the microenvironment, decreased proliferation, induced apoptosis and reduced the tumor burden in vivo. Thus, our data demonstrate that the SP of xenografted NSG mice can, in part, recapitulate the role of the human LN for CLL cells. In addition, we show that ibrutinib effectively disrupts tumor-host interactions essential for CLL cell proliferation and survival in vivo. C1 [Herman, S. E. M.; Sun, X.; McAuley, E. M.; Hsieh, M. M.; Liu, D.; Keyvanfar, K.; Chapman, C. M.; Chen, J.; Aue, G.; Tisdale, J. F.; Wiestner, A.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Pittaluga, S.; Raffeld, M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Buggy, J. J.] Pharmacyclics Inc, Sunnyvale, CA USA. [Perez-Galan, P.] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Dept Hematooncol, Barcelona, Spain. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM Adrian.Wiestner@nih.gov FU National, Heart, Lung and Blood Institute FX We thank Dr Nalini Raghavachari for her assistance setting up the Taqman microfluidics cards, Dr Zu Xi Yu and the NHLBI pathology core for help with slide preparation, and Christina Corsino and the NIAID building 50 animal technicians for their assistance with animal experiments. This research was funded through the Intramural Research Program of the National, Heart, Lung and Blood Institute. NR 48 TC 28 Z9 30 U1 3 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD DEC PY 2013 VL 27 IS 12 BP 2311 EP 2321 DI 10.1038/leu.2013.131 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 272KX UT WOS:000328460600006 PM 23619564 ER PT J AU Zhao, X Lwin, T Zhang, X Huang, A Wang, J Marquez, VE Chen-Kiang, S Dalton, WS Sotomayor, E Tao, J AF Zhao, X. Lwin, T. Zhang, X. Huang, A. Wang, J. Marquez, V. E. Chen-Kiang, S. Dalton, W. S. Sotomayor, E. Tao, J. TI Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity SO LEUKEMIA LA English DT Article DE B-cell lymphoma; MYC; EZH2; miRNA-26a; survival; clonogenicity ID NON-HODGKIN-LYMPHOMA; MANTLE CELL; C-MYC; SELECTIVE-INHIBITION; THERAPEUTIC STRATEGY; SOMATIC MUTATIONS; BET BROMODOMAINS; TRANSGENIC MICE; DOWN-REGULATION; EZH2 AB c-MYC (hereafter MYC) overexpression has been recognized in aggressive B-cell lymphomas and linked to adverse prognosis. MYC activation results in widespread repression of micro-RNA (miRNA) expression and associated with lymphoma aggressive progression. Our recent study identified a MYC-miRNA-EZH2 feed-forward loop linking overexpression of MYC, EZH2 and miRNA repression. Here, using a novel small-molecule BET bromodomain inhibitor, JQ1, and the EZH2 inhibitor, DZNep, we demonstrated that combined treatment of JQ1 and DZNep cooperatively disrupted MYC activation, resulting in a greater restoration of miR-26a expression and synergistically suppressed lymphoma growth and clonogenicity in aggressive lymphoma cells. Furthermore, CHIP assay demonstrated that MYC recruited EZH2 to miR-26a promoter and cooperatively repressed miR-26a expression in aggressive lymphoma cell lines, as well as primary lymphoma cells. Loss-or gain-of-function approaches revealed that miR-26a functioned as a tumor suppressor miRNA and mediated the combinatorial effects of JQ1 and DZNep. These findings represent a novel promising approach for silencing MYC-miRNA-EZH2 amplification loop for combinatorial therapy of aggressive B-cell lymphomas. C1 [Zhao, X.; Lwin, T.; Zhang, X.; Huang, A.; Wang, J.; Dalton, W. S.; Sotomayor, E.; Tao, J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33612 USA. [Zhao, X.; Lwin, T.; Zhang, X.; Huang, A.; Wang, J.; Dalton, W. S.; Sotomayor, E.; Tao, J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Expt Therapeut Program, Tampa, FL 33612 USA. [Zhang, X.; Wang, J.] Tianjin Canc Hosp, Dept Immunol & Surg, Tianjin, Peoples R China. [Marquez, V. E.] NCI, Chem Biol Lab, Frederick Natl Lab Canc Res, CCR,NIH, Frederick, MD 21701 USA. [Chen-Kiang, S.] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. RP Tao, J (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, MCC LAB 2071,12902 Magnolia Dr, Tampa, FL 33612 USA. EM Jianguo.Tao@moffitt.org FU National Cancer Institutes [R01 CA137123]; Maher Fund; Lymphoma Research Foundation; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from the National Cancer Institutes (R01 CA137123, to JT), Maher Fund (to JT) and Lymphoma Research Foundation (to JT), and supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to VM). JQ1 was kindly provided by James E Bradner (Boston, MA, USA), and DZNep was kindly provided by Victor E Marquez (Frederick, MD, USA). NR 37 TC 49 Z9 54 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD DEC PY 2013 VL 27 IS 12 BP 2341 EP 2350 DI 10.1038/leu.2013.94 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 272KX UT WOS:000328460600009 PM 23538750 ER PT J AU Denny, JC Bastarache, L Ritchie, MD Carroll, RJ Zink, R Mosley, JD Field, JR Pulley, JM Ramirez, AH Bowton, E Basford, MA Carrell, DS Peissig, PL Kho, AN Pacheco, JA Rasmussen, LV Crosslin, DR Crane, PK Pathak, J Bielinski, SJ Pendergrass, SA Xu, H Hindorff, LA Li, RL Manolio, TA Chute, CG Chisholm, RL Larson, EB Jarvik, GP Brilliant, MH McCarty, CA Kullo, IJ Haines, JL Crawford, DC Masys, DR Roden, DM AF Denny, Joshua C. Bastarache, Lisa Ritchie, Marylyn D. Carroll, Robert J. Zink, Raquel Mosley, Jonathan D. Field, Julie R. Pulley, Jill M. Ramirez, Andrea H. Bowton, Erica Basford, Melissa A. Carrell, David S. Peissig, Peggy L. Kho, Abel N. Pacheco, Jennifer A. Rasmussen, Luke V. Crosslin, David R. Crane, Paul K. Pathak, Jyotishman Bielinski, Suzette J. Pendergrass, Sarah A. Xu, Hua Hindorff, Lucia A. Li, Rongling Manolio, Teri A. Chute, Christopher G. Chisholm, Rex L. Larson, Eric B. Jarvik, Gail P. Brilliant, Murray H. McCarty, Catherine A. Kullo, Iftikhar J. Haines, Jonathan L. Crawford, Dana C. Masys, Daniel R. Roden, Dan M. TI Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data SO NATURE BIOTECHNOLOGY LA English DT Article ID RISK; VARIANTS; DISEASES; BIOBANK; TRAITS; TOOL; METAANALYSIS; PHENOTYPES; MELANOMA AB Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for a human disease; many of these associations require further study to replicate the results. Here we report the first c large-scale application of the phenome-wide association "study (PheWAS) paradigm within electronic medical records E (EMRs), an unbiased approach to replication and discovery. v that interrogates relationships between targeted genotypes 1s and multiple phenotypes. We scanned for associations z between 3,144 single-nucleotide polymorphisms (previously N implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 x 10(-6) (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease. C1 [Denny, Joshua C.; Mosley, Jonathan D.; Ramirez, Andrea H.; Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Denny, Joshua C.; Bastarache, Lisa; Carroll, Robert J.; Zink, Raquel] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA. [Ritchie, Marylyn D.; Pendergrass, Sarah A.] Penn State Univ, Dept Biochem & Mol Biol, Ctr Syst Genom, University Pk, PA 16802 USA. [Field, Julie R.; Pulley, Jill M.; Bowton, Erica; Basford, Melissa A.] Vanderbilt Univ, Sch Med, Res Off, Nashville, TN 37212 USA. [Pulley, Jill M.] Vanderbilt Univ, Sch Med, Dept Med Adm, Nashville, TN 37212 USA. [Carrell, David S.; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [Peissig, Peggy L.] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Kho, Abel N.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Pacheco, Jennifer A.] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Rasmussen, Luke V.] Northwestern Univ, Dept Preventat Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Crosslin, David R.; Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Crane, Paul K.; Jarvik, Gail P.] Univ Washington, Dept Med, Seattle, WA USA. [Pathak, Jyotishman; Chute, Christopher G.] Mayo Clin, Div Biomed Informat, Rochester, MN USA. [Pathak, Jyotishman; Jarvik, Gail P.] Mayo Clin, Div Stat, Rochester, MN USA. [Bielinski, Suzette J.] Mayo Clin, Div Epidemiol, Rochester, MN USA. [Xu, Hua] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA. [Li, Rongling; Manolio, Teri A.] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Chisholm, Rex L.] Northwestern Univ, Dept Cell & Mol Biol, Feinberg Sch Med, Chicago, IL 60611 USA. [Brilliant, Murray H.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Haines, Jonathan L.; Crawford, Dana C.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37212 USA. [Masys, Daniel R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. RP Denny, JC (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. EM josh.denny@vanderbilt.edu RI Crane, Paul/C-8623-2014; Jarvik, Gail/N-6476-2014; Bielinski, Suzette/A-2238-2009; OI Jarvik, Gail/0000-0002-6710-8708; Bielinski, Suzette/0000-0002-2905-5430; Rasmussen, Luke/0000-0002-4497-8049; Crane, Paul/0000-0003-4278-7465 FU eMERGE Network; National Human Genome Research Institute (NHGRI); National Institute of General Medical Sciences (NIGMS) (Group Health Cooperative/University of Washington) [U01-HG004610, U01-HG006375]; Marshfield Clinic [U01-HG004608]; Mayo Clinic [U01-HG004599, U01-HG006379]; Northwestern University [U01-HG004609, U01-HG006388]; Essentia Institute of Rural Health/Marshfield Clinic [U01-HG006389]; Vanderbilt University [U01-HG004603, U01-HG006378]; Vanderbilt University serving as the Coordinating Center [U01-HG006385]; NHGRI [U01-HG004424]; Johns Hopkins University, Center for Inherited Disease Research [U01-HG004438]; NIGMS [RC2-GM092318]; National Library of Medicine [R01-LM010685]; National Center for Advancing Translational Sciences [UL1TR000427, UL1 RR024975, 2 UL1 TR000445] FX This work was supported by the eMERGE Network, initiated and funded by the National Human Genome Research Institute (NHGRI), with additional funding from the National Institute of General Medical Sciences (NIGMS), through the following grants: U01-HG004610 and U01-HG006375 (Group Health Cooperative/University of Washington); U01-HG004608 (Marshfield Clinic); U01-HG004599 and U01-HG006379 (Mayo Clinic); U01-HG004609 and U01-HG006388 (Northwestern University); U01-HG006389 (Essentia Institute of Rural Health/Marshfield Clinic); U01-HG004603 and U01-HG006378 (Vanderbilt University); and U01-HG006385 (Vanderbilt University serving as the Coordinating Center). Funding support for eMERGE genotyping was provided by NHGRI through the grants: U01-HG004424 (The Broad Institute) and U01-HG004438 (Johns Hopkins University, Center for Inherited Disease Research). Replication genotypes were derived from a pharmacogenomics resource supported by NIGMS RC2-GM092318. Development of the PheWAS method is also supported by R01-LM010685 from the National Library of Medicine. BioVU received and continues to receive support through the National Center for Research Resources UL1 RR024975, which is now the National Center for Advancing Translational Sciences, 2 UL1 TR000445. Additional support for this work at the University of Washington was partially provided by the National Center for Advancing Translational Sciences grant UL1TR000427. NR 48 TC 130 Z9 131 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD DEC PY 2013 VL 31 IS 12 BP 1102 EP + DI 10.1038/nbt.2749 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 269OW UT WOS:000328251900023 PM 24270849 ER PT J AU Chuang, PY Hsieh, CH Addullah, B AF Chuang, Pei-Ying Hsieh, Ching Hsiu Addullah, Bashira TI Nursing Genomics Its Role in Health Trajectory SO NURSING CLINICS OF NORTH AMERICA LA English DT Article DE Human genomics; Nursing science; Essential competencies; Clinical practice; Bioscience skills ID DNA METHYLATION; PROSTATE-CANCER; GENETICS; EDUCATION; COMPETENCES; CURRICULA; DISEASE; PROJECT; RECOMMENDATIONS; HYBRIDIZATION AB The human genome, which is the complete set of human genetic information, significantly contributes to the health of an individual; it can lead to single or complex medical conditions (including cancer and heart disease) also affected by environmental and behavioral risk factors. To date, the challenges related to human genomics and nursing science focus on the following areas: (1) curriculum application, (2) advanced clinical practice in specific fields, and (3) hands-on bioscience laboratory skills. This review article summarizes current efforts and addresses critical components in nursing genomics. C1 [Chuang, Pei-Ying] Univ Texas Hlth Sci Ctr Houston, Sch Nursing, Houston, TX 77030 USA. [Hsieh, Ching Hsiu] Chang Gung Univ Sci & Technol, Dept Nursing, Putzu City 61363, Chiayi County, Taiwan. [Addullah, Bashira] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20814 USA. RP Chuang, PY (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Nursing, 6901 Bertner Ave,Room 613, Houston, TX 77030 USA. EM peiyingc@yahoo.com NR 112 TC 0 Z9 0 U1 0 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0029-6465 EI 1558-1357 J9 NURS CLIN N AM JI Nurs. Clin. North Am. PD DEC PY 2013 VL 48 IS 4 BP 523 EP + DI 10.1016/j.cnur.2013.08.003 PG 35 WC Nursing SC Nursing GA 278VD UT WOS:000328917100003 PM 24295186 ER PT J AU Tronnes, H Wilcox, AJ Lie, RT Markestad, T Moster, D AF Tronnes, Havard Wilcox, Allen J. Lie, Rolv Terje Markestad, Trond Moster, Dag TI The association of preterm birth with severe asthma and atopic dermatitis: a national cohort study SO PEDIATRIC ALLERGY AND IMMUNOLOGY LA English DT Article DE premature birth; atopic dermatitis; asthma; pregnancy complications; gestational age ID CHILDHOOD ASTHMA; GESTATIONAL-AGE; RISK-FACTORS; CHILDREN; PREGNANCY; ECZEMA; SCHOOLCHILDREN; PREVALENCE; PREMATURE; DISEASE AB BackgroundAsthma and atopic dermatitis are both regarded as atopic diseases. Being born too early is associated with increased risk of asthma, but some studies have indicated that the opposite might be true for atopic dermatitis. We explored in more detail the associations between preterm birth, asthma, and atopic dermatitis. MethodsWe analyzed data from Norwegian registries with prospectively collected data. All live births in Norway from 1967 through 2001 were followed through 2005 by linking the Medical Birth Registry of Norway to the National Insurance Scheme and to Statistics Norway. Only severe asthma and atopic dermatitis were registered in the National Insurance Scheme. ResultsOf a total of 1,760,821 children, we identified 9,349 cases (0.5%) with severe asthma and 6,930 cases (0.4%) with severe atopic dermatitis. Compared with children born at term (37-41wk gestation), preterm birth was associated with increased odds for severe asthma (odds ratio (OR) 1.7 (95% confidence interval (CI): 1.6-1.8) for 32-36wk gestation and OR 3.6 (95% CI: 3.1-4.2) for 23-31wk) and decreased odds for severe atopic dermatitis (OR 0.9 (95% CI: 0.8-1.0) for 32-36wk gestation and OR 0.7 (95% CI: 0.5-1.0) for 23-31wk). Adjustment for perinatal and socio-demographic factors weakened the association between gestational age and severe asthma, while slightly strengthening the association between gestational age and severe atopic dermatitis. ConclusionsPreterm birth was associated with increased risk of severe asthma and decreased risk of severe atopic dermatitis. image= 12 years was assessed by computer-assisted self-interviewing methods. Respondents' self-reported race/ethnicity, age, gender, household income, government assistance, county type, residential stability, major depressive episode, history of being arrested, tobacco use, and alcohol use were examined as correlates. We stratified the analysis by race/ethnicity and used logistic regression to estimate odds of drug use. Results: Prevalence of past-year marijuana use among Whites increased from 10.7% in 2005 to 11.6-11.8% in 2009-2011 (P < 0.05). There were no significant yearly changes in drug use prevalences among Asian-Americans, NHs/PIs, and mixed-race people; but use of any drug, especially marijuana, was prevalent among NHs/PIs and mixed-race people (21.2% and 23.3%, respectively, in 2011). Compared with Asian-Americans, NHs/PIs had higher odds of marijuana use, and mixed-race individuals had higher odds of using marijuana, cocaine, hallucinogens, stimulants, sedatives, and tranquilizers. Compared with Whites, mixed-race individuals had greater odds of any drug use, mainly marijuana, and NHs/PIs resembled Whites in odds of any drug use. Conclusions: Findings reveal alarmingly prevalent drug use among NHs/PIs and mixed-race people. Research on drug use is needed in these rising populations to inform prevention and treatment efforts. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Wu, Li-Tzy; Blazer, Dan G.; Swartz, Marvin S.; Burchett, Bruce] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Brady, Kathleen T.] Med Univ S Carolina, Clin Neurosci Div, Charleston, SC 29425 USA. [NIDA AAPI Workgrp] NIDA, Asian Amer & Pacific Islander Researchers & Schol, Bethesda, MD 20892 USA. RP Wu, LT (reprint author), Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Med Ctr, Box 3903, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU U.S. National Institute on Drug Abuse of the National Institutes of Health [HHSN271200900499P, R01DA019623, R01DA019901, R33DA027503]; Duke University Department of Psychiatry and Behavioral Sciences FX This work was made possible by research support from the U.S. National Institute on Drug Abuse of the National Institutes of Health (HHSN271200900499P, R01DA019623, R01DA019901, and R33DA027503 to Li-Tzy Wu) and by Duke University Department of Psychiatry and Behavioral Sciences. The sponsoring agency had no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors. NR 44 TC 7 Z9 7 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD DEC 1 PY 2013 VL 133 IS 2 BP 360 EP 367 DI 10.1016/j.drugalcdep.2013.06.008 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 269KT UT WOS:000328240900009 PM 23890491 ER PT J AU Belkaid, Y Artis, D AF Belkaid, Yasmine Artis, David TI Immunity at the Barriers Preface SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Editorial Material DE Gastrointestinal tract; Lung; Mucosal immunity; Skin ID DENDRITIC CELLS; INNATE C1 [Belkaid, Yasmine] NIAID, Program Barrier Immun & Repair, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Artis, David] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Artis, David] Perelman Sch Med, Inst Immunol, Philadelphia, PA USA. [Artis, David] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov; dartis@mail.med.upenn.edu FU Intramural NIH HHS [Z01 AI001061-01]; NIAID NIH HHS [AI061570, AI087990, AI097333, R01 AI074878, R01 AI102942, R01 AI097333, AI074878, AI095466, AI095608, AI095776, AI102942, R01 AI061570, R21 AI087990, U01 AI095608, U01 AI095776, R01 AI095466] NR 13 TC 4 Z9 4 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2013 VL 43 IS 12 BP 3096 EP 3097 DI 10.1002/eji.201344133 PG 2 WC Immunology SC Immunology GA 266YX UT WOS:000328061600005 PM 24166766 ER PT J AU Hillyer, P Raviv, N Gold, DM Dougherty, D Liu, J Johnson, TR Graham, BS Rabin, RL AF Hillyer, Philippa Raviv, Nataly Gold, Doria M. Dougherty, Danielle Liu, Jie Johnson, Teresa R. Graham, Barney S. Rabin, Ronald L. TI Subtypes of type I IFN differentially enhance cytokine expression by suboptimally stimulated CD4(+) T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD4(+) Tcells; Cytokine expression; IFNs; Memory cells; Th cells ID RESPIRATORY SYNCYTIAL VIRUS; HUMAN INTERFERON-ALPHA; DENDRITIC CELLS; EFFECTOR FUNCTIONS; CD154 EXPRESSION; C-MAF; RESPONSES; INFECTION; MEMORY; INTERLEUKIN-10 AB Human type I interferons (IFNs) include IFN- and 12 subtypes of IFN-. During viral infection, infiltrating memory CD4(+) T cells are exposed to IFNs, but their impact on memory T-cell function is poorly understood. To address this, we pretreated PBMCs with different IFNs for 16 h before stimulation with Staphylococcus aureus enterotoxin B and measured cytokine expression by flow cytometry. IFN-8 and -10 most potently enhanced expression of IFN-, IL-2, and IL-4. Potency among the subtypes differed most at doses between 10 and 100 U/mL. While enhancement of IL-2 and IL-4 correlated with the time of preincubation with type I IFN, IFN- production was enhanced best when IFN- was added immediately preceding or simultaneously with T-cell stimulation. Comparison of T-cell responses to multiple doses of Staphylococcus aureus enterotoxin B and to peptide libraries from RSV or CMV demonstrated that IFN- best enhanced cytokine expression when CD4(+) T cells were suboptimally stimulated. We conclude that type I IFNs enhance Th1 and Th2 function with dose dependency and subtype specificity, and best when T-cell stimulation is suboptimal. While type I IFNs may beneficially enhance CD4(+) T-cell memory responses to vaccines or viral pathogens, they may also enhance the function of resident Th2 cells and exacerbate allergic inflammation. C1 [Hillyer, Philippa; Raviv, Nataly; Gold, Doria M.; Dougherty, Danielle; Rabin, Ronald L.] US FDA, Lab Immunobiochem, Div Bacterial Parasit & Allergen Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Liu, Jie; Johnson, Teresa R.; Graham, Barney S.] NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Rabin, RL (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Bldg 29,Room 203A,29 Lincoln Dr, Bethesda, MD 20892 USA. EM ronald.rabin@fda.hhs.gov FU CBER FX The authors thank Howard Mostowski for performing flow-activated cell sorting, Joanne Yu for antibody conjugation, Rachel Shepard for help with preparing the figures, Joe Casazza for the CMV pp65 peptide library, and Dragana Jankovic, Jack Ragheb, and Calman Prussin for helpful discussion in preparing the manuscript. This project was supported by CBER intramural funds. NR 62 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2013 VL 43 IS 12 BP 3197 EP 3208 DI 10.1002/eji.201243288 PG 12 WC Immunology SC Immunology GA 266YX UT WOS:000328061600018 PM 24030809 ER PT J AU Nakaya, N Sultana, A Munasinghe, J Cheng, AW Mattson, MP Tomarev, SI AF Nakaya, Naoki Sultana, Afia Munasinghe, Jeeva Cheng, Aiwu Mattson, Mark P. Tomarev, Stanislav I. TI Deletion in the N-terminal half of olfactomedin 1 modifies its interaction with synaptic proteins and causes brain dystrophy and abnormal behavior in mice SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Olfactomedin 1; AMPA receptor; Neurobiology; Proteomics; Cell signaling; Mouse; Anxiety behavior; Olfactory defects ID OPEN-ANGLE GLAUCOMA; PAIR-RULE GENE; IN-VIVO; RECEPTOR; CALCIUM; IDENTIFICATION; EXPRESSION; DISTINCT; DOMAIN; AMPA AB Olfactomedin 1 (Olfm1) is a secreted glycoprotein that is preferentially expressed in neuronal tissues. Here we show that deletion of exons 4 and 5 from the Olfm1 gene, which encodes a 52 amino acid long region in the N-terminal part of the protein, increased neonatal death and reduced body weight of surviving homozygous mice. Magnetic resonance imaging analyses revealed reduced brain volume and attenuated size of white matter tracts such as the anterior commissure, corpus callosum, and optic nerve. Adult Olfm1 mutant mice demonstrated abnormal behavior in several tests including reduced marble digging, elevated plus maze test, nesting activity and latency on balance beam tests as compared with their wild-type littermates. The olfactory system was both structurally and functionally disturbed by the mutation in the Olfml gene as shown by functional magnetic resonance imaging analysis and a smell test. Deficiencies of the olfactory system may contribute to the neonatal death and loss of body weight of Olfm1 mutant. Shotgun proteomics revealed 59 candidate proteins that coprecipitated with wild-type or mutant Olfml proteins in postnatal day 1 brain. Olfm1-binding targets included GluR2, Cav2.1, teneurin-4 and Kidins220. Modified interaction of Olfml with binding targets led to an increase in intracellular Ca2+ concentration and activation of ERK1/2, MEK1 and CaMKII in the hippocampus and olfactory bulb of If-TO mutant mice compared with their wild-type littermates. Excessive activation of the CaMKII and Ras-ERK pathways in the Olfm1 mutant olfactory bulb and hippocampus by elevated intracellular calcium may contribute to the abnormal behavior and olfactory activity of Olfm1 mutant mice. Published by Elsevier Inc. C1 [Nakaya, Naoki; Sultana, Afia; Tomarev, Stanislav I.] NEI, Gangl Cell Biol Sect, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva] NINDS, In Vivo NMR Ctr, NIH, Bethesda, MD 20892 USA. [Cheng, Aiwu; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Tomarev, SI (reprint author), NEI, Gangl Cell Biol Sect, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM nakayan@nei.nih.gov; sultana@nei.nih.gov; munasinj@ninds.nih.gov; chengai@grc.nia.nih.gov; mattsonm@grc.nia.nih.gov; tomarevs@nei.nih.gov FU Intramural Research Programs of the National Eye Institute, National Institute of Neurological Disorders; National Aging Institute National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Eye Institute, National Institute of Neurological Disorders, and National Aging Institute - National Institutes of Health. NR 56 TC 6 Z9 6 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD DEC PY 2013 VL 250 BP 205 EP 218 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 270FZ UT WOS:000328305600022 PM 24095980 ER PT J AU Wellman, CL Camp, M Jones, VM MacPherson, KP Ihne, J Fitzgerald, P Maroun, M Drabant, E Bogdan, R Hariri, AR Holmes, A AF Wellman, Cara L. Camp, Marguerite Jones, V. Morgan MacPherson, Kathryn P. Ihne, Jessica Fitzgerald, Paul Maroun, Mouna Drabant, Emily Bogdan, Ryan Hariri, Ahmad R. Holmes, Andrew TI Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Basolateral amygdala; Medial prefrontal cortex; Fear conditioning; Serotonin; FEV ID TRANSPORTER KNOCKOUT MICE; SEROTONIN TRANSPORTER; STRAIN DIFFERENCES; BASOLATERAL AMYGDALA; MOLECULAR-GENETICS; CONDITIONED FEAR; BRAIN-SEROTONIN; CANDIDATE GENE; STRESS; EXTINCTION AB Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive P knockout (KO) causes major loss of serotonin neurons and forebrain serotonin availability, and behavioral abnormalities. We phenotyped Pet-1 KO mice for fear conditioning and extinction, and on a battery of assays for anxiety- and depression-related behaviors. Morphology of Golgi-stained neurons in basolateral amygdala (BLA) and prelimbic cortex was examined. Using human imaging genetics, a common variant (rs860573) in the PET-1 (FEY) gene was tested for effects on threat-related amygdala reactivity and psychopathology in 88 Asian-ancestry subjects. Pet-1 KO mice exhibited increased acquisition and expression of fear, and elevated fear recovery following extinction, relative to wild-type (WT). BLA dendrites of Pet-1 KO mice were significantly longer than in WT. Human PET-1 variation associated with differences in amygdala threat processing and psychopathology. This novel evidence for the role of Pet-1 in fear processing and dendritic organization of amygdala neurons and in human amygdala threat processing extends a growing literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation via effects on structure and function of underlying corticolimbic circuitry. (C) 2013 Elsevier Inc. All rights reserved. C1 [Wellman, Cara L.; Jones, V. Morgan] Indiana Univ, Ctr Integrat Study Anim Behav, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. [Camp, Marguerite; MacPherson, Kathryn P.; Ihne, Jessica; Fitzgerald, Paul; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Maroun, Mouna] Univ Haifa, Fac Nat Sci, Dept Neurobiol, IL-31999 Haifa, Israel. [Drabant, Emily] 23&Me, Mountain View, CA USA. [Bogdan, Ryan; Hariri, Ahmad R.] Duke Univ, Lab NeuroGenet, Dept Psychol & Neurosci, Inst Genome Sci & Policy, Durham, NC USA. RP Wellman, CL (reprint author), Indiana Univ, 1101 E 10th St, Bloomington, IN 47405 USA. EM wellmanc@indiana.edu OI Bogdan, Ryan/0000-0002-1430-1045; Reed, Jessica/0000-0003-0550-7284 FU US-Israel Binational Science Foundation [2007096]; Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse [Z01-AA000411]; Duke University FX This work was supported by the US-Israel Binational Science Foundation (grant number 2007096 to AH, CLW, MM); the Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse (Z01-AA000411 to AH), and Duke University. NR 74 TC 9 Z9 9 U1 1 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 DEC PY 2013 VL 250 BP 260 EP 269 DI 10.1016/j.expneurol.2013.09.025 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 270FZ UT WOS:000328305600028 PM 24100022 ER PT J AU Dalal, M Jacobs-El, N Nicholson, B Tuo, J Chew, E Chan, CC Nussenblatt, R Ferris, F Meyerle, C AF Dalal, Monica Jacobs-El, Naima Nicholson, Benjamin Tuo, Jingsheng Chew, Emily Chan, Chi-Chao Nussenblatt, Robert Ferris, Frederick Meyerle, Catherine TI Subconjunctival Palomid 529 in the treatment of neovascular age-related macular degeneration SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE Akt/mTOR; Choroidal neovascularization; Neovascular age-related macular degeneration; Palomid 529 ID ANGIOGENESIS; RAPAMYCIN; INHIBITOR; NLRP3; CELLS AB Recent evidence suggests that neovascular age-related macular degeneration (AMD) may have an immune mediated component. Palomid 529, an investigational medication involving the immune Akt/mTOR pathway, is unique in dissociating both targets of rapamycin complexes TORC1 and TORC2. This small short-term pilot study assesses the safety of subconjunctival Palomid 529 in the treatment of neovascular AMD, with some limited efficacy information. In this 12-week phase I open-label prospective pilot study, five participants with neovascular age-related macular degeneration that were refractory to intravitreal anti-vascular endothelial growth factor (VEGF) received three serial monthly subconjunctival doses of 1.9 mg Palomid 529. All participants were also offered concomitant monthly intravitreal anti-VEGF injections. Safety was monitored via adverse events recording. Additional outcome measures included visual acuity, optical coherence tomography, fluorescein angiography, indocyanine green angiography and fundus photography. The study drug was well-tolerated by all participants. There were no drug-related adverse events and no serious adverse events. A depot formed at the injection site, which persisted at the end of the study. In these anti-VEGF refractory patients, no clinically important changes in best-corrected visual acuity, fluorescein leakage pattern, choroidal neovascularization size on indocyanine green angiography, or autofluorescence pattern on fundus autofluorescence were observed compared to baseline. The fluid status, assessed with optical coherence tomography showed that central retinal thickness and macular volume remained stable in three participants, while the other two participants clinically progressed. Serial subconjunctival injections of Palomid 529 were well-tolerated and resulted in depot formation. There were no concerns for any ocular or systemic toxicity during this small short-term study. Larger randomized studies are required to determine efficacy. C1 [Dalal, Monica; Tuo, Jingsheng; Chan, Chi-Chao; Nussenblatt, Robert] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Jacobs-El, Naima; Nicholson, Benjamin; Chew, Emily; Ferris, Frederick; Meyerle, Catherine] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Meyerle, C (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, Bldg 10 Magnuson Room 10D40,10 Ctr Dr, Bethesda, MD 20892 USA. EM meyerlec@nei.nih.gov FU Intramural NIH HHS [ZIA EY000418-10] NR 18 TC 8 Z9 8 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X EI 1435-702X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD DEC PY 2013 VL 251 IS 12 BP 2705 EP 2709 DI 10.1007/s00417-013-2375-7 PG 5 WC Ophthalmology SC Ophthalmology GA 270US UT WOS:000328345000006 PM 23689994 ER PT J AU Kessler, RC Colpe, LJ Fullerton, CS Gebler, N Naifeh, JA Nock, MK Sampson, NA Schoenbaum, M Zaslavsky, AM Stein, MB Ursano, RJ Heeringa, SG AF Kessler, Ronald C. Colpe, Lisa J. Fullerton, Carol S. Gebler, Nancy Naifeh, James A. Nock, Matthew K. Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Stein, Murray B. Ursano, Robert J. Heeringa, Steven G. TI Design of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE Suicide; mental disorders; US Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling ID ADOLESCENT SUICIDE; PROPENSITY SCORE; VETERANS; BEHAVIORS; DISORDER; MEN AB The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi-component epidemiological and neurobiological study designed to generate actionable evidence-based recommendations to reduce US Army suicides and increase basic knowledge about the determinants of suicidality. This report presents an overview of the designs of the six components of the Army STARRS. These include: an integrated analysis of the Historical Administrative Data Study (HADS) designed to provide data on significant administrative predictors of suicides among the more than 1.6 million soldiers on active duty in 2004-2009; retrospective case-control studies of suicide attempts and fatalities; separate large-scale cross-sectional studies of new soldiers (i.e. those just beginning Basic Combat Training [BCT], who completed self-administered questionnaires [SAQs] and neurocognitive tests and provided blood samples) and soldiers exclusive of those in BCT (who completed SAQs); a pre-post deployment study of soldiers in three Brigade Combat Teams about to deploy to Afghanistan (who completed SAQs and provided blood samples) followed multiple times after returning from deployment; and a platform for following up Army STARRS participants who have returned to civilian life. Department of Defense/Army administrative data records are linked with SAQ data to examine prospective associations between self-reports and subsequent suicidality. The presentation closes with a discussion of the methodological advantages of cross-component coordination. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Kessler, Ronald C.; Sampson, Nancy A.; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Fullerton, Carol S.; Naifeh, James A.; Ursano, Robert J.] Univ Sch Med, Ctr Study Traumat Stress, Dept Psychiat, Uniformed Serv, Bethesda, MD USA. [Gebler, Nancy; Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM NCS@hcp.med.harvard.edu FU US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH); Department of the Army [U01MH087981] FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the Department of Defense. NR 25 TC 30 Z9 30 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1049-8931 EI 1557-0657 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD DEC PY 2013 VL 22 IS 4 SI SI BP 267 EP 275 DI 10.1002/mpr.1401 PG 9 WC Psychiatry SC Psychiatry GA 266BP UT WOS:000327997600001 PM 24318217 ER PT J AU Heeringa, SG Gebler, N Colpe, LJ Fullerton, CS Hwang, I Kessler, RC Naifeh, JA Nock, MK Sampson, NA Schoenbaum, M Zaslavsky, AM Stein, MB Ursano, RJ AF Heeringa, Steven G. Gebler, Nancy Colpe, Lisa J. Fullerton, Carol S. Hwang, Irving Kessler, Ronald C. Naifeh, James A. Nock, Matthew K. Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Stein, Murray B. Ursano, Robert J. TI Field procedures in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE suicide; mental disorders; US Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling ID SEROTONIN TRANSPORTER BINDING; DEPRESSED SUICIDE ATTEMPTERS; ADRENERGIC-RECEPTOR BINDING; OXIDASE-A GENE; IMPULSIVE BEHAVIOR; MAJOR DEPRESSION; MENTAL-HEALTH; VICTIMS; POLYMORPHISM; BRAIN AB The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi-component epidemiological and neurobiological study of unprecedented size and complexity designed to generate actionable evidence-based recommendations to reduce US Army suicides and increase basic knowledge about determinants of suicidality by carrying out coordinated component studies. A number of major logistical challenges were faced in implementing these studies. The current report presents an overview of the approaches taken to meet these challenges, with a special focus on the field procedures used to implement the component studies. As detailed in the paper, these challenges were addressed at the onset of the initiative by establishing an Executive Committee, a Data Coordination Center (the Survey Research Center [SRC] at the University of Michigan), and study-specific design and analysis teams that worked with staff on instrumentation and field procedures. SRC staff, in turn, worked with the Office of the Deputy Under Secretary of the Army (ODUSA) and local Army Points of Contact (POCs) to address logistical issues and facilitate data collection. These structures, coupled with careful fieldworker training, supervision, and piloting, contributed to the major Army STARRS data collection efforts having higher response rates than previous large-scale studies of comparable military samples. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Heeringa, Steven G.; Gebler, Nancy] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Fullerton, Carol S.; Naifeh, James A.; Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Sch Med, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD 20814 USA. [Hwang, Irving; Kessler, Ronald C.; Sampson, Nancy A.; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM NCS@hcp.med.harvard.edu FU Department of the Army [U01MH087981]; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the Department of Defense. NR 51 TC 7 Z9 7 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1049-8931 EI 1557-0657 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD DEC PY 2013 VL 22 IS 4 SI SI BP 276 EP 287 DI 10.1002/mpr.1400 PG 12 WC Psychiatry SC Psychiatry GA 266BP UT WOS:000327997600002 PM 24038395 ER PT J AU Kessler, RC Heeringa, SG Colpe, LJ Fullerton, CS Gebler, N Hwang, I Naifeh, JA Nock, MK Sampson, NA Schoenbaum, M Zaslavsky, AM Stein, MB Ursano, RJ AF Kessler, Ronald C. Heeringa, Steven G. Colpe, Lisa J. Fullerton, Carol S. Gebler, Nancy Hwang, Irving Naifeh, James A. Nock, Matthew K. Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Stein, Murray B. Ursano, Robert J. TI Response bias, weighting adjustments, and design effects in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE suicide; mental disorders; US Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling ID MENTAL-HEALTH; SURVEY PARTICIPATION; SEXUAL-BEHAVIOR; DATA-COLLECTION; DRUG-USE; COMBAT; ANONYMITY; DISCLOSURE; IMPACT AB The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi-component epidemiological and neurobiological study designed to generate actionable recommendations to reduce US Army suicides and increase knowledge about determinants of suicidality. Three Army STARRS component studies are large-scale surveys: one of new soldiers prior to beginning Basic Combat Training (BCT; n=50,765 completed self-administered questionnaires); another of other soldiers exclusive of those in BCT (n=35,372); and a third of three Brigade Combat Teams about to deploy to Afghanistan who are being followed multiple times after returning from deployment (n=9421). Although the response rates in these surveys are quite good (72.0-90.8%), questions can be raised about sample biases in estimating prevalence of mental disorders and suicidality, the main outcomes of the surveys based on evidence that people in the general population with mental disorders are under-represented in community surveys. This paper presents the results of analyses designed to determine whether such bias exists in the Army STARRS surveys and, if so, to develop weights to correct for these biases. Data are also presented on sample inefficiencies introduced by weighting and sample clustering and on analyses of the trade-off between bias and efficiency in weight trimming. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Kessler, Ronald C.; Hwang, Irving; Sampson, Nancy A.; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Heeringa, Steven G.; Gebler, Nancy] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [Fullerton, Carol S.; Naifeh, James A.; Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Sch Med, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD 20814 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM NCS@hcp.med.harvard.edu FU Department of the Army [U01MH087981]; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the Department of Defense. NR 29 TC 14 Z9 14 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1049-8931 EI 1557-0657 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD DEC PY 2013 VL 22 IS 4 SI SI BP 288 EP 302 DI 10.1002/mpr.1399 PG 15 WC Psychiatry SC Psychiatry GA 266BP UT WOS:000327997600003 PM 24318218 ER PT J AU Kessler, RC Santiago, PN Colpe, LJ Dempsey, CL First, MB Heeringa, SG Stein, MB Fullerton, CS Gruber, MJ Naifeh, JA Nock, MK Sampson, NA Schoenbaum, M Zaslavsky, AM Ursano, RJ AF Kessler, Ronald C. Santiago, Patcho N. Colpe, Lisa J. Dempsey, Catherine L. First, Michael B. Heeringa, Steven G. Stein, Murray B. Fullerton, Carol S. Gruber, Michael J. Naifeh, James A. Nock, Matthew K. Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Ursano, Robert J. TI Clinical reappraisal of the Composite International Diagnostic Interview Screening Scales (CIDI-SC) in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE Composite International Diagnostic Interview (CIDI); CIDI Screening Scales (CIDI-SC); diagnostic concordance; PTSD checklist (PCL); screening scales; validity ID COMORBIDITY SURVEY REPLICATION; WORLD-HEALTH-ORGANIZATION; DEFICIT HYPERACTIVITY DISORDER; POSTTRAUMATIC-STRESS-DISORDER; BIPOLAR SPECTRUM DISORDER; PSYCHOMETRIC PROPERTIES; PSYCHIATRIC-DISORDERS; MULTIPLE IMPUTATION; GENERAL-POPULATION; MAJOR DEPRESSION AB A clinical reappraisal study was carried out in conjunction with the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) All-Army Study (AAS) to evaluate concordance of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses based on the Composite International Diagnostic Interview Screening Scales (CIDI-SC) and post-traumatic stress disorder (PTSD) checklist (PCL) with diagnoses based on independent clinical reappraisal interviews (Structured Clinical Interview for DSM-IV [SCID]). Diagnoses included: lifetime mania/hypomania, panic disorder, and intermittent explosive disorder; six-month adult attention-deficit/hyperactivity disorder; and 30-day major depressive episode, generalized anxiety disorder, PTSD, and substance (alcohol or drug) use disorder (abuse or dependence). The sample (n=460) was weighted for over-sampling CIDI-SC/PCL screened positives. Diagnostic thresholds were set to equalize false positives and false negatives. Good individual-level concordance was found between CIDI-SC/PCL and SCID diagnoses at these thresholds (area under curve [AUC]=0.69-0.79). AUC was considerably higher for continuous than dichotomous screening scale scores (AUC=0.80-0.90), arguing for substantive analyses using not only dichotomous case designations but also continuous measures of predicted probabilities of clinical diagnoses. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Kessler, Ronald C.; Gruber, Michael J.; Sampson, Nancy A.; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Santiago, Patcho N.; Dempsey, Catherine L.; Fullerton, Carol S.; Naifeh, James A.; Ursano, Robert J.] Uniformed Serv Univ Hlth Sci, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD 20814 USA. [Colpe, Lisa J.; Schoenbaum, Michael] NIMH, Bethesda, MD 20892 USA. [First, Michael B.] Columbia Univ, Dept Psychiat, New York, NY USA. [First, Michael B.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM NCS@hcp.med.harvard.edu FU Department of the Army [U01MH087981]; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Department of the Army, or the Department of Defense. NR 59 TC 15 Z9 15 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1049-8931 EI 1557-0657 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD DEC PY 2013 VL 22 IS 4 SI SI BP 303 EP 321 DI 10.1002/mpr.1398 PG 19 WC Psychiatry SC Psychiatry GA 266BP UT WOS:000327997600004 PM 24318219 ER PT J AU Bottaro, S Lindorff-Larsen, K Best, RB AF Bottaro, Sandro Lindorff-Larsen, Kresten Best, Robert B. TI Variational Optimization of an All-Atom Implicit Solvent Force Field To Match Explicit Solvent Simulation Data SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; PROTEIN-FOLDING THERMODYNAMICS; INHOMOGENEOUS FLUID APPROACH; BETA-HAIRPIN FORMATION; CONTINUUM ELECTROSTATICS; SOLVATION THERMODYNAMICS; NMR-SPECTROSCOPY; ALANINE PEPTIDES; AQUEOUS-SOLUTION; CHEMICAL-SHIFTS AB The development of accurate implicit solvation models with low computational cost is essential for addressing many large-scale biophysical problems. Here, we present an efficient solvation term based on a Gaussian solvent-exclusion model (EEF1) for simulations of proteins in aqueous environment, with the primary aim of having a good overlap with explicit solvent simulations, particularly for unfolded and disordered states as would be needed for multiscale applications. In order to achieve this, we have used a recently proposed coarse-graining procedure based on minimization of an entropy-related objective function to train the model to reproduce the equilibrium distribution obtained from explicit water simulations. Via this methodology, we have optimized both a charge screening parameter and a backbone torsion term against explicit solvent simulations of an alpha-helical and a beta-stranded peptide. The performance of the resulting effective energy function, termed EEF1-SB, is tested with respect to the properties of folded proteins, the folding of small peptides or fast-folding proteins, and NMR data for intrinsically disordered proteins. The results show that EEF-SB provides a reasonable description of a wide range of systems, but its key advantage over other methods tested is that it captures very well the structure and dimensions of disordered or weakly structured peptides. EEF1-SB is thus a computationally inexpensive (similar to 10 times faster than Generalized-Born methods) and transferable approximation for treating solvent effects. C1 [Bottaro, Sandro; Lindorff-Larsen, Kresten] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Bottaro, Sandro] SISSA, I-34014 Trieste, Italy. RP Lindorff-Larsen, K (reprint author), Univ Copenhagen, Dept Biol, Copenhagen, Denmark. EM lindorff@bio.ku.dk; robertbe@helix.nih.gov RI Lindorff-Larsen, Kresten/K-6469-2014; Bottaro, Sandro/A-4141-2015; Best, Robert/H-7588-2016 OI Lindorff-Larsen, Kresten/0000-0002-4750-6039; Bottaro, Sandro/0000-0003-1606-890X; Best, Robert/0000-0002-7893-3543 FU Royal Society University Research Fellowship at Cambridge; National Institute for Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Novo-Nordisk Foundation FX R.B.B. was supported by a Royal Society University Research Fellowship while at Cambridge and by the Intramural Research Program of the National Institute for Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. S.B. and K.L.-L. were supported by a Hallas-Moller stipend from the Novo-Nordisk Foundation. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 90 TC 14 Z9 14 U1 0 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD DEC PY 2013 VL 9 IS 12 BP 5641 EP 5652 DI 10.1021/ct400730n PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 272CI UT WOS:000328437500044 PM 24748852 ER PT J AU Lionakis, MS Swamydas, M Fischer, BG Plantinga, TS Johnson, MD Jaeger, M Green, NM Masedunskas, A Weigert, R Mikelis, C Wan, WZ Lee, CCR Lim, JK Rivollier, A Yang, JC Laird, GM Wheeler, RT Alexander, BD Perfect, JR Gao, JL Kullberg, BJ Netea, MG Murphy, PM AF Lionakis, Michail S. Swamydas, Muthulekha Fischer, Brett G. Plantinga, Theo S. Johnson, Melissa D. Jaeger, Martin Green, Nathaniel M. Masedunskas, Andrius Weigert, Roberto Mikelis, Constantinos Wan, Wuzhou Lee, Chyi-Chia Richard Lim, Jean K. Rivollier, Aymeric Yang, John C. Laird, Greg M. Wheeler, Robert T. Alexander, Barbara D. Perfect, John R. Gao, Ji-Liang Kullberg, Bart-Jan Netea, Mihai G. Murphy, Philip M. TI CX(3)CR1-dependent renal macrophage survival promotes Candida control and host survival SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CHEMOKINE FRACTALKINE; CELL PROLIFERATION; UNITED-STATES; CX(3)CR1; CX3CR1; MICE; INFLAMMATION; MONOCYTES; DIFFERENTIATION; SUSCEPTIBILITY AB Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX(3)CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1(-/-) mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1(-/-) mice was clue to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX(3)CR1 allele CX(3)CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX(3)CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis. C1 [Lionakis, Michail S.; Swamydas, Muthulekha; Fischer, Brett G.] NIAID, Clin Mycol Unit, NIH, Bethesda, MD 20892 USA. [Lionakis, Michail S.; Fischer, Brett G.; Wan, Wuzhou; Lim, Jean K.; Gao, Ji-Liang; Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Lionakis, Michail S.; Swamydas, Muthulekha; Green, Nathaniel M.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Plantinga, Theo S.; Jaeger, Martin; Kullberg, Bart-Jan; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Johnson, Melissa D.; Yang, John C.; Laird, Greg M.; Alexander, Barbara D.; Perfect, John R.] Duke Univ, Sch Med, Div Infect Dis, Durham, NC USA. [Masedunskas, Andrius; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Mikelis, Constantinos] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rivollier, Aymeric] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Wheeler, Robert T.] Univ Maine, Dept Mol & Biomed Sci, Orono, ME USA. RP Lionakis, MS (reprint author), NIH, Bldg 10,Room 11C102,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov; pmm@nih.gov RI Kullberg, Bart Jan/C-8520-2013; Plantinga, Theo/A-6895-2015; Netea, Mihai/N-5155-2014; Jaeger, Martin/H-3359-2015; OI Masedunskas, Andrius/0000-0002-4533-5467; Johnson, Melissa/0000-0002-6606-9460; Wheeler, Robert/0000-0003-3223-7021 FU Division of Intramural Research (DIR), NIAID, NIH; Transition Program in Clinical Research (TPCR) of the DIR, NIAID, NIH; ERC [310372] FX This work was supported by the Division of Intramural Research (DIR), NIAID, NIH, and in part by the Transition Program in Clinical Research (TPCR) of the DIR, NIAID, NIH. M.G. Netea was supported by an ERC Consolidator Grant (no. 310372). The funding source had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Elizabeth Fischer of the Research Technologies Branch, NIAID, for performing the TEM, and the NIAID FACS sorting facility and the Comparative Medicine Branch animal facilities for technical assistance and animal handling. This work was presented in part at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, September 9-12, 2012, and at the 2nd Gordon Research Conference on Immunology of Fungal Infections, Galveston, Texas, January 13-18,2013. NR 46 TC 62 Z9 63 U1 0 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2013 VL 123 IS 12 BP 5035 EP 5051 DI 10.1172/JCI71307 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 263RQ UT WOS:000327826100012 PM 24177428 ER PT J AU Price, JV Haddon, DJ Kemmer, D Delepine, G Mandelbaum, G Jarrell, JA Gupta, R Balboni, I Chakravarty, EF Sokolove, J Shum, AK Anderson, MS Cheng, MH Robinson, WH Browne, SK Holland, SM Baechler, EC Utz, PJ AF Price, Jordan V. Haddon, David J. Kemmer, Dodge Delepine, Guillaume Mandelbaum, Gil Jarrell, Justin A. Gupta, Rohit Balboni, Imelda Chakravarty, Eliza F. Sokolove, Jeremy Shum, Anthony K. Anderson, Mark S. Cheng, Mickie H. Robinson, William H. Browne, Sarah K. Holland, Steven M. Baechler, Emily C. Utz, Paul J. TI Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ANTI-CYTOKINE AUTOANTIBODIES; CELL-ACTIVATING FACTOR; CHRONIC MUCOCUTANEOUS CANDIDIASIS; INTERFERON-REGULATED CHEMOKINES; B-CELLS; ANTICYTOKINE AUTOANTIBODIES; AUTOIMMUNE-DISEASES; SIGNATURE; GAMMA; IMMUNODEFICIENCY AB Autoantibodies against cytokines, chemokines, and growth factors inhibit normal immunity and are implicated in inflammatory autoimmune disease and diseases of immune deficiency. In an effort to evaluate serum from autoimmune and immunodeficient patients for Abs against cytokines, chemokines, and growth factors in a high-throughput and unbiased manner, we constructed a multiplex protein microarray for detection of serum factor-binding Abs and used the microarray to detect autoantibody targets in SLE. We designed a nitrocellulose-surface microarray containing human cytoldnes, chemokines, and other circulating proteins and demonstrated that the array permitted specific detection of serum factor-binding probes. We used the arrays to detect previously described autoantibodies against cytokines in samples from individuals with autoimmune polyenclocrine syndrome type 1 and chronic mycobacterial infection. Serum profiling from individuals with SLE revealed that among several targets, elevated IgG autoantibody reactivity to B cell-activating factor (BAFF) was associated with SLE compared with control samples. BAFF reactivity correlated with the severity of disease-associated features, including IFN-alpha-driven SLE pathology. Our results showed that serum factor protein microarrays facilitate detection of autoantibod.y reactivity to serum factors in human samples and that BAFF-reactive autoantibodies may be associated with an elevated inflammatory disease state within the spectrum of SLE. C1 [Price, Jordan V.; Haddon, David J.; Kemmer, Dodge; Delepine, Guillaume; Mandelbaum, Gil; Jarrell, Justin A.; Gupta, Rohit; Sokolove, Jeremy; Robinson, William H.; Utz, Paul J.] Stanford Univ, Sch Med, Div Rheumatol & Immunol, Dept Med, Stanford, CA 94305 USA. [Price, Jordan V.; Haddon, David J.; Kemmer, Dodge; Delepine, Guillaume; Mandelbaum, Gil; Jarrell, Justin A.; Gupta, Rohit; Utz, Paul J.] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect ITI, Stanford, CA 94305 USA. [Balboni, Imelda] Stanford Univ, Sch Med, Dept Pediat, Div Allergy Immunol & Rheumatol, Stanford, CA 94305 USA. [Chakravarty, Eliza F.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Sokolove, Jeremy; Robinson, William H.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Shum, Anthony K.] UCSF, Dept Med, Div Pulm & Crit Care, San Francisco, CA USA. [Anderson, Mark S.; Cheng, Mickie H.] UCSF, Dept Med, Diabet Ctr, Div Endocrinol & Metab, San Francisco, CA USA. [Browne, Sarah K.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Baechler, Emily C.] Univ Minnesota, Sch Med, Ctr Immunol, Minneapolis, MN 55455 USA. RP Price, JV (reprint author), Stanford Univ, Sch Med, Div Rheumatol & Immunol, CCSR Bldg,Room 2215, Stanford, CA 94305 USA. EM jvp2099@gmail.com; pjutz@stanford.edu FU US National Science Foundation Graduate Research Fellowship (NSF GRFP); Stanford Genome Training Program (SGTP); Canadian Institutes of Health Research (CIHR); NIH [K08 AI080945, 5 U19AI082719, 1 U19-AI090019]; NHLBI Proteomics [HHSN288201000034C]; Alliance for Lupus Research [21858]; Canadian Institutes of Health Research [OR-92141]; Stanford Institute for Immunity, Transplantation, and Infection (ITI) Pilot Grant; FP [261]; European Union Seventh Framework Programme [261382]; NIH, US National Human Genome Research Institute; National Organization for Rare Disorders; Donald E. and Delia B. Baxter Foundation Career Development Award FX We thank E. Munoz and L. Tarter for coordination with the Stanford Chronic Immunologic Disease Registry and Repository and A. Meager for providing the FL-17 BAFF reporter cell line. J.V. Price was funded by a US National Science Foundation Graduate Research Fellowship (NSF GRFP) and was supported by the Stanford Genome Training Program (SGTP; NIH, US National Human Genome Research Institute). DJ. Haddon was funded by a Canadian Institutes of Health Research (CIHR) postdoctoral fellowship. A.K. Shum, M.H. Cheng, and M.S. Anderson were funded by the National Organization for Rare Disorders. I. Balboni is supported by NIH grant K08 AI080945. P.J. Utz is the recipient of a Donald E. and Delia B. Baxter Foundation Career Development Award, a gift from the Floren Family Trust, and a gift from the Ben May Charitable Trust of Mobile, Alabama, and is supported by NHLBI Proteomics Contract HHSN288201000034C, Proteomics of Inflammatory Immunity and Pulmonary Arterial Hypertension, NIH (grant nos. 5 U19AI082719 and 1 U19-AI090019), Alliance for Lupus Research (grant no. 21858), Canadian Institutes of Health Research (grant no. OR-92141), Stanford Institute for Immunity, Transplantation, and Infection (ITI) Pilot Grant, and FP grant no. 261. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261382. NR 51 TC 35 Z9 37 U1 1 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2013 VL 123 IS 12 BP 5135 EP 5145 DI 10.1172/JCI70231 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 263RQ UT WOS:000327826100020 PM 24270423 ER PT J AU Mondal, AM Horikawa, I Pine, SR Fujita, K Morgan, KM Vera, E Mazur, SJ Appella, E Vojtesek, B Blasco, MA Lane, DP Harris, CC AF Mondal, Abdul M. Horikawa, Izumi Pine, Sharon R. Fujita, Kaori Morgan, Katherine M. Vera, Elsa Mazur, Sharlyn J. Appella, Ettore Vojtesek, Borivoj Blasco, Maria A. Lane, David P. Harris, Curtis C. TI p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CELLULAR SENESCENCE; HUMAN-CELLS; THERAPEUTIC OPPORTUNITIES; SHORTENED TELOMERES; SECRETORY PHENOTYPE; HIV-INFECTION; LIFE-SPAN; EXPRESSION; CANCER; MEMORY AB Cellular senescence contributes to aging and decline in tissue function. p53 isoform switching regulates replicative senescence in cultured fibroblasts and is associated with tumor progression. Here, we found that the endogenous p53 isoforms Delta 133p53 and p53 beta are physiological regulators of proliferation and senescence in human T lymphocytes in vivo. Peripheral blood CD8(+) T lymphocytes collected from healthy donors displayed an age-dependent accumulation of senescent cells (CD28(-)CD57(+)) with decreased Delta 133p53 and increased p53 beta expression. Human lung tumor-associated CD8+ T lymphocytes also harbored senescent cells. Cultured CD8(+) blood T lymphocytes underwent replicative senescence that was associated with loss of CD28 and Delta 133p53 protein. In poorly proliferative, Delta 133p53-low CD8(+)CD28(-) cells, reconstituted expression of either Delta 133p53 or CD28 upregulated endogenous expression of each other, which restored cell proliferation, extended replicative lifespan and rescued senescence phenotypes. Conversely, Delta 133p53 knockdown or p53 beta overexpression in CD8(+)CD28(+) cells inhibited cell proliferation and induced senescence. This study establishes a role for Delta 133p53 and p53 beta in regulation of cellular proliferation and senescence in vivo. Furthermore, Delta 133p53-induced restoration of cellular replicative potential may lead to a new therapeutic paradigm for treating immunosenescence disorders, including those associated with aging, cancer, autoimmune diseases, and HIV infection. C1 [Mondal, Abdul M.; Horikawa, Izumi; Pine, Sharon R.; Fujita, Kaori; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pine, Sharon R.; Morgan, Katherine M.] UMDNJ Robert Wood Johnson Med Sch, Dept Med, Canc Inst New Jersey, New Brunswick, NJ USA. [Vera, Elsa; Blasco, Maria A.] Ctr Nacl Invest Oncol, Mol Oncol Programme, Telomeres & Telomerase Grp, Madrid, Spain. [Mazur, Sharlyn J.; Appella, Ettore] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Vojtesek, Borivoj] Masaryk Mem Canc Inst, Reg Ctr Appl Mol Oncol, Brno, Czech Republic. [Lane, David P.] ASTAR, Inst Mol & Cell Biol, Agcy Sci, Singapore, Singapore. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI ASTAR, IMCB/E-2320-2012; OI Blasco, Maria A./0000-0002-4211-233X FU Intramural Research Program of the NIH, NCI; Grant Agency of the Czech Republic [P301/11/1678, P206/12/G151]; RECAMO [CZ.1.05/2.1.00/03.0101]; Biospecimen Repository Service; FACS Sorting; CINJ [P30CA072720]; NIH, NCI [5K22CA140719]; ERC Project TEL STEM CELL; FP7 Project MARK-AGE; FP7 Project EuroBATS; [SAF2008-05384]; [CSD2007-00017]; [S2010/BMD-2303] FX We thank Rita Effros and Mark E. Dudley for reagents, Aaron Schetter and Ana Robles for statistical analysis, Barbara J. Taylor and Subhadra Banerjee for cell sorting, and Elisa Spillare for technical assistance. This research was supported in part by the Intramural Research Program of the NIH, NCI. B. Vojtesek was funded by grants from the Grant Agency of the Czech Republic (P301/11/1678 and P206/12/G151) and the RECAMO (CZ.1.05/2.1.00/03.0101). S.R. Pine was supported by the Biospecimen Repository Service (Julia Friedman), FACS Sorting (Arthur Roberts) Shared Resources of the CINJ (P30CA072720) and by a grant from the NIH, NCI (5K22CA140719). M.A. Blasco was funded by ERC Project TEL STEM CELL, FP7 Projects MARK-AGE and EuroBATS, and other projects SAF2008-05384, CSD2007-00017 and S2010/BMD-2303 (Spain). NR 59 TC 18 Z9 18 U1 2 U2 13 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2013 VL 123 IS 12 BP 5247 EP 5257 DI 10.1172/JCI70355 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 263RQ UT WOS:000327826100029 PM 24231352 ER PT J AU Anderson, SAR Michaelides, M Zarnegar, P Ren, YH Fagergren, P Thanos, PK Wang, GJ Bannon, M Neumaier, JF Keller, E Volkow, ND Hurd, YL AF Anderson, Sarah Ann R. Michaelides, Michael Zarnegar, Parisa Ren, Yanhua Fagergren, Pernilla Thanos, Panayotis K. Wang, Gene-Jack Bannon, Michael Neumaier, John F. Keller, Eva Volkow, Nora D. Hurd, Yasmin L. TI Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MESSENGER-RNA EXPRESSION; GLUCOSE-METABOLISM; GENE-EXPRESSION; PARKINSONS-DISEASE; EXTENDED AMYGDALA; ANXIETY DISORDERS; DRUG-ADDICTION; HEROIN ABUSERS; OPIOID-SYSTEM; HUMAN BRAIN AB Negative affect is critical for conferring vulnerability to opiate addiction as reflected by the high comorbidity of opiate abuse with major depressive disorder (MDD). Rodent models implicate amygdala prodynorphin (Pdyn) as a mediator of negative affect; however, evidence of PDYN involvement in human negative affect is limited. Here, we found reduced PDYN mRNA expression in the postmortem human amygdala nucleus of the periamygdaloid. cortex (PAC) in both heroin abusers and MDD subjects. Similar to humans, rats that chronically self-administered heroin had reduced Pdyn mRNA expression in the PAC at a time point associated with a negative affective state. Using the in vivo functional imaging technology DREAMM (DREADD-assisted. metabolic mapping, where DREADD indicates designer receptors exclusively activated. by designer drugs), we found that selective inhibition of Pdyn-expressing neurons in the rat PAC increased metabolic activity in the extended amygdala, which is a key substrate of the extrahypothalamic brain stress system. In parallel, PAC-specific Pdyn inhibition provoked negative affect-related physiological and behavioral changes. Altogether, our translational study supports a functional role for impaired Pdyn in the PAC in opiate abuse through activation of the stress and negative affect neurocircuitry implicated in addiction vulnerability. C1 [Anderson, Sarah Ann R.; Michaelides, Michael; Ren, Yanhua; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA. [Anderson, Sarah Ann R.; Michaelides, Michael; Ren, Yanhua; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY USA. [Anderson, Sarah Ann R.; Michaelides, Michael; Ren, Yanhua; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY USA. [Zarnegar, Parisa; Fagergren, Pernilla] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Bethesda, MD USA. [Wang, Gene-Jack] SUNY Stony Brook, Dept Radiol, Upton, NY USA. [Bannon, Michael] Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA. [Neumaier, John F.] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Neumaier, John F.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Keller, Eva] Semmelweis Univ, Dept Forens & Insurance Med, H-1085 Budapest, Hungary. [Hurd, Yasmin L.] James J Peters VA Med Ctr, New York, NY USA. RP Hurd, YL (reprint author), Hess Ctr Sci & Med, 1 Gustave L Levy Pl,Box 1065,1470 Madison Ave,Flo, New York, NY 10029 USA. EM Yasmin.hurd@mssm.edu FU UNCF-Merck Graduate Fellowship [DA015546, T32-GM007280-34S1-NHLBI/NIGMS]; NIDA Postdoctoral Training Program [DA007135]; [DA023214]; [DA030359]; [DA006470] FX This work was supported by DA015546, DA023214, DA030359, DA006470. S.A.R. Anderson was supported by the UNCF-Merck Graduate Fellowship, Diversity Supplement to DA015546 and T32-GM007280-34S1-NHLBI/NIGMS supplement to the Mount Sinai Medical Scientist Training Program. M. Michaelides was supported by NIDA Postdoctoral Training Program DA007135. NR 56 TC 12 Z9 12 U1 2 U2 9 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2013 VL 123 IS 12 BP 5334 EP 5341 DI 10.1172/JCI70395 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 263RQ UT WOS:000327826100036 PM 24231353 ER PT J AU Michaelides, M Anderson, SAR Ananth, M Smirnov, D Thanos, PK Neumaier, JF Wang, GJ Volkow, ND Hurd, YL AF Michaelides, Michael Anderson, Sarah Ann R. Ananth, Mala Smirnov, Denis Thanos, Panayotis K. Neumaier, John F. Wang, Gene-Jack Volkow, Nora D. Hurd, Yasmin L. TI Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID STRIATOPALLIDAL NEURONS; RAT-BRAIN; PET; NORMALIZATION; ORGANIZATION; INHIBITION; MODULATION; TEMPLATE; PATHWAYS; F-18-FDG AB The ability to map the functional connectivity of discrete cell types in the intact mammalian brain during behavior is crucial for advancing our understanding of brain function in normal and disease states. We combined designer receptor exclusively activated by designer drug (DREADD) technology and behavioral imaging with mu PET and [F-18]fluorodeoxyglucose (FDG) to generate whole-brain metabolic maps of cell-specific functional circuits during the awake, freely moving state. We have termed this approach DREADD-assisted metabolic mapping (DREAMM) and documented its ability in rats to map whole-brain functional anatomy. We applied this strategy to evaluating changes in the brain associated with inhibition of prodynorphin-expressing (Pdyn-expressing) and of proenkephalin-expressing (Penk-expressing) medium spiny neurons (MSNs) of the nucleus accumbens shell (NAcSh), which have been implicated in neuropsychiatric disorders. DREAMM revealed discrete behavioral manifestations and concurrent engagement of distinct corticolimbic networks associated with dysregulation of Pdyn and Penk in MSNs of the NAcSh. Furthermore, distinct neuronal networks were recruited in awake versus anesthetized conditions. These data demonstrate that DREAMM is a highly sensitive, molecular, high-resolution quantitative imaging approach. C1 [Michaelides, Michael; Anderson, Sarah Ann R.; Wang, Gene-Jack; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Psychiat, Friedman Brain Inst, New York, NY 10029 USA. [Michaelides, Michael; Anderson, Sarah Ann R.; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Neurosci, Friedman Brain Inst, New York, NY 10029 USA. [Ananth, Mala; Thanos, Panayotis K.; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Smirnov, Denis; Neumaier, John F.] Univ Washington, Seattle, WA 98195 USA. [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, Bethesda, MD USA. [Hurd, Yasmin L.] James J Peters VA Med Ctr, New York, NY USA. RP Hurd, YL (reprint author), Icahn Sch Med Mt Sinai, Hess Ctr Sci & Med, 10th Floor Room 105,1470 Madison Ave, New York, NY 10029 USA. EM yasmin.hurd@mssm.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [AA11034, AA07574, AA07611]; National Institute on Drug Abuse (NIDA) [DA015446, DA023214, DA030359]; NIDA Postdoctoral Training Program at MSSM [DA007135] FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (AA11034, AA07574, and AA07611) and the National Institute on Drug Abuse (NIDA) (DA015446, DA023214, and DA030359). M. Michaelides was supported by the NIDA Postdoctoral Training Program at MSSM (DA007135). The authors thank the Mount Sinai Microscopy Shared Resource Facility and the microPET Facility (Wade Koba, Linda Jelicks) at the Albert Einstein College of Medicine of Yeshiva University. NR 30 TC 19 Z9 19 U1 2 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC PY 2013 VL 123 IS 12 BP 5342 EP 5350 DI 10.1172/JCI72117 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 263RQ UT WOS:000327826100037 PM 24231358 ER PT J AU Uzasci, L Nath, A AF Uzasci, Lerna Nath, Avindra TI Robert J. Cotter (1943-2012): From Mass Spectrometer Development to the Exploration of Life SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Editorial Material DE Mass spectrometry; Time-of flightmass spectrometers; MALDI-ToFmass spectrometry; Biomarkers C1 [Uzasci, Lerna] Johns Hopkins Univ, Dept Pharmacol, Baltimore, MD USA. [Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. RP Nath, A (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM avindra.nath@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD DEC PY 2013 VL 8 IS 5 BP 1049 EP 1050 DI 10.1007/s11481-013-9482-4 PG 2 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 272XI UT WOS:000328496000001 PM 23771593 ER PT J AU Uzasci, L Nath, A Cotter, R AF Uzasci, Lerna Nath, Avindra Cotter, Robert TI Oxidative Stress and the HIV-Infected Brain Proteome SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Review DE HIV; Dementia; Oxidation; Nitration; Biomarker; Mass spectrometry ID HUMAN-IMMUNODEFICIENCY-VIRUS; NITRIC-OXIDE SYNTHASE; CENTRAL-NERVOUS-SYSTEM; NF-KAPPA-B; CEREBROSPINAL-FLUID; TAT PROTEIN; MASS-SPECTROMETRY; NEUROCOGNITIVE DISORDERS; NITROSATIVE STRESS; NADPH OXIDASE AB Human immunodeficiency virus (HIV) is capable of infiltrating the brain and infecting brain cells. In the years following HIV infection, patients show signs of various levels of neurocognitive problems termed HIV-associated neurocognitive disorders (HAND). Although the introduction of highly active antiretroviral therapy (HAART) has reduced the incidence of HIV-dementia, which is the most severe form of HAND, the milder forms have become more prevalent today due to the increased life expectancy of infected individuals. Pre-HAART era markers such as HIV RNA level, CD4+ count, TNF-alpha, MCP-1 and M-CSF are not able to clearly distinguish mild from advanced HAND. One promising approach for new biomarker discovery is the identification and quantitation of proteins that are post-translationally modified by oxidative and nitrosative species. The occurrence of oxidative and nitrosative stress in HIV-infected brain, both through the early direct and indirect effects of viral proteins and through the later effect on mitochondrial integrity during apoptosis, is well-established. This review will focus on how the reactive species are produced in the brain after HIV infection, the specific oxidative and nitrosative species that are involved in the post-translational modification of the brain proteome, and the methods that are currently used for the detection of such modified proteins. This review also provides an overview of related research pertaining to oxidative stress-related HAND using cerebrospinal fluid and human brain tissue. C1 [Uzasci, Lerna; Cotter, Robert] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Uzasci, L (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. EM luzasci1@jhu.edu FU National Institute of Neurological Disorders and Stroke [R01NS039253]; National Institute of Mental Health [P30MH075673]; NIH FX RJC and LU were supported by grants R01NS039253 (Cotter R, PI) from the National Institute of Neurological Disorders and Stroke and P30MH075673 (McArthur J, PI) from the National Institute of Mental Health. AN is supported by intramural NIH funds. NR 124 TC 10 Z9 10 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD DEC PY 2013 VL 8 IS 5 BP 1167 EP 1180 DI 10.1007/s11481-013-9444-x PG 14 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 272XI UT WOS:000328496000015 PM 23475542 ER PT J AU Ferenczy, MW Johnson, KR Steinberg, SM Marshall, LJ Monaco, MC Beschloss, AM Jensen, PN Major, EO AF Ferenczy, Michael W. Johnson, Kory R. Steinberg, Shannon M. Marshall, Leslie J. Monaco, Maria Chiara Beschloss, Alexander M. Jensen, Peter N. Major, Eugene O. TI Clonal Immortalized Human Glial Cell Lines Support Varying Levels of JC Virus Infection due to Differences in Cellular Gene Expression SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE SVG; JC Virus; SVG-10B1; SVG-5F4; Progressive multifocal leukoenephalopathy; Persistent infection ID NERVE GROWTH-FACTOR; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; HUMAN B-LYMPHOCYTES; LARGE T-ANTIGEN; NF-KAPPA-B; PROGENITOR CELLS; C-JUN; HUMAN-BRAIN; HUMAN POLYOMAVIRUS; TUMOR-SUPPRESSOR AB JC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells). A subset of SVG cells could support JCV replication. In the current study, clonal cell lines were selected from the original SVG cell culture. The 5F4 clone showed low levels of viral growth. The 10B1 clone was highly permissive for JCV DNA replication and gene expression and supported persistent and stable JCV infection over months in culture. Microarray analysis revealed that viral infection did not significantly change gene expression in these cells. More resistant 5F4 cells expressed high levels of transcription factors known to inhibit JCV transcription. Interestingly, 5F4 cells expressed high levels of RNA of markers of radial glia and 10B1 cells had high expression of markers of immature glial cells and activation of transcription regulators important for stem/progenitor cell self-renewal. These SVG-derived clonal cell lines provide a biologically relevant model to investigate cell type differences in JCV host range and pathogenesis, as well as neural development. Several transcription regulators were identified which may be targets for therapeutic modulation of expression to abrogate JCV replication in PML patients. Additionally, these clonal cell lines can provide a consistent culture platform for testing therapies against JCV infection of the central nervous system. C1 [Ferenczy, Michael W.; Steinberg, Shannon M.; Marshall, Leslie J.; Monaco, Maria Chiara; Beschloss, Alexander M.; Jensen, Peter N.; Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Johnson, Kory R.] NINDS, Bioinformat Sect, NIH, Bethesda, MD 20892 USA. [Ferenczy, Michael W.; Major, Eugene O.] Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. RP Ferenczy, MW (reprint author), Lab Mol Med & Neurosci, NINDS Bldg 10,Room 3B13 10 Ctr Dr,MSC 1296, Bethesda, MD 20892 USA. EM michael.ferenczy@nih.gov; majorg@ninds.nih.gov OI Steinberg, Shannon/0000-0003-1711-2423 FU Intramural AIDS Research Fellowship from the NIH Office of AIDS Research; Division of Intramural Research of the NINDS FX The authors would like to thank members of the Laboratory of Molecular Medicine and Neuroscience for helpful comments and insight and Rick V. Dreyfuss from the NIH Medical Imaging Branch for help preparing in situ hybridization images. RNA sample processing and initial analysis of DNA microarrays were performed by Dr. Abdel Elkahloun and Weiwei Wu of the Microarray Core Facility of the National Human Genome Institute. M.W.F. is supported in part by the Intramural AIDS Research Fellowship from the NIH Office of AIDS Research. The Laboratory of Molecular Medicine and Neuroscience and the Bioinformatics Section are supported by the Division of Intramural Research of the NINDS. NR 60 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 EI 1557-1904 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD DEC PY 2013 VL 8 IS 5 BP 1303 EP 1319 DI 10.1007/s11481-013-9499-8 PG 17 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 272XI UT WOS:000328496000025 PM 24052414 ER PT J AU Skates, SJ Gillette, MA LaBaer, J Carr, SA Anderson, L Liebler, DC Ransohoff, D Rifai, N Kondratovich, M Tezak, Z Mansfield, E Oberg, AL Wright, I Barnes, G Gail, M Mesri, M Kinsinger, CR Rodriguez, H Boja, ES AF Skates, Steven J. Gillette, Michael A. LaBaer, Joshua Carr, Steven A. Anderson, Leigh Liebler, Daniel C. Ransohoff, David Rifai, Nader Kondratovich, Marina Tezak, Zivana Mansfield, Elizabeth Oberg, Ann L. Wright, Ian Barnes, Grady Gail, Mitchell Mesri, Mehdi Kinsinger, Christopher R. Rodriguez, Henry Boja, Emily S. TI Statistical Design for Biospecimen Cohort Size in Proteomics-based Biomarker Discovery and Verification Studies SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE statistical experiment design; biomarker; proteomics; unbiasedness; power calculation ID MONITORING MASS-SPECTROMETRY; CARDIOVASCULAR-DISEASE; PROTEIN BIOMARKERS; MULTIPLEX ASSAYS; PIPELINE; PLASMA; ASSOCIATION; DIAGNOSTICS; VALIDATION; MARKERS AB Protein biomarkers are needed to deepen our understanding of cancer biology and to improve our ability to diagnose, monitor, and treat cancers. Important analytical and clinical hurdles must be overcome to allow the most promising protein biomarker candidates to advance into clinical validation studies. Although contemporary proteomics technologies support the measurement of large numbers of proteins in individual clinical specimens, sample throughput remains comparatively low. This problem is amplified in typical clinical proteomics research studies, which routinely suffer from a lack of proper experimental design, resulting in analysis of too few biospecimens to achieve adequate statistical power at each stage of a biomarker pipeline. To address this critical shortcoming, a joint workshop was held by the National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), and American Association for Clinical Chemistry (AACC) with participation from the U.S. Food and Drug Administration (FDA). An important output from the workshop was a statistical framework for the design of biomarker discovery and verification studies. Herein, we describe the use of quantitative clinical judgments to set statistical criteria for clinical relevance and the development of an approach to calculate biospecimen sample size for proteomic studies in discovery and verification stages prior to clinical validation stage. This represents a first step toward building a consensus on quantitative criteria for statistical design of proteomics biomarker discovery and verification research. C1 [Skates, Steven J.] Massachusetts Gen Hosp, Ctr Canc, Ctr Biostat, Boston, MA 02114 USA. [Gillette, Michael A.; Carr, Steven A.] Broad Inst Massachusetts Inst Technol & Harvard, Prote Platform, Cambridge, MA 02142 USA. [LaBaer, Joshua] Arizona State Univ, Biodesign Inst, Tempe, AZ 85287 USA. [Anderson, Leigh] Plasma Proteome Inst, Washington, DC 20009 USA. [Anderson, Leigh; Wright, Ian] SISCAPA Technol Inc, Washington, DC 20009 USA. [Liebler, Daniel C.] Vanderbilt Univ, Sch Med, Jim Ayers Inst Precanc Detect & Diag, Nashville, TN 37232 USA. [Liebler, Daniel C.] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Ransohoff, David] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27514 USA. [Rifai, Nader] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Rifai, Nader] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Rifai, Nader] King Abdulaziz Univ, Jeddah 22254, Saudi Arabia. [Kondratovich, Marina; Tezak, Zivana; Mansfield, Elizabeth] US FDA, Off In Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Dept Hlth & Human Serv, Silver Spring, MD 20993 USA. [Oberg, Ann L.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Barnes, Grady] Fujirebio Diagnost Inc, Malvern, PA 19355 USA. [Gail, Mitchell] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mesri, Mehdi; Kinsinger, Christopher R.; Rodriguez, Henry; Boja, Emily S.] NCI, Off Canc Clin Prote Res, Ctr Strateg Sci Initiat, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Skates, SJ (reprint author), Massachusetts Gen Hosp, 50 Staniford St,Suite 560, Boston, MA 02114 USA. EM sskates@partners.org; bojae@mail.nih.gov OI Liebler, Daniel/0000-0002-7873-3031 FU National Cancer Institute of the National Institutes of Health through the Clinical Proteomic Tumor Analysis Consortium (CPTAC) [10XS136, U24CA160034]; Early Detection Research Network [U01CAI52990]; Mayo Clinic Specialized Program in Research Excellence [P50CA136393] FX Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grants and contracts through the Clinical Proteomic Tumor Analysis Consortium (CPTAC) program (10XS136 SJS, U24CA160034 SAC, MAG), the Early Detection Research Network (U01CAI52990 SJS), and Mayo Clinic Specialized Program in Research Excellence grant (P50CA136393 AO). NR 29 TC 32 Z9 32 U1 2 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD DEC PY 2013 VL 12 IS 12 BP 5383 EP 5394 DI 10.1021/pr400132j PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 269HD UT WOS:000328231300004 PM 24063748 ER PT J AU Cossio, P Hummer, G AF Cossio, Pilar Hummer, Gerhard TI Bayesian analysis of individual electron microscopy images: Towards structures of dynamic and heterogeneous biomolecular assemblies SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Electron microscopy; Cryo-EM; Bayesian inference; Ensemble refinement; Validation; Disorder; GroEL; ESCRT ID EM STRUCTURE DETERMINATION; AB-INITIO RECONSTRUCTION; MACROMOLECULAR STRUCTURE DETERMINATION; CRYOELECTRON MICROSCOPY; CRYO-EM; CRYSTAL-STRUCTURE; CHAPERONIN GROEL; PARTICLE ORIENTATION; ANGSTROM RESOLUTION; MOLECULAR-DYNAMICS AB We develop a method to extract structural information from electron microscopy (EM) images of dynamic and heterogeneous molecular assemblies. To overcome the challenge of disorder in the imaged structures, we analyze each image individually, avoiding information loss through clustering or averaging. The Bayesian inference of EM (BioEM) method uses a likelihood-based probabilistic measure to quantify the consistency between each EM image and given structural models. The likelihood function accounts for uncertainties in the molecular position and orientation, variations in the relative intensities and noise in the experimental images. The BioEM formalism is physically intuitive and mathematically simple. We show that for experimental GroEL images, BioEM correctly identifies structures according to the functional state. The top-ranked structure is the corresponding X-ray crystal structure, followed by an EM structure generated previously from a superset of the EM images used here. To analyze EM images of highly flexible molecules, we propose an ensemble refinement procedure, and validate it with synthetic EM maps of the ESCRT-I-II supercomplex. Both the size of the ensemble and its structural members are identified correctly. BioEM offers an alternative to 3D-reconstruction methods, extracting accurate population distributions for highly flexible structures and their assemblies. We discuss limitations of the method, and possible applications beyond ensemble refinement, including the cross-validation and unbiased post-assessment of model structures, and the structural characterization of systems where traditional approaches fail. Overall, our results suggest that the BioEM framework can be used to analyze EM images of both ordered and disordered molecular systems. (C) 2013 Elsevier Inc. All rights reserved. C1 [Hummer, Gerhard] Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), Max Planck Inst Biophys, Dept Theoret Biophys, Max von Laue Strage 3, D-60438 Frankfurt, Germany. EM gerhard.hummer@biophys.mpg.de RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Max Planck Society FX To obtain the source code please contact the corresponding author. The authors thank Dr. J. Bernard Heymann for help with the Bsoft program, and Drs. James Hurley and Alasdair Steven for stimulating discussions. We also thank Dr. Jurgen Kofinger for useful discussions concerning the Bayesian methodology. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and by the Max Planck Society, and used the biowulf computing resource at the National Institutes of Health, and the high-performance computers at the Rechenzentrum Garching of the Max Planck Society. NR 72 TC 9 Z9 9 U1 1 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD DEC PY 2013 VL 184 IS 3 BP 427 EP 437 DI 10.1016/j.jsb.2013.10.006 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 274FA UT WOS:000328591000006 PM 24161733 ER PT J AU Kuczmarski, MF Mason, MA Allegro, D Zonderman, AB Evans, MK AF Kuczmarski, Marie Fanelli Mason, Marc A. Allegro, Deanne Zonderman, Alan B. Evans, Michele K. TI Diet Quality Is Inversely Associated with C-Reactive Protein Levels in Urban, Low-Income African-American and White Adults SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE C-reactive protein; Dietary quality; Micronutrients ID SOCIOECONOMIC-STATUS; UNITED-STATES; CARDIOVASCULAR-DISEASE; US ADULTS; INFLAMMATION; POPULATION; MARKERS; PATTERNS; OBESITY; CONSEQUENCES AB Background C-reactive protein (CRP), an inflammatory biomarker, is influenced by many factors, including socioeconomic position, genetics, and diet. The inverse association between diet and CRP is biologically feasible because micronutrients with antioxidative properties may enable the body to manage the balance between production and accumulation of reactive species that cause oxidative stress. Objective To determine the quality of the diet consumed by urban, low-income African-American and white adults aged 30 to 64 years, and association of diet quality with CRP. Design Data from a cross-sectional study were used to evaluate diet quality assessed by mean adequacy ratio (MAR). Two 24-hour recalls were collected by trained interviewers using the US Department of Agriculture automated multiple pass method. Participants The sample consisted of Healthy Aging in Neighborhoods of Diversity across the Life Span baseline study participants, 2004-2009, who completed both recalls (n=2,017). Main outcome measures MAR equaled the average of the ratio of intakes to Recommended Dietary Allowance for 15 vitamins and minerals. CRP levels were assessed by the nephelometric method utilizing latex particles coated with CRP monoclonal antibodies. Statistical analysis Linear ordinary least square regression and generalized linear models were performed to determine the association of MAR (independent variable) with CRP (dependent variable) while adjusting for potential confounders. Results MAR scores ranged from 74.3 to 82.2. Intakes of magnesium and vitamins A, C, and E were the most inadequate compared with Estimated Average Requirements. CRP levels were significantly associated with MAR, dual-energy x-ray absorptiometry-measured body fat, and hypertension. A 10% increase in MAR was associated with a 4% decrease in CRP. Conclusions The MAR was independently and significantly inversely associated with CRP, suggesting diet is associated with the regulation of inflammation. Interventions to assist people make better food choices may not only improve diet quality but also their health, thereby possibly reducing risk for cardiovascular disease. C1 [Kuczmarski, Marie Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE 19716 USA. [Kuczmarski, Marie Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, HANDLS Study, Newark, DE 19716 USA. [Allegro, Deanne] Univ Delaware, Dept Behav Hlth & Nutr, HANDLS Hlth Aging Neighborhoods Divers Life Span, Newark, DE 19716 USA. [Mason, Marc A.] NIA, NIH, Baltimore, MD 21224 USA. [Mason, Marc A.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Zonderman, Alan B.] NIA, Lifespan Cognit & Hlth Sect, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, Baltimore, MD 21224 USA. [Evans, Michele K.] NIA, HANDLS Study, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. RP Kuczmarski, MF (reprint author), Univ Delaware, Dept Behav Hlth & Nutr, 010 Carpenter Sports Bldg, Newark, DE 19716 USA. EM mfk@udel.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program, National Institute on Aging, National Institutes of Health FX This work is supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 54 TC 12 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD DEC PY 2013 VL 113 IS 12 BP 1620 EP 1631 DI 10.1016/j.jand.2013.07.004 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 269JU UT WOS:000328238400006 PM 24035460 ER PT J AU Pan, X Liu, J Nguyen, T Liu, CY Sun, JH Teng, YJ Fergusson, MM Rovira, II Allen, M Springer, DA Aponte, AM Gucek, M Balaban, RS Murphy, E Finkel, T AF Pan, Xin Liu, Jie Nguyen, Tiffany Liu, Chengyu Sun, Junhui Teng, Yanjie Fergusson, Maria M. Rovira, Ilsa I. Allen, Michele Springer, Danielle A. Aponte, Angel M. Gucek, Marjan Balaban, Robert S. Murphy, Elizabeth Finkel, Toren TI The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter SO NATURE CELL BIOLOGY LA English DT Article ID PERMEABILITY TRANSITION PORE; RAT KIDNEY MITOCHONDRIA; ESSENTIAL COMPONENT; S-NITROSYLATION; CYCLOSPORINE-A; CA2+ UPTAKE; CELL-DEATH; TRANSPORT; PHOSPHORYLATION; ENERGETICS AB Mitochondrial calcium has been postulated to regulate a wide range of processes from bioenergetics to cell death. Here, we characterize a mouse model that lacks expression of the recently discovered mitochondrial calcium uniporter (MCU). Mitochondria derived from MCU-/- mice have no apparent capacity to rapidly uptake calcium. Whereas basal metabolism seems unaffected, the skeletal muscle of MCU-/- mice exhibited alterations in the phosphorylation and activity of pyruvate dehydrogenase. In addition, MCU-/- mice exhibited marked impairment in their ability to perform strenuous work. We further show that mitochondria from MCU-/- mice lacked evidence for calcium-induced permeability transition pore (PIP) opening. The lack of PIP opening does not seem to protect MCU-/- cells and tissues from cell death, although MCU-/- hearts fail to respond to the PIP inhibitor cyclosporin A. Taken together, these results clarify how acute alterations in mitochondrial matrix calcium can regulate mammalian physiology. C1 [Pan, Xin; Liu, Jie; Teng, Yanjie; Fergusson, Maria M.; Rovira, Ilsa I.; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Pan, Xin] Natl Ctr Biomed Anal, Beijing 100850, Peoples R China. [Nguyen, Tiffany; Sun, Junhui; Balaban, Robert S.; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, IPSC, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Genome Engn Core, NIH, Bethesda, MD 20892 USA. [Allen, Michele; Springer, Danielle A.] NHLBI, Murine Phenotyping Core, NIH, Bethesda, MD 20892 USA. [Aponte, Angel M.; Gucek, Marjan] NHLBI, Prote Core, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM murphy1@nih.gov; finkelt@nih.gov FU NIH FX We are grateful to C. Brantner, P. S. Connelly and M. P. Daniels of the NHLBI Electron Microscopy Core Facility for assistance with electron microscopy, C. Petucci of the Metabolomics Core Facility Sanford-Burnham Medical Research Institute for aiding in the metabolomic profiling, C. Combs and the NHLBI Microscopy Core for help with the Rhod-2 fluorescent measurements and A. Wiederkehr for the original mito-aequorin adenovirus. This work was supported by NIH Intramural funds. NR 48 TC 152 Z9 156 U1 5 U2 34 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 DEC PY 2013 VL 15 IS 12 BP 1464 EP + DI 10.1038/ncb2868 PG 20 WC Cell Biology SC Cell Biology GA 265IL UT WOS:000327944200011 PM 24212091 ER PT J AU Solomon, DA Kim, JS Bondaruk, J Shariat, SF Wang, ZF Elkahloun, AG Ozawa, T Gerard, J Zhuang, DZ Zhang, SZ Navai, N Siefker-Radtke, A Phillips, JJ Robinson, BD Rubin, MA Volkmer, B Hautmann, R Kufer, R Hogendoorn, PCW Netto, G Theodorescu, D James, CD Czerniak, B Miettinen, M Waldman, T AF Solomon, David A. Kim, Jung-Sik Bondaruk, Jolanta Shariat, Shahrokh F. Wang, Zeng-Feng Elkahloun, Abdel G. Ozawa, Tomoko Gerard, Julia Zhuang, DaZhong Zhang, Shizhen Navai, Neema Siefker-Radtke, Arlene Phillips, Joanna J. Robinson, Brian D. Rubin, Mark A. Volkmer, Bjoern Hautmann, Richard Kuefer, Rainer Hogendoorn, Pancras C. W. Netto, George Theodorescu, Dan James, C. David Czerniak, Bogdan Miettinen, Markku Waldman, Todd TI Frequent truncating mutations of STAG2 in bladder cancer SO NATURE GENETICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INACTIVATION; ANEUPLOIDY AB Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer. C1 [Solomon, David A.; Kim, Jung-Sik; Gerard, Julia; Waldman, Todd] Georgetown Univ, Sch Med, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Solomon, David A.; Phillips, Joanna J.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Bondaruk, Jolanta; Zhang, Shizhen; Czerniak, Bogdan] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Shariat, Shahrokh F.; Zhuang, DaZhong; Robinson, Brian D.; Rubin, Mark A.] Weill Cornell Coll Med, Dept Urol, New York, NY USA. [Shariat, Shahrokh F.] Weill Cornell Coll Med, Div Med Oncol, New York, NY USA. [Wang, Zeng-Feng; Miettinen, Markku] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Ozawa, Tomoko; James, C. David] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Navai, Neema] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Siefker-Radtke, Arlene] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Robinson, Brian D.; Rubin, Mark A.] Weill Cornell Coll Med, Dept Pathol, New York, NY USA. [Volkmer, Bjoern] Hosp Kassel, Dept Urol, Kassel, Germany. [Hautmann, Richard] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Kuefer, Rainer] Hosp Eichert, Dept Urol, Goppingen, Germany. [Hogendoorn, Pancras C. W.] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Netto, George] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Theodorescu, Dan] Univ Colorado, Sch Med, Ctr Canc, Dept Surg, Aurora, CO USA. RP Waldman, T (reprint author), Georgetown Univ, Sch Med, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. EM waldmant@georgetown.edu RI Hogendoorn, Pancras/H-5859-2015; OI Hogendoorn, Pancras/0000-0002-1513-8104; Rubin, Mark/0000-0002-8321-9950 FU US National Institutes of Health [R01CA169345, R01CA159467, R21CA143282]; MD Anderson Cancer Center Bladder Cancer SPORE grant [P50CA091846]; National Human Genome Research Institute, US National Institutes of Health FX We thank B. Vogelstein for assistance in acquiring samples and preparing genomic DNA. This work was supported by US National Institutes of Health grants R01CA169345, R01CA159467 and R21CA143282 to T. W., by the MD Anderson Cancer Center Bladder Cancer SPORE grant P50CA091846 and by the Intramural Research Program of the National Human Genome Research Institute, US National Institutes of Health. NR 13 TC 56 Z9 57 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD DEC PY 2013 VL 45 IS 12 BP 1428 EP U171 DI 10.1038/ng.2800 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 262EA UT WOS:000327715800006 PM 24121789 ER PT J AU Lambert, JC Ibrahim-Verbaas, CA Harold, D Naj, AC Sims, R Bellenguez, C Jun, G DeStefano, AL Bis, JC Beecham, GW Grenier-Boley, B Russo, G Thornton-Wells, TA Jones, N Smith, AV Chouraki, V Thomas, C Ikram, MA Zelenika, D Vardarajan, BN Kamatani, Y Lin, CF Gerrish, A Schmidt, H Kunkle, B Dunstan, ML Ruiz, A Bihoreau, MT Choi, SH Reitz, C Pasquier, F Hollingworth, P Ramirez, A Hanon, O Fitzpatrick, AL Buxbaum, JD Campion, D Crane, PK Baldwin, C Becker, T Gudnason, V Cruchaga, C Craig, D Amin, N Berr, C Lopez, OL De Jager, PL Deramecourt, V Johnston, JA Evans, D Lovestone, S Letenneur, L Moron, FJ Rubinsztein, DC Eiriksdottir, G Sleegers, K Goate, AM Fievet, N Huentelman, MJ Gill, M Brown, K Kamboh, MI Keller, L Barberger-Gateau, P McGuinness, B Larson, EB Green, R Myers, AJ Dufouil, C Todd, S Wallon, D Love, S Rogaeva, E Gallacher, J St George-Hyslop, P Clarimon, J Lleo, A Bayer, A Tsuang, DW Yu, L Tsolaki, M Bossu, P Spalletta, G Proitsi, P Collinge, J Sorbi, S Sanchez-Garcia, F Fox, NC Hardy, J Naranjo, MCD Bosco, P Clarke, R Brayne, C Galimberti, D Mancuso, M Matthews, F Moebus, S Mecocci, P Del Zompo, M Maier, W Hampel, H Pilotto, A Bullido, M Panza, F Caffarra, P Nacmias, B Gilbert, JR Mayhaus, M Lannfelt, L Hakonarson, H Pichler, S Carrasquillo, MM Ingelsson, M Beekly, D Alvarez, V Zou, FG Valladares, O Younkin, SG Coto, E Hamilton-Nelson, KL Gu, W Razquin, C Pastor, P Mateo, I Owen, MJ Faber, KM Jonsson, PV Combarros, O O'Donovan, MC Cantwell, LB Soininen, H Blacker, D Mead, S Mosley, TH Bennett, DA Harris, TB Fratiglioni, L Holmes, C de Bruijn, RFAG Passmore, P Montine, TJ Bettens, K Rotter, JI Brice, A Morgan, K Foroud, TM Kukull, WA Hannequin, D Powell, JF Nalls, MA Ritchie, K Lunetta, KL Kauwe, JSK Boerwinkle, E Riemenschneider, M Boada, M Hiltunen, M Martin, ER Schmidt, R Rujescu, D Wang, LS Dartigues, JF Mayeux, R Tzourio, C Hofman, A Nothen, MM Graff, C Psaty, BM Jones, L Haines, JL Holmans, PA Lathrop, M Pericak-Vance, MA Launer, LJ Farrer, LA van Duijn, CM Van Broeckhoven, C Moskvina, V Seshadri, S Williams, J Schellenberg, GD Amouyel, P AF Lambert, Jean-Charles Ibrahim-Verbaas, Carla A. Harold, Denise Naj, Adam C. Sims, Rebecca Bellenguez, Celine Jun, Gyungah DeStefano, Anita L. Bis, Joshua C. Beecham, Gary W. Grenier-Boley, Benjamin Russo, Giancarlo Thornton-Wells, Tricia A. Jones, Nicola Smith, Albert V. Chouraki, Vincent Thomas, Charlene Ikram, M. Arfan Zelenika, Diana Vardarajan, Badri N. Kamatani, Yoichiro Lin, Chiao-Feng Gerrish, Amy Schmidt, Helena Kunkle, Brian Dunstan, Melanie L. Ruiz, Agustin Bihoreau, Marie-Therese Choi, Seung-Hoan Reitz, Christiane Pasquier, Florence Hollingworth, Paul Ramirez, Alfredo Hanon, Olivier Fitzpatrick, Annette L. Buxbaum, Joseph D. Campion, Dominique Crane, Paul K. Baldwin, Clinton Becker, Tim Gudnason, Vilmundur Cruchaga, Carlos Craig, David Amin, Najaf Berr, Claudine Lopez, Oscar L. De Jager, Philip L. Deramecourt, Vincent Johnston, Janet A. Evans, Denis Lovestone, Simon Letenneur, Luc Moron, Francisco J. Rubinsztein, David C. Eiriksdottir, Gudny Sleegers, Kristel Goate, Alison M. Fievet, Nathalie Huentelman, Matthew J. Gill, Michael Brown, Kristelle Kamboh, M. Ilyas Keller, Lina Barberger-Gateau, Pascale McGuinness, Bernadette Larson, Eric B. Green, Robert Myers, Amanda J. Dufouil, Carole Todd, Stephen Wallon, David Love, Seth Rogaeva, Ekaterina Gallacher, John St George-Hyslop, Peter Clarimon, Jordi Lleo, Alberto Bayer, Anthony Tsuang, Debby W. Yu, Lei Tsolaki, Magda Bossu, Paola Spalletta, Gianfranco Proitsi, Petroula Collinge, John Sorbi, Sandro Sanchez-Garcia, Florentino Fox, Nick C. Hardy, John Naranjo, Maria Candida Deniz Bosco, Paolo Clarke, Robert Brayne, Carol Galimberti, Daniela Mancuso, Michelangelo Matthews, Fiona Moebus, Susanne Mecocci, Patrizia Del Zompo, Maria Maier, Wolfgang Hampel, Harald Pilotto, Alberto Bullido, Maria Panza, Francesco Caffarra, Paolo Nacmias, Benedetta Gilbert, John R. Mayhaus, Manuel Lannfelt, Lars Hakonarson, Hakon Pichler, Sabrina Carrasquillo, Minerva M. Ingelsson, Martin Beekly, Duane Alvarez, Victoria Zou, Fanggeng Valladares, Otto Younkin, Steven G. Coto, Eliecer Hamilton-Nelson, Kara L. Gu, Wei Razquin, Cristina Pastor, Pau Mateo, Ignacio Owen, Michael J. Faber, Kelley M. Jonsson, Palmi V. Combarros, Onofre O'Donovan, Michael C. Cantwell, Laura B. Soininen, Hilkka Blacker, Deborah Mead, Simon Mosley, Thomas H., Jr. Bennett, David A. Harris, Tamara B. Fratiglioni, Laura Holmes, Clive de Bruijn, Renee F. A. G. Passmore, Peter Montine, Thomas J. Bettens, Karolien Rotter, Jerome I. Brice, Alexis Morgan, Kevin Foroud, Tatiana M. Kukull, Walter A. Hannequin, Didier Powell, John F. Nalls, Michael A. Ritchie, Karen Lunetta, Kathryn L. Kauwe, John S. K. Boerwinkle, Eric Riemenschneider, Matthias Boada, Merce Hiltunen, Mikko Martin, Eden R. Schmidt, Reinhold Rujescu, Dan Wang, Li-San Dartigues, Jean-Francois Mayeux, Richard Tzourio, Christophe Hofman, Albert Noethen, Markus M. Graff, Caroline Psaty, Bruce M. Jones, Lesley Haines, Jonathan L. Holmans, Peter A. Lathrop, Mark Pericak-Vance, Margaret A. Launer, Lenore J. Farrer, Lindsay A. van Duijn, Cornelia M. Van Broeckhoven, Christine Moskvina, Valentina Seshadri, Sudha Williams, Julie Schellenberg, Gerard D. Amouyel, Philippe CA EADI GERAD ADGC CHARGE TI Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; GENETIC RISK; RECEPTOR; CD33; IMPUTATION; MUTATIONS; GENOTYPES; SEQUENCE; NEURONS AB Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease. C1 [Lambert, Jean-Charles; Bellenguez, Celine; Grenier-Boley, Benjamin; Chouraki, Vincent; Fievet, Nathalie; Amouyel, Philippe] INSERM, U744, F-59045 Lille, France. [Lambert, Jean-Charles; Bellenguez, Celine; Grenier-Boley, Benjamin; Chouraki, Vincent; Pasquier, Florence; Deramecourt, Vincent; Amouyel, Philippe] Univ Lille 2, Lille, France. [Lambert, Jean-Charles; Bellenguez, Celine; Grenier-Boley, Benjamin; Chouraki, Vincent; Fievet, Nathalie; Amouyel, Philippe] Inst Pasteur, F-59019 Lille, France. [Ibrahim-Verbaas, Carla A.; Ikram, M. Arfan; de Bruijn, Renee F. A. 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[Berr, Claudine; Ritchie, Karen] Hop La Colombiere, Fac Med, U1061, INSERM, Montpellier, France. [Lopez, Oscar L.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol & Psychiat, Inst Neurosci, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [De Jager, Philip L.; Green, Robert] Harvard Univ, Sch Med, Boston, MA USA. [De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Boston, MA USA. [Evans, Denis] Rush Univ, Med Ctr, Dept Internal Med, Rush Inst Hlth Aging, Chicago, IL 60612 USA. [Lovestone, Simon; Proitsi, Petroula; Powell, John F.] Univ London, Kings Coll London, Inst Psychiat, London SW3 6LX, England. [Letenneur, Luc; Barberger-Gateau, Pascale; Dufouil, Carole; Dartigues, Jean-Francois] Victor Segalen Univ, INSERM, U897, Bordeaux, France. [Moron, Francisco J.] Neocodex, Dept Genom Estruct, Seville, Spain. [Rubinsztein, David C.; St George-Hyslop, Peter] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [Sleegers, Kristel; Bettens, Karolien; Van Broeckhoven, Christine] Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium. [Sleegers, Kristel; Bettens, Karolien; Van Broeckhoven, Christine] Univ Antwerp, Neurogenet Lab, Inst Born Bunge, B-2020 Antwerp, Belgium. [Huentelman, Matthew J.] Translat Genom Res Inst, Neurogenom Div, Phoenix, AZ USA. [Gill, Michael] St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland. [Gill, Michael] Univ Dublin Trinity Coll, Dublin 2, Ireland. [Brown, Kristelle; Morgan, Kevin] Univ Nottingham, Inst Genet, Queens Med Ctr, Nottingham NG7 2RD, England. [Kamboh, M. Ilyas] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Kamboh, M. Ilyas] Univ Pittsburgh, Alzheimers Dis Res Ctr, Pittsburgh, PA USA. 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[Clarimon, Jordi; Lleo, Alberto] Univ Autonoma Barcelona, Dept Neurol, Biomed Res Inst Sant Pau IIB Sant Pau, St Pau Hosp, E-08193 Barcelona, Spain. [Clarimon, Jordi; Lleo, Alberto] Ctr Networker Biomed Res Neurodegenerat Dis, Barcelona, Spain. [Tsuang, Debby W.] Vet Adm Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Tsolaki, Magda] Aristotle Univ Thessaloniki, Dept Neurol, GR-54006 Thessaloniki, Greece. [Bossu, Paola; Spalletta, Gianfranco] Fdn Santa Lucia, Rome, Italy. [Collinge, John; Mead, Simon] UCL, Inst Neurol, MRC, Pr Unit,Dept Neurodegenerat Dis, London, England. [Sorbi, Sandro; Nacmias, Benedetta] Univ Florence, NEUROFARBA Dept Neurosci Psychol Drug Res & Child, Florence, Italy. [Sorbi, Sandro; Nacmias, Benedetta] Univ Florence, Ctr Ric Trasferimento Alta Formaz DENOTH, Florence, Italy. [Sanchez-Garcia, Florentino; Naranjo, Maria Candida Deniz] Hosp Univ Dr Negrin, Dept Immunol, Las Palmas Gran Canaria, Spain. [Fox, Nick C.] UCL, Dementia Res Ctr, Dept Neurodegenerat Dis, Inst Neurol, London, England. [Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, John] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England. [Bosco, Paolo] Assoc Oasi Maria Santissima Srl, IRCCS, Troina, Italy. [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, OHAP, Oxford, England. [Brayne, Carol] Univ Cambridge, Inst Publ Hlth, Cambridge, England. [Galimberti, Daniela] Univ Milan, Fdn Ca Granda, IRCCS Osped Policlin, Milan, Italy. [Mancuso, Michelangelo] Univ Pisa, Neurol Clin, Pisa, Italy. [Matthews, Fiona] MRC, Biostat Unit, Cambridge CB2 2BW, England. [Moebus, Susanne] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Mecocci, Patrizia] Univ Perugia, Sect Gerontol & Geriatr, Dept Clin & Expt Med, I-06100 Perugia, Italy. [Del Zompo, Maria] Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy. [Hampel, Harald] Goethe Univ Frankfurt, Dept Psychiat, D-60054 Frankfurt, Germany. [Hampel, Harald] Univ Munich, Dept Psychiat, D-80539 Munich, Germany. [Pilotto, Alberto] IRCCS Casa Sollievo Sofferenza, Gerontol & Geriatr Res Lab, San Giovanni Rotondo, Italy. [Bullido, Maria] Univ Autonoma Madrid, Consejo Super Invest Cient, Ctr Biol Mol Severo Ochoa, Madrid, Spain. [Bullido, Maria] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Bullido, Maria] Inst Invest Sanitaria Hosp Paz IdIPaz, Madrid, Spain. [Panza, Francesco] Univ Bari, Dept Geriatr, Ctr Aging Brain, Bari, Italy. [Caffarra, Paolo] Univ Parma, Dept Neurosci, I-43100 Parma, Italy. [Caffarra, Paolo] AUSL, Ctr Cognit Disorders, Parma, Italy. [Mayhaus, Manuel; Pichler, Sabrina; Gu, Wei; Riemenschneider, Matthias] Saarland Univ Hosp, Dept Psychiat, Homburg, Germany. [Lannfelt, Lars; Ingelsson, Martin] Uppsala Univ, Dept Publ Health Geriatr, Uppsala, Sweden. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Carrasquillo, Minerva M.; Zou, Fanggeng; Younkin, Steven G.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Beekly, Duane] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA. [Alvarez, Victoria; Coto, Eliecer] Hosp Univ Cent Asturias, Oviedo, Spain. [Razquin, Cristina; Pastor, Pau] Univ Navarra, Ctr Appl Med Res, Sch Med, Neurogenet Lab,Div Neurosci, E-31080 Pamplona, Spain. [Pastor, Pau] Inst Salud Carlos III, CIBERNED, Madrid, Spain. [Mateo, Ignacio; Combarros, Onofre] Univ Cantabria, Neurol Serv, Marques de Valdecilla Univ Hosp, E-39005 Santander, Spain. [Mateo, Ignacio; Combarros, Onofre] Inst Formac & Invest Marques Valdecilla IFIMAV, Santander, Spain. [Mateo, Ignacio; Combarros, Onofre] Univ Cantabria, Marques de Valdecilla Univ Hosp, CIBERNED, E-39005 Santander, Spain. [Mateo, Ignacio; Combarros, Onofre] IFIMAV, Santander, Spain. [Faber, Kelley M.; Foroud, Tatiana M.] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. [Jonsson, Palmi V.] Landspitali Univ Hosp, Geriatr Dept, Reykjavik, Iceland. [Soininen, Hilkka; Hiltunen, Mikko] Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland. [Soininen, Hilkka; Hiltunen, Mikko] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. [Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Med Geriatr, Jackson, MS 39216 USA. 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[Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77030 USA. [Boada, Merce] Univ Autonoma Barcelona VHIR UAB, Hosp Univ Vall dHebron, Inst Recerca, Barcelona, Spain. [Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Rujescu, Dan] Univ Halle, Dept Psychiat, Halle, Germany. [Dartigues, Jean-Francois] CHU Bordeaux, Ctr Memoire Ressources & Rech Bordeaux, Bordeaux, France. [Tzourio, Christophe] Victor Segalen Univ, INSERM, U708, Bordeaux, France. [Noethen, Markus M.] Univ Bonn, Inst Human Genet, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Graff, Caroline] Karolinska Inst, Dept Neurobiol, Alzheimers Dis Res Ctr, Stockholm, Sweden. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Haines, Jonathan L.] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN 37235 USA. [Lathrop, Mark] McGill Univ, Montreal, PQ, Canada. [Lathrop, Mark] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Farrer, Lindsay A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Amouyel, Philippe] Ctr Hosp Reg Univ Lille, Lille, France. RP Amouyel, P (reprint author), INSERM, U744, F-59045 Lille, France. EM williamsj@cardiff.ac.uk; philippe.amouyel@pasteur-lille.fr RI Kowall, Neil/G-6364-2012; Hardy, John/C-2451-2009; Reposo, Ramirez-Lorca/D-7907-2014; Aspelund, Thor/C-5983-2008; Powell, John/G-4412-2011; Lambert, jean-charles/A-9553-2014; Gu, Wei/G-4003-2010; Crane, Paul/C-8623-2014; berr, Claudine/D-5238-2014; Bosso, Paola/E-4832-2014; Schott, Jonathan/A-9065-2011; Singleton, Andrew/C-3010-2009; Ciaramella, Antonio/F-1170-2011; Deloukas, Panos/B-2922-2013; Pastor, Pau/C-9834-2009; Tzourio, christophe/B-4015-2009; Fox, Nick/B-1319-2009; lambert, jean-charles/F-8787-2013; Holmans, Peter/F-4518-2015; LICEND, CEMND/F-1296-2015; Frank Garcia, Ana/I-5159-2015; Gudnason, Vilmundur/K-6885-2015; Kamatani, Yoichiro/N-5513-2015; graff, caroline/A-2545-2009; Bullido, Maria/C-8509-2014; IBIS, TERAPIA CELULA/P-3297-2015; Smith, Albert/K-5150-2015; Ritchie, Karen/G-3571-2013; Caffarra, Paolo/K-6567-2016; Tsuang, Debby/L-7234-2016; Guerreiro, Rita/A-1327-2011; Vandenberghe, Rik/K-2145-2014; Epelbaum, Jacques/B-2263-2013; OI Kowall, Neil/0000-0002-6624-0213; Aspelund, Thor/0000-0002-7998-5433; Powell, John/0000-0001-6124-439X; Lambert, jean-charles/0000-0003-0829-7817; Gu, Wei/0000-0003-3951-6680; berr, Claudine/0000-0001-5254-7655; Bosso, Paola/0000-0002-1432-0078; Schott, Jonathan/0000-0003-2059-024X; Ciaramella, Antonio/0000-0001-9888-8156; Deloukas, Panos/0000-0001-9251-070X; Pastor, Pau/0000-0002-7493-8777; Tzourio, christophe/0000-0002-6517-2984; Fox, Nick/0000-0002-6660-657X; Holmans, Peter/0000-0003-0870-9412; Frank Garcia, Ana/0000-0003-3858-9116; Gudnason, Vilmundur/0000-0001-5696-0084; Bullido, Maria/0000-0002-6477-1117; Smith, Albert/0000-0003-1942-5845; Caffarra, Paolo/0000-0003-2246-5223; Tsuang, Debby/0000-0002-4716-1894; Vandenberghe, Rik/0000-0001-6237-2502; Ibrahim-verbaas, Carla/0000-0002-4325-0857; Ikram, Mohammad Arfan/0000-0003-0372-8585; Seshadri, Sudha/0000-0001-6135-2622; Chouraki, Vincent/0000-0002-4698-1794; Bayer, Antony/0000-0002-7514-248X; Kamboh, M. Ilyas/0000-0002-3453-1438; Sanchez-Garcia, Florentino/0000-0003-0304-6023; Escott-Price, Valentina/0000-0003-1784-5483; Reisberg, Barry/0000-0002-9104-7423; duron, emmanuelle/0000-0001-6680-3613; Harold, Denise/0000-0001-5195-0143; Lacour, Andre/0000-0003-2692-2583; Ferris, Steven/0000-0001-8641-6223; Buxbaum, Joseph/0000-0001-8898-8313; Panza, Francesco/0000-0002-7220-0656; Nothen, Markus/0000-0002-8770-2464; Pickering-Brown, Stuart/0000-0003-1561-6054; Squassina, Alessio/0000-0001-7415-7607; Beiser, Alexa/0000-0001-8551-7778; Alcolea, Daniel/0000-0002-3819-3245; Todd, Stephen/0000-0002-2312-9195; Matthews, Fiona/0000-0002-1728-2388 FU French National Foundation on Alzheimer's Disease and Related Disorders; Institut Pasteur de Lille; INSERM; FRC (Fondation pour la Recherche sur le Cerveau); Rotary; LABEX (Laboratory of Excellence Program Investment for the Future); DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease); Alzheimer's Association (Chicago, Illinois); Wellcome Trust; MRC; Alzheimer's Research UK (ARUK); Welsh government; US National Institutes of Health, National Institute on Aging (NIH-NIA) [U01 AG032984, R01 AG033193]; US National Institutes of Health; Erasmus Medical Center; Erasmus University FX This work was made possible by the generous participation of the control subjects, the patients and their families. iSelect chips were funded by the French National Foundation on Alzheimer's Disease and Related Disorders. Data management involved the Centre National de Genotypage and was supported by the Institut Pasteur de Lille, INSERM, FRC (Fondation pour la Recherche sur le Cerveau) and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease). The French National Foundation on Alzheimer's Disease and Related Disorders and the Alzheimer's Association (Chicago, Illinois) grant supported in-person meetings and communication for IGAP, and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses.; GERAD was supported by the Wellcome Trust, the MRC, Alzheimer's Research UK (ARUK) and the Welsh government. ADGC and CHARGE were supported by the US National Institutes of Health, National Institute on Aging (NIH-NIA), including grants U01 AG032984 and R01 AG033193 (additional US National Institutes of Health grant numbers are listed in the Supplementary Note).; CHARGE was also supported by Erasmus Medical Center and Erasmus University. NR 52 TC 620 Z9 631 U1 29 U2 215 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 DEC PY 2013 VL 45 IS 12 BP 1452 EP U206 DI 10.1038/ng.2802 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 262EA UT WOS:000327715800010 PM 24162737 ER PT J AU Guo, GW Sun, XJ Chen, C Wu, S Huang, PD Li, ZS Dean, M Huang, Y Jia, WL Zhou, Q Tang, AF Yang, ZQ Li, XX Song, PF Zhao, XK Ye, R Zhang, SQ Lin, Z Qi, MF Wan, SQ Xie, LF Fan, F Nickerson, ML Zou, XJ Hu, XD Xing, L Lv, ZJ Mei, HB Gao, SJ Liang, CZ Gao, ZB Lu, JX Yu, Y Liu, CX Li, L Fang, XD Jiang, ZM Yang, J Li, CL Zhao, X Chen, J Zhang, F Lai, YQ Lin, ZG Zhou, FJ Chen, H Chan, HC Tsang, S Theodorescu, D Li, YR Zhang, XQ Wang, J Yang, HM Gui, YT Wang, J Cai, ZM AF Guo, Guangwu Sun, Xiaojuan Chen, Chao Wu, Song Huang, Peide Li, Zesong Dean, Michael Huang, Yi Jia, Wenlong Zhou, Quan Tang, Aifa Yang, Zuoquan Li, Xianxin Song, Pengfei Zhao, Xiaokun Ye, Rui Zhang, Shiqiang Lin, Zhao Qi, Mingfu Wan, Shengqing Xie, Liangfu Fan, Fan Nickerson, Michael L. Zou, Xiangjun Hu, Xueda Xing, Li Lv, Zhaojie Mei, Hongbin Gao, Shengjie Liang, Chaozhao Gao, Zhibo Lu, Jingxiao Yu, Yuan Liu, Chunxiao Li, Lin Fang, Xiaodong Jiang, Zhimao Yang, Jie Li, Cailing Zhao, Xin Chen, Jing Zhang, Fang Lai, Yongqi Lin, Zheguang Zhou, Fangjian Chen, Hao Chan, Hsiao Chang Tsang, Shirley Theodorescu, Dan Li, Yingrui Zhang, Xiuqing Wang, Jian Yang, Huanming Gui, Yaoting Wang, Jun Cai, Zhiming TI Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation SO NATURE GENETICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; SHORT READ ALIGNMENT; COLORECTAL CANCERS; CELL-CARCINOMA; RNA-SEQ; MUTATIONS; FGFR3; ANEUPLOIDY; FUSIONS; VARIANT AB Bladder cancer is one of the most common cancers worldwide, with transitional cell carcinoma (TCC) being the predominant form. Here we report a genomic analysis of TCC by both whole-genome and whole-exome sequencing of 99 individuals with TCC. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, we identified additional altered genes and pathways that were implicated in TCC. Notably, we discovered frequent alterations in STAG2 and ESPL1, two genes involved in the sister chromatid cohesion and segregation (SCCS) process. Furthermore, we also detected a recurrent fusion involving FGFR3 and TACC3, another component of SCCS, by transcriptome sequencing of 42 DNA-sequenced tumors. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the SCCS process. Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer. C1 [Guo, Guangwu; Sun, Xiaojuan; Wu, Song; Li, Zesong; Huang, Yi; Tang, Aifa; Zhang, Shiqiang; Qi, Mingfu; Xie, Liangfu; Zou, Xiangjun; Xing, Li; Lv, Zhaojie; Mei, Hongbin; Chen, Hao; Cai, Zhiming] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Dept Urol Surg, Shenzhen, Peoples R China. [Guo, Guangwu; Chen, Chao; Huang, Peide; Jia, Wenlong; Zhou, Quan; Yang, Zuoquan; Song, Pengfei; Ye, Rui; Lin, Zhao; Wan, Shengqing; Fan, Fan; Hu, Xueda; Gao, Shengjie; Gao, Zhibo; Yu, Yuan; Li, Lin; Fang, Xiaodong; Yang, Jie; Zhao, Xin; Zhang, Fang; Li, Yingrui; Zhang, Xiuqing; Wang, Jian; Yang, Huanming; Wang, Jun] BGI Shenzhen, Shenzhen, Peoples R China. [Sun, Xiaojuan; Wu, Song; Li, Zesong; Huang, Yi; Tang, Aifa; Zhang, Shiqiang; Qi, Mingfu; Xie, Liangfu; Zou, Xiangjun; Xing, Li; Lv, Zhaojie; Mei, Hongbin; Chen, Hao; Cai, Zhiming] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Natl Reg Key Technol Engn Lab Clin Applicat Canc, Shenzhen, Peoples R China. [Sun, Xiaojuan; Wu, Song; Li, Zesong; Huang, Yi; Tang, Aifa; Zhang, Shiqiang; Qi, Mingfu; Xie, Liangfu; Zou, Xiangjun; Xing, Li; Lv, Zhaojie; Mei, Hongbin; Chen, Hao; Cai, Zhiming] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Shenzhen Engn Lab Tumor Clin Immune Gene Therapy, Shenzhen, Peoples R China. [Sun, Xiaojuan; Wu, Song; Li, Zesong; Huang, Yi; Tang, Aifa; Zhang, Shiqiang; Qi, Mingfu; Xie, Liangfu; Zou, Xiangjun; Xing, Li; Lv, Zhaojie; Mei, Hongbin; Chen, Hao; Cai, Zhiming] Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Shenzhen Key Lab Genitourinary Tumor, Shenzhen, Peoples R China. [Wu, Song] Sun Yat Sen Univ, Zhongshan Sch Med, Inst Immunol, Guangzhou 510275, Guangdong, Peoples R China. [Wu, Song; Zhou, Fangjian] Sun Yat Sen Univ, Ctr Canc, Dept Urol, Guangzhou 510275, Guangdong, Peoples R China. [Dean, Michael; Nickerson, Michael L.] NCI, Canc & Inflammat Program, US Natl Inst Hlth NIH, Frederick, MD 21701 USA. [Li, Xianxin; Lu, Jingxiao; Jiang, Zhimao; Li, Cailing; Chen, Jing; Lai, Yongqi; Lin, Zheguang; Gui, Yaoting] Peking Univ Shenzhen Hosp, Shenzhen PKU HKUST Med Ctr, Inst Urol, Guangdong & Shenzhen Key Lab Male Reprod Med & Ge, Shenzhen, Peoples R China. [Zhao, Xiaokun] Cent Southern Univ, Xiangya Hosp 2, Dept Urol, Changsha, Hunan, Peoples R China. [Liang, Chaozhao] Anhui Med Univ, Affiliated Hosp 1, Dept Urol, Hefei, Peoples R China. [Liu, Chunxiao] Southern Med Univ, Zhujiang Hosp, Dept Urol, Guangzhou, Guangdong, Peoples R China. [Chan, Hsiao Chang] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Epithelial Cell Biol Res Ctr, Shatin, Hong Kong, Peoples R China. [Tsang, Shirley] BioMatrix, Rockville, MD USA. [Theodorescu, Dan] Univ Colorado, Ctr Comprehens Canc, Dept Surg, Aurora, CO USA. [Wang, Jun] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Wang, Jun] Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark. RP Cai, ZM (reprint author), Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Dept Urol Surg, Shenzhen, Peoples R China. EM guiyaoting@hotmail.com; wangj@genomics.org.cn; caizhiming2000@163.com RI Chen, Hao/D-3425-2012; Li, Yingrui/K-1064-2015; Wang, Jun/C-8434-2016; Chan, Hsiao Chang/E-1507-2016; Wang, Jun/B-9503-2016 OI Wang, Jun/0000-0002-8540-8931; Peide, Huang/0000-0001-6108-5069; Wang, Jun/0000-0002-2113-5874 FU Chinese High-Tech (863) Program [2012AA02A201, 2012AA02A208]; Guangdong Innovative Research Team Program [2009010016]; State Key Development Program for Basic Research of China-973 Program [2011CB809203, 2014CB745200]; Shenzhen Municipal Government of China [JC201005260191A, CXB201108250096A, ZDSY20120615154448514, BGI20100001] FX This work was supported by grants from the Chinese High-Tech (863) Program (2012AA02A201 and 2012AA02A208), the Guangdong Innovative Research Team Program (2009010016), the State Key Development Program for Basic Research of China-973 Program (2011CB809203 and 2014CB745200) and the Shenzhen Municipal Government of China (JC201005260191A, CXB201108250096A, ZDSY20120615154448514 and BGI20100001). NR 39 TC 140 Z9 146 U1 13 U2 70 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 DEC PY 2013 VL 45 IS 12 BP 1459 EP U213 DI 10.1038/ng.2798 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 262EA UT WOS:000327715800011 PM 24121792 ER PT J AU Balbas-Martinez, C Sagrera, A Carrillo-de-Santa-Pau, E Earl, J Marquez, M Vazquez, M Lapi, E Castro-Giner, F Beltran, S Bayes, M Carrato, A Cigudosa, JC Dominguez, O Gut, M Herranz, J Juanpere, N Kogevinas, M Langa, X Lopez-Knowles, E Lorente, JA Lloreta, J Pisano, DG Richart, L Rico, D Salgado, RN Tardon, A Chanock, S Heath, S Valencia, A Losada, A Gut, I Malats, N Real, FX AF Balbas-Martinez, Cristina Sagrera, Ana Carrillo-de-Santa-Pau, Enrique Earl, Julie Marquez, Mirari Vazquez, Miguel Lapi, Eleonora Castro-Giner, Francesc Beltran, Sergi Bayes, Monica Carrato, Alfredo Cigudosa, Juan C. Dominguez, Orlando Gut, Marta Herranz, Jesus Juanpere, Nuria Kogevinas, Manolis Langa, Xavier Lopez-Knowles, Elena Lorente, Jose A. Lloreta, Josep Pisano, David G. Richart, Laia Rico, Daniel Salgado, Rocio N. Tardon, Adonina Chanock, Stephen Heath, Simon Valencia, Alfonso Losada, Ana Gut, Ivo Malats, Nuria Real, Francisco X. TI Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy SO NATURE GENETICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; COPY-NUMBER; FUNCTIONAL IMPACT; FGFR3 MUTATIONS; CELL-CARCINOMA; GENOME; COHESIN-SA1; VARIANTS; TUMORS; GENES AB Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management(1). A discovery exome sequencing screen (n = 17), followed by a prevalence screen (n = 60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2 and BPTF), cell division (STAG2, SMC1A and SMC1B) and DNA repair (ATM, ERCC2 and FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy. C1 [Balbas-Martinez, Cristina; Sagrera, Ana; Carrillo-de-Santa-Pau, Enrique; Earl, Julie; Lapi, Eleonora; Langa, Xavier; Richart, Laia; Real, Francisco X.] CNIO Spanish Natl Canc Res Ctr, Mol Pathol Programme, Epithelial Carcinogenesis Grp, Madrid, Spain. [Earl, Julie; Carrato, Alfredo] Hosp Ramon & Cajal, Serv Oncol Med, E-28034 Madrid, Spain. [Marquez, Mirari; Herranz, Jesus; Malats, Nuria] CNIO Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Genet & Mol Epidemiol Grp, Madrid, Spain. [Vazquez, Miguel; Rico, Daniel; Valencia, Alfonso] CNIO Spanish Natl Canc Res Ctr, Struct Biol & Biocomp Programme, Struct Computat Biol Grp, Madrid, Spain. [Castro-Giner, Francesc; Beltran, Sergi; Bayes, Monica; Gut, Marta; Heath, Simon; Gut, Ivo] CNAG, Barcelona, Spain. [Cigudosa, Juan C.; Salgado, Rocio N.] CNIO Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Mol Cytogenet Grp, Madrid, Spain. [Dominguez, Orlando] CNIO Spanish Natl Canc Res Ctr, Biotechnol Programme, Madrid, Spain. [Juanpere, Nuria; Lloreta, Josep] Hosp Mar Parc Salut Mar, Dept Pathol, Barcelona, Spain. [Kogevinas, Manolis] Ctr Recerca Epidemiol Ambiental, Barcelona, Spain. [Kogevinas, Manolis; Lopez-Knowles, Elena] Inst Recerca Hosp Mar, IMIM, Barcelona, Spain. [Kogevinas, Manolis] CIBERESP, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Lorente, Jose A.] Hosp Mar Parc Salut Mar, Urol Serv, Barcelona, Spain. [Lloreta, Josep; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Pisano, David G.] CNIO Spanish Natl Canc Res Ctr, Struct Biol & Biocomp Programme, Bioinformat Unit, Madrid, Spain. [Tardon, Adonina] Univ Oviedo, Dept Med, Oviedo, Spain. [Chanock, Stephen] NCI, Translat Genom Lab, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Losada, Ana] CNIO Spanish Natl Canc Res Ctr, Mol Oncol Programme, Chromosome Dynam Grp, Madrid, Spain. RP Real, FX (reprint author), CNIO Spanish Natl Canc Res Ctr, Mol Pathol Programme, Epithelial Carcinogenesis Grp, Madrid, Spain. EM preal@cnio.es RI Real Arribas, Francisco/H-5275-2015; Kogevinas, Manolis/C-3918-2017; Castro-Giner, Francesc/D-7992-2014; Lloreta, J/I-2112-2014; Losada, Ana/H-5917-2015; Valencia, Alfonso/I-3127-2015; Beltran, Sergi/I-3408-2015; Pisano, David/N-5817-2014; Herranz Valera, Jesus/M-8657-2014; OI Real Arribas, Francisco/0000-0001-9501-498X; Castro-Giner, Francesc/0000-0001-6111-0754; Lloreta, J/0000-0003-1644-9470; Losada, Ana/0000-0001-5251-3383; Valencia, Alfonso/0000-0002-8937-6789; Beltran, Sergi/0000-0002-2810-3445; Pisano, David/0000-0002-4895-4124; Herranz Valera, Jesus/0000-0002-7385-1311; Rico, Daniel/0000-0002-6561-2310; Malats, Nuria/0000-0003-2538-3784 FU Ministerio de Economia y Competitividad, Madrid [SAF-2010-21517, SAF2011-15934-E]; Instituto de Salud Carlos III [G03/174, 00/0745, PI051436, PI061614, PI080440, PI120425]; Asociacion Espanola Contra el Cancer [EU-FP7-201663]; US National Institutes of Health [RO1 CA089715]; La Caixa International PhD Fellowship; Fundacion Banco Santander Postdoctoral Programme FX We thank F. Algaba, Y. Allory, A. Cuadrado, C. Gonzalez, E. Lopez, P. Lapunzina, T. Lobato, M. Malumbres, S. Remeseiro, V.J. Sanchez-Arevalo, F. Waldman and the CNIO core facilities for valuable contributions. We also thank TCGA investigators for providing unpublished information for analysis. This work was supported, in part, by grants from Ministerio de Economia y Competitividad, Madrid (grants Consolider ONCOBIO, Consolider INESGEN, SAF-2010-21517 and SAF2011-15934-E), Instituto de Salud Carlos III (grants G03/174, 00/0745, PI051436, PI061614, G03/174, PI080440, PI120425 and Red Tematica de Investigacion Cooperativa en Cancer (RTICC)), Asociacion Espanola Contra el Cancer, EU-FP7-201663 and US National Institutes of Health grant RO1 CA089715. C. B.-M. is the recipient of a La Caixa International PhD Fellowship. E. L. is supported by a grant from the Fundacion Banco Santander Postdoctoral Programme. NR 34 TC 82 Z9 82 U1 0 U2 9 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 DEC PY 2013 VL 45 IS 12 BP 1464 EP U221 DI 10.1038/ng.2799 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 262EA UT WOS:000327715800012 PM 24121791 ER PT J AU Levine, DM Ek, WE Zhang, R Liu, XX Onstad, L Sather, C Lao-Sirieix, P Gammon, MD Corley, DA Shaheen, NJ Bird, NC Hardie, LJ Murray, LJ Reid, BJ Chow, WH Risch, HA Nyren, O Ye, WM Liu, G Romero, Y Bernstein, L Wu, AH Casson, AG Chanock, SJ Harrington, P Caldas, I Debiram-Beecham, I Caldas, C Hayward, NK Pharoah, PD Fitzgerald, RC MacGregor, S Whiteman, DC Vaughan, TL AF Levine, David M. Ek, Weronica E. Zhang, Rui Liu, Xinxue Onstad, Lynn Sather, Cassandra Lao-Sirieix, Pierre Gammon, Marilie D. Corley, Douglas A. Shaheen, Nicholas J. Bird, Nigel C. Hardie, Laura J. Murray, Liam J. Reid, Brian J. Chow, Wong-Ho Risch, Harvey A. Nyren, Olof Ye, Weimin Liu, Geoffrey Romero, Yvonne Bernstein, Leslie Wu, Anna H. Casson, Alan G. Chanock, Stephen J. Harrington, Patricia Caldas, Isabel Debiram-Beecham, Irene Caldas, Carlos Hayward, Nicholas K. Pharoah, Paul D. Fitzgerald, Rebecca C. MacGregor, Stuart Whiteman, David C. Vaughan, Thomas L. TI A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus SO NATURE GENETICS LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; GASTROESOPHAGEAL-REFLUX; QUALITY-CONTROL; CANCER; RISK; POLYMORPHISM; METAANALYSIS; POPULATION; CARCINOMA; VARIANTS AB Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 x 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 x 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 x 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma. C1 [Levine, David M.; Zhang, Rui] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Ek, Weronica E.; MacGregor, Stuart; Whiteman, David C.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Liu, Xinxue; Lao-Sirieix, Pierre; Debiram-Beecham, Irene; Fitzgerald, Rebecca C.] Hutchison MRC Res Ctr, Med Res Council MRC Canc Cell Unit, Cambridge, England. [Liu, Xinxue; Lao-Sirieix, Pierre; Debiram-Beecham, Irene; Fitzgerald, Rebecca C.] Univ Cambridge, Cambridge, England. [Onstad, Lynn; Reid, Brian J.; Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Sather, Cassandra] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Corley, Douglas A.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Corley, Douglas A.] Kaiser Permanente No Calif, San Francisco Med Ctr, San Francisco, CA USA. [Shaheen, Nicholas J.] Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Bird, Nigel C.] Univ Sheffield, Sch Med, Dept Oncol, Sheffield, S Yorkshire, England. [Hardie, Laura J.] Univ Leeds, Div Epidemiol, Leeds, W Yorkshire, England. [Murray, Liam J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Reid, Brian J.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98104 USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Nyren, Olof; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Liu, Geoffrey] Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. [Romero, Yvonne] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Romero, Yvonne] Mayo Clin, Romero Registry, Rochester, MN USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. [Bernstein, Leslie] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Wu, Anna H.] Univ So Calif, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Casson, Alan G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Harrington, Patricia; Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth, Cambridge, England. [Harrington, Patricia; Pharoah, Paul D.] Univ Cambridge, Dept Primary Care, Cambridge, England. [Harrington, Patricia; Caldas, Isabel; Caldas, Carlos; Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Caldas, Carlos] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England. [Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Oncogen Lab, Brisbane, Qld, Australia. RP Vaughan, TL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM tvaughan@u.washington.edu RI Macgregor, Stuart/C-6442-2009; hayward, nicholas/C-1367-2015; Whiteman, David/P-2728-2014; Liu, Geoffrey/N-4421-2016 OI Macgregor, Stuart/0000-0001-6731-8142; hayward, nicholas/0000-0003-4760-1033; Whiteman, David/0000-0003-2563-9559; FU US National Institutes of Health (NIH) [R01CA136725]; Australian Research Council [FT0990987]; Australian National Health and Medical Research Council (NHMRC); NHMRC of Australia; US NIH [NIDDK 02956, R01DK63616, R01CA59636, R01CA100264, P30CA016672, R01CA133996, HHSN268200782096C, U01CA57949, U01CA57983, U01CA57923]; Robert Wood Johnson Foundation; Fraternal Order of the Eagles; National Cancer Institute [R01 CA57947-03]; Swedish Cancer Society [4559-B01-01XAA, 4758-B02-01XAB]; California Tobacco-Related Research Program [3RT-0122, 10RT-0251]; Medical Research Council; Cancer Research UK; Cambridge National Institute for Health Research Biomedical Research Centre; Cambridge Experimental Cancer Medicine Centre; Cancer Research UK [C490/A10119, C490/A10124]; UTMDACC NIH SPORE in Melanoma [2P50CA093459]; Marit Peterson Fund for Melanoma Research; Wellcome Trust [076113]; American Digestive Health Foundation Endoscopic Research Award; American College of Gastroenterology Junior Faculty Development Award; Glaxo Wellcome, Inc.; Institute for Digestive Health Clinical Research Award; Miles and Shirley Fiterman Center for Digestive Diseases at the Mayo Clinic (Rochester, Minnesota); [K05CA124911] FX This work was primarily funded by a US National Institutes of Health (NIH) grant (R01CA136725) to T. L. V. and D. C. W. T. L. V. is also supported by grant K05CA124911. D. C. W. is supported by a Future Fellowship (FT0990987) from the Australian Research Council. S. M. is supported by an Australian National Health and Medical Research Council (NHMRC) Career Development Award. N.K.H. is supported by Research Fellowships from the NHMRC of Australia. Y.R. is supported in part by a grant from the US NIH (NIDDK 02956), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program and the Fraternal Order of the Eagles.; The Swedish Esophageal Cancer Study was funded by grants (R01 CA57947-03) from the National Cancer Institute and the Swedish Cancer Society (4559-B01-01XAA and 4758-B02-01XAB). The Kaiser-Permanente Study was supported by grants from the US NIH (R01DK63616 and R01CA59636) and from the California Tobacco-Related Research Program (3RT-0122 and 10RT-0251). The UK Barrett's oesophagus gene study was funded by a Medical Research Council Programme grant, and the UK SOCS study was funded by Cancer Research UK as well as by the Cambridge National Institute for Health Research Biomedical Research Centre and the Cambridge Experimental Cancer Medicine Centre. The SEARCH grant was funded by Cancer Research UK grants C490/A10119 and C490/A10124.; Genotyping of MD Anderson controls (C. Amos, PI) was performed through the University of Texas MD Anderson Cancer Center (UTMDACC) and the Johns Hopkins University Center for Inherited Disease Research (CIDR), supported in part by US NIH grants R01CA100264, P30CA016672 and R01CA133996 and the UTMDACC NIH SPORE in Melanoma 2P50CA093459, as well as by the Marit Peterson Fund for Melanoma Research. CIDR is supported by contract HHSN268200782096C from the US NIH.; This study made use of data generated by the Wellcome Trust Case Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs).; The Romero Registry is supported in part by the American Digestive Health Foundation Endoscopic Research Award, the American College of Gastroenterology Junior Faculty Development Award, the Glaxo Wellcome, Inc., Institute for Digestive Health Clinical Research Award and the Miles and Shirley Fiterman Center for Digestive Diseases at the Mayo Clinic (Rochester, Minnesota). The Romero Registry also receives charitable gifts from five industry partners (Affymetrix, AstraZeneca, Santarus, Takeda and Wyeth). The US Multicenter Study was funded by grants U01CA57949, U01CA57983 and U01CA57923 from the US NIH. NR 39 TC 68 Z9 69 U1 0 U2 9 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 DEC PY 2013 VL 45 IS 12 BP 1487 EP U119 DI 10.1038/ng.2796 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 262EA UT WOS:000327715800017 PM 24121790 ER PT J AU Perez-Andreu, V Roberts, KG Harvey, RC Yang, WJ Cheng, C Pei, DQ Xu, H Gastier-Foster, J E, SY Lim, JYS Chen, IM Fan, YP Devidas, M Borowitz, MJ Smith, C Neale, G Burchard, EG Torgerson, DG Klussmann, FA Villagran, CRN Winick, NJ Camitta, BM Raetz, E Wood, B Yue, F Carroll, WL Larsen, E Bowman, WP Loh, ML Dean, M Bhojwani, D Pui, CH Evans, WE Relling, MV Hunger, SP Willman, CL Mullighan, CG Yang, JJ AF Perez-Andreu, Virginia Roberts, Kathryn G. Harvey, Richard C. Yang, Wenjian Cheng, Cheng Pei, Deqing Xu, Heng Gastier-Foster, Julie E, Shuyu Lim, Joshua Yew-Suang Chen, I-Ming Fan, Yiping Devidas, Meenakshi Borowitz, Michael J. Smith, Colton Neale, Geoffrey Burchard, Esteban G. Torgerson, Dara G. Antillon Klussmann, Federico Najera Villagran, Cesar Rolando Winick, Naomi J. Camitta, Bruce M. Raetz, Elizabeth Wood, Brent Yue, Feng Carroll, William L. Larsen, Eric Bowman, W. Paul Loh, Mignon L. Dean, Michael Bhojwani, Deepa Pui, Ching-Hon Evans, William E. Relling, Mary V. Hunger, Stephen P. Willman, Cheryl L. Mullighan, Charles G. Yang, Jun J. TI Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse SO NATURE GENETICS LA English DT Article ID CHILDRENS ONCOLOGY GROUP; MINIMAL RESIDUAL DISEASE; GENOME-WIDE ASSOCIATION; ACUTE MYELOID-LEUKEMIA; MYELOPROLIFERATIVE NEOPLASMS; GENE-EXPRESSION; JAK2 HAPLOTYPE; CELL-TYPES; SUSCEPTIBILITY; POPULATIONS AB Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a high-risk subtype with an expression signature resembling that of Philadelphia chromosome-positive ALL and poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a susceptibility locus for Ph-like ALL (GATA3, rs3824662; P = 2.17 x 10(-14), odds ratio (OR) = 3.85 for Ph-like ALL versus non-ALL; P = 1.05 x 10(-8), OR = 3.25 for Ph-like ALL versus non-Ph-like ALL), with independent validation. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (CRLF2 rearrangement, JAK gene mutation and IKZF1 deletion) and with variation in GATA3 expression. Finally, genotype at the GATA3 SNP was also associated with early treatment response and risk of ALL relapse. Our results provide insights into interactions between inherited and somatic variants and their role in ALL pathogenesis and prognosis. C1 [Perez-Andreu, Virginia; Yang, Wenjian; Xu, Heng; E, Shuyu; Lim, Joshua Yew-Suang; Smith, Colton; Evans, William E.; Relling, Mary V.; Yang, Jun J.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Roberts, Kathryn G.; Mullighan, Charles G.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Harvey, Richard C.; Chen, I-Ming; Willman, Cheryl L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Cheng, Cheng; Pei, Deqing] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA. [Gastier-Foster, Julie] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH USA. [Gastier-Foster, Julie] Ohio State Univ, Sch Med, Dept Pediat, Columbus, OH 43210 USA. [Lim, Joshua Yew-Suang] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pediat, Singapore 117595, Singapore. [Fan, Yiping] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA. [Devidas, Meenakshi] Univ Florida, Dept Epidemiol & Hlth Policy Res, Gainesville, FL USA. [Borowitz, Michael J.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Neale, Geoffrey] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Burchard, Esteban G.; Torgerson, Dara G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci & Med, San Francisco, CA 94143 USA. [Antillon Klussmann, Federico; Najera Villagran, Cesar Rolando] Unidad Nacl Oncol Pediat, Guatemala City, Guatemala. [Winick, Naomi J.] Univ Texas SW Med Ctr Dallas, Dept Pediat Hematol Oncol, Dallas, TX 75390 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Raetz, Elizabeth; Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Wood, Brent] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Yue, Feng] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA USA. [Larsen, Eric] Maine Childrens Canc Program, Scarborough, ME USA. [Bowman, W. Paul] Cook Childrens Med Ctr, Dept Hematol & Oncol, Ft Worth, TX USA. [Loh, Mignon L.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Dean, Michael] NCI, Expt Immunol Lab, Frederick, MD 21701 USA. [Bhojwani, Deepa; Pui, Ching-Hon] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Hunger, Stephen P.] Univ Colorado, Childrens Hosp Colorado, Dept Hematol & Oncol, Aurora, CO USA. RP Yang, JJ (reprint author), St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA. EM jun.yang@stjude.org OI Harvey, Richard/0000-0002-4904-9767; Mullighan, Charles/0000-0002-1871-1850; Bhojwani, Deepa/0000-0002-7559-7927 FU Jeffrey Pride Foundation; National Childhood Cancer Foundation; Spanish Ministry of Education; St. Jude Children's Research Hospital Academic Programs Special Fellowship; American Society of Hematology Scholar Award; Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Grant; Order of St. Francis Foundation; National Health and Medical Research Council (Australia); Haematology Society of Australia; New Zealand Novartis New Investigator Scholarship; US National Institutes of Health [CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729, GM92666]; National Cancer Institute; American Lebanese Syrian Associated Charities (ALSAC) FX We thank the patients and parents who participated in the COG protocols included in this study, the clinicians and research staff at COG institutions and J. Pullen (University of Mississippi at Jackson) for assistance in the classification of patients with ALL. Genome-wide genotyping of COG P9905 samples was performed by the Center for Molecular Medicine with generous financial support from the Jeffrey Pride Foundation and the National Childhood Cancer Foundation. V. P.-A. is supported by a Spanish Ministry of Education Fellowship Grant and by a St. Jude Children's Research Hospital Academic Programs Special Fellowship. J.J.Y. is supported by an American Society of Hematology Scholar Award, an Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Grant and by the Order of St. Francis Foundation. K. G. R. is supported by a National Health and Medical Research Council (Australia) Overseas Training Fellowship and by a Haematology Society of Australia and New Zealand Novartis New Investigator Scholarship. C. G. M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick's Scholar. We thank M. Shriver (Pennsylvania State University) for sharing SNP genotype data for the Native American references, J. Pritchard and J. Degner (University of Chicago) for sharing DNase I hypersensitivity data for HapMap YRI cell lines, R. C. Ribeiro (St. Jude Children's Research Hospital) and P. De Alarcon (University of Illinois College of Medicine at Peoria) for coordinating collaborations in Guatemala and S. Naron for her editorial assistance. This work was supported by the US National Institutes of Health (grant numbers CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729 and GM92666), in part by the intramural Program of the National Cancer Institute and by the American Lebanese Syrian Associated Charities (ALSAC). Study sponsors were not directly involved in the design of the study, the collection, analysis and interpretation of data, the writing of the manuscript or the decision to submit the manuscript. Detailed acknowledgments for the dbGaP data sets are provided in the Supplementary Note. NR 48 TC 58 Z9 60 U1 4 U2 20 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 DEC PY 2013 VL 45 IS 12 BP 1494 EP U127 DI 10.1038/ng.2803 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 262EA UT WOS:000327715800018 PM 24141364 ER PT J AU He, Y Yu, SJ Bae, E Shen, H Wang, Y AF He, Yi Yu, Seongjin Bae, Eunkyung Shen, Hui Wang, Yun TI Methamphetamine alters reference gene expression in nigra and striatum of adult rat brain SO NEUROTOXICOLOGY LA English DT Article DE Methamphetamine; Housekeeping genes; Nigra; Real-time PCR; Reference genes; Striatum ID REAL-TIME PCR; HOUSEKEEPING GENES; RT-PCR; IN-VITRO; NORMALIZATION; ISCHEMIA; CORTEX AB The nigrostriatal dopaminergic system is a major lesion target for methamphetamine (MA), one of the most addictive and neurotoxic drugs of abuse. High doses of MA alter the expression of a large number of genes. Reference genes (RGs) are considered relatively stable and are often used as standards for quantitative real-time PCR (qRT-PCR) reactions. The purpose of this study was to determine whether MA altered the expression of RGs and to identify the appropriate RGs for gene expression studies in animals receiving MA. Adult male Sprague-Dawley rats were treated with high doses of MA or saline. Striatum and substantia nigra were harvested at 2 h or 24 h after MA administration. The expression and stability of 10 commonly used RGs were examined using qRT-PCR and then evaluated by geNorm and Normfinder. We found that MA altered the expression of selected RGs. These candidate RGs presented differential stability in the striatum and in substantia nigra at both 2 h and 24 h after MA injection. Selection of an unstable RG as a standard altered the significance of tyrosine hydroxylase (TH) mRNA expression after MA administration. In conclusion, our data show that MA site- and time-dependently altered the expression of RGs in nigrostriatal dopaminergic system. These temporal and spatial factors should be considered when selecting appropriate RGs for interpreting the expression of target genes in animals receiving MA. Published by Elsevier Inc. C1 [He, Yi; Shen, Hui; Wang, Yun] NIDA, Neural Protect & Regenerat Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Yu, Seongjin; Bae, Eunkyung; Wang, Yun] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Zhunan 35053, Miaoli County, Taiwan. RP Wang, Y (reprint author), Natl Hlth Res Inst, Ctr Neuropsychiat Res, 35 Keyan Rd, Zhunan 35053, Miaoli County, Taiwan. EM yi.he2@nih.gov; b7508@nhri.org.tw; baee@nhri.org.tw; HShen@intra.nida.nih.gov; ywang@nhri.org.tw FU National Health Research Institutes, Taiwan; National Institute on Drug Abuse, IRP, USA FX This study was supported by National Health Research Institutes, Taiwan and National Institute on Drug Abuse, IRP, USA. NR 26 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD DEC PY 2013 VL 39 BP 138 EP 145 DI 10.1016/j.neuro.2013.08.009 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 270GK UT WOS:000328306700018 PM 24042092 ER PT J AU Edderkaoui, B Kesavan, C Baylink, DJ Wergedal, JE Srivastava, AK Mohan, S AF Edderkaoui, Bouchra Kesavan, Chandrasekhar Baylink, David J. Wergedal, Jon E. Srivastava, Apurva K. Mohan, Subburaman TI ENU mutation mapped to a distal region of chromosome 11 is a major determinant of bone size SO PHYSIOLOGICAL GENOMICS LA English DT Article DE mutation; growth hormone; bone formation ID QUANTITATIVE TRAIT LOCI; NITROSOUREA-MUTAGENIZED MICE; CHEMICAL MUTAGENESIS; GENETIC-LOCI; MECHANICAL-PROPERTIES; MOUSE STRAINS; C57BL/6J MICE; SCREEN; GROWTH; IDENTIFICATION AB Using a phenotype driven n-ethyl-nitrosourea (ENU) screen in growth hormone-deficient mice, we have identified a mutant (named 14104) that exhibited a smaller bone size. Phenotype measurements by microcomputed tomography revealed that mutant mice exhibited a 43 and 34% reduction in tissue area and bone area, respectively at the femur middiaphysis. Dynamic histomorphometry revealed a 30 and 15% lower bone formation rate at the periosteal and endosteal surface, respectively. Breaking strength of the femur was reduced by 30% in the mutant mice. To determine if the 14104 locus is involved in a mechanical loading signaling pathway, the skeletal anabolic response to tibia axial loading was evaluated. The increase in trabecular response in the loaded region was severely compromised by the 14014 mutation. To identify the location of mutation, we performed linkage analysis using 62 polymorphic markers in the B6-DBA/2J F2 mice. The genome-wide linkage analysis identified the location of the mutation to a 72 to 83 cM region on chromosome 11 with peak logarithm of the odds scores of 15 for periosteal circumference at marker D11mit338. Sequence analysis revealed no mutation in the coding region of 11 potential candidate genes. Based on these data and published data on the skeletal phenotype of genes in this region, we concluded that the 109-119 Mb region of chromosome 11 harbors a bone size gene that regulates periosteal bone formation. The mutant strain developed in this study provides an important tool to identify a novel mechanosensitive gene that determines bone size during postnatal development. C1 [Edderkaoui, Bouchra; Kesavan, Chandrasekhar; Wergedal, Jon E.; Mohan, Subburaman] Loma Linda VA Hlth Care Syst, Musculoskeletal Dis Ctr, Loma Linda, CA 92357 USA. [Edderkaoui, Bouchra; Kesavan, Chandrasekhar; Baylink, David J.; Wergedal, Jon E.; Mohan, Subburaman] Loma Linda Univ, Dept Med, Loma Linda, CA 92350 USA. [Srivastava, Apurva K.] Frederick Natl Lab Canc Res, Lab Human Toxicol Pharmacol, Appl Dev Res Directorate, SAIC Frederick, Frederick, MD USA. RP Mohan, S (reprint author), Loma Linda VA Hlth Care Syst, Musculoskeletal Dis Ctr, 11201 Benton St, Loma Linda, CA 92357 USA. EM Subburaman.Mohan@va.gov FU Army Assistance Award [DAMD17-99-1-9571]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR-048139] FX This work was supported by the Army Assistance Award No. DAMD17-99-1-9571 and National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-048139. NR 25 TC 0 Z9 0 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD DEC PY 2013 VL 45 IS 24 BP 1222 EP 1228 DI 10.1152/physiolgenomics.00142.2013 PG 7 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 273CA UT WOS:000328509600006 PM 24151243 ER PT J AU de las Heras, H Minniti, R Wilson, S Mitchell, C Skopec, M Brunner, CC Chakrabarti, K AF de las Heras, Hugo Minniti, Ronaldo Wilson, Sean Mitchell, Chad Skopec, Marlene Brunner, Claudia C. Chakrabarti, Kish TI Experimental estimates of peak skin dose and its relationship to the CT dose index using the CTDI head phantom SO RADIATION PROTECTION DOSIMETRY LA English DT Article ID PERFUSION COMPUTED-TOMOGRAPHY; RADIOCHROMIC FILM; CORONARY-ANGIOGRAPHY; ENERGY-DEPENDENCE; DOSIMETRY; SIMULATIONS; SCANNER; PATIENT AB A straightforward method is presented to estimate peak skin doses (PSDs) delivered by computed tomography (CT) scanners. The measured PSD values are related to the well-known volume CT dose index (CTDIvol), displayed on the console of CT scanners. PSD measurement estimates were obtained, in four CT units, by placing radiochromic film on the surface of a CTDI head phantom. Six different X-ray tube currents including the maximum allowed value were used to irradiate the phantom. PSD and CTDIvol were independently measured and later related to the CTDIvol value displayed on the console. A scanner-specific relationship was found between the measured PSD and the associated CTDIvol displayed on the console. The measured PSD values varied between 27 and 136 mGy among all scanners when the routine head scan parameters were used. The results of this work allow relating the widely used CTDIvol to an actual radiation dose delivered to the skin of a patient. C1 [de las Heras, Hugo; Brunner, Claudia C.; Chakrabarti, Kish] US FDA, Silver Spring, MD 20993 USA. [Minniti, Ronaldo] NIST, Gaithersburg, MD 20899 USA. [Wilson, Sean; Mitchell, Chad] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20889 USA. [Skopec, Marlene] NIH, Bethesda, MD 20892 USA. RP de las Heras, H (reprint author), US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM hugo.heras@daad-alumni.de OI de las Heras, Hugo/0000-0003-3227-0032 FU Critical Path Project of FDA FX Kish Chakrabarti acknowledges funding from Critical Path Project of FDA, which enabled him to fund H.H. and C.B. for this work. NR 40 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 EI 1742-3406 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD DEC PY 2013 VL 157 IS 4 BP 536 EP 542 DI 10.1093/rpd/nct171 PG 7 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 271FI UT WOS:000328376600008 PM 23864642 ER PT J AU Lamart, S Moroz, BE Lee, C AF Lamart, Stephanie Moroz, Brian E. Lee, Choonsik TI Evaluation of the use of surrogate tissues for calculating radiation dose to lymphatic nodes from external photon beams SO RADIATION PROTECTION DOSIMETRY LA English DT Article ID ADULT HUMAN PHANTOMS; COMPUTATIONAL PHANTOMS; RADIOLOGICAL PROTECTION; HYBRID PHANTOMS; HUMAN ANATOMY; DOSIMETRY; MODELS; CONSTRUCTION; DISTRIBUTIONS; EXPOSURES AB Lymphatic node chains of the human body are particularly difficult to realistically model in computational human phantoms. In the absence of a lymphatic node model, researchers have used the following surrogate tissues to calculate the radiation dose to the lymphatic nodes: blood vessels, muscle and the combination of the muscle and adipose tissues. In the present work, the authors investigated whether and in which extent the use of different surrogate tissues is appropriate to assess the lymph node dose, using a realistic model of lymphatic nodes that the authors recently reported. Using a Monte Carlo radiation transport method coupled with the adult male hybrid phantom that included the lymph node model, the air kerma-to-absorbed dose conversion coefficients (Gy Gy(1)) to the lymph nodes and other tissues used as surrogates for external photon beams of 15 discrete energies (0.01510 MeV) were computed using the following six idealised geometries: anteriorposterior (AP), posterioranterior (PA), right lateral, left lateral, rotational and isotropic. To validate the results of this study, the lymph node dose calculated here was compared with the dose published by the International Commission on Radiological Protection for the adult male reference phantom. The lymph node dose conversion coefficients with the values calculated for the blood vessels, muscle, adipose tissue and the combination of muscle and adipose tissues were then compared. It was found that muscle was the best estimator for the lymph nodes, with a dose difference averaged across energies 0.08 MeV of 8 in all irradiation geometries excluding the AP and PA geometries for which the blood vessels were found to be the best estimator. In conclusion, muscle and blood vessels may preferably be used as surrogate tissues in the absence of lymphatic nodes in a given voxel phantom. For energies 0.08 MeV, for which the authors observed a difference of up to 30-fold, an explicit lymph node model may be required to prevent increasing differences with the lymph node dose as the photon energy decreases, though the absolute values of the dose conversion coefficients are smaller than at higher energy. C1 [Lamart, Stephanie; Moroz, Brian E.; Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. RP Lee, C (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM leechoonsik@mail.nih.gov RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU National Cancer Institute, National Institutes of Health, US Department of Health and Human Services FX This study was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. NR 34 TC 0 Z9 0 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 EI 1742-3406 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD DEC PY 2013 VL 157 IS 4 BP 600 EP 609 DI 10.1093/rpd/nct164 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 271FI UT WOS:000328376600017 PM 23847324 ER PT J AU Wang, D Piknova, B Solomon, SB Cortes-Puch, I Kern, SJ Sun, JF Kanias, T Gladwin, MT Helms, C Kim-Shapiro, DB Schechter, AN Natanson, C AF Wang, Dong Piknova, Barbora Solomon, Steven B. Cortes-Puch, Irene Kern, Steven J. Sun, Junfeng Kanias, Tamir Gladwin, Mark T. Helms, Christine Kim-Shapiro, Daniel B. Schechter, Alan N. Natanson, Charles TI In vivo reduction of cell-free methemoglobin to oxyhemoglobin results in vasoconstriction in canines SO TRANSFUSION LA English DT Article ID INHALED NITRIC-OXIDE; HEME-GLOBIN LINKAGE; PLASMA HEMOGLOBIN; BLOOD SUBSTITUTES; MYOCARDIAL-INFARCTION; HEMORRHAGIC-SHOCK; OXYGEN CARRIERS; S-NITROSOTHIOLS; BYPASS-SURGERY; BLINDED TRIAL AB BackgroundCell-free hemoglobin (Hb) in the vasculature leads to vasoconstriction and injury. Proposed mechanisms have been based on nitric oxide (NO) scavenging by oxyhemoglobin (oxyHb) or processes mediated by oxidative reactions of methemoglobin (metHb). To clarify this, we tested the vascular effect and fate of oxyHb or metHb infusions. Study Design and MethodsTwenty beagles were challenged with 1-hour similar infusions of (200mol/L) metHb (n=5), oxyHb (n=5), albumin (n=5), or saline (n=5). Measurements were taken over 3 hours. ResultsInfusions of the two pure Hb species resulted in increases in mean arterial blood pressure (MAP), systemic vascular resistance index, and NO consumption capacity of plasma (all p<0.05) with the effects of oxyHb being greater than that from metHb (MAP; increase 0 to 3hr; 276% vs. 7 +/- 2%, respectively; all p<0.05). The significant vasoconstrictive response of metHb (vs. albumin and saline controls) was related to in vivo autoreduction of metHb to oxyHb, and the vasoactive Hb species that significantly correlated with MAP was always oxyHb, either from direct infusion or after in vivo reduction from metHb. Clearance of total Hb from plasma was faster after metHb than oxyHb infusion (p<0.0001). ConclusionThese findings indicate that greater NO consumption capacity makes oxyHb more vasoactive than metHb. Additionally, metHb is reduced to oxyHb after infusion and cleared faster or is less stable than oxyHb. Although we found no direct evidence that metHb itself is involved in acute vascular effects, in aggregate, these studies suggest that metHb is not inert and its mechanism of vasoconstriction is due to its delayed conversion to oxyHb by plasma-reducing agents. C1 NIDDK, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Piknova, Barbora] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. Sichuan Univ, Anesthesia & Crit Care Med Dept, West China Hosp, Chengdu 610064, Peoples R China. Hosp Univ Getafe, Dept Crit Care Med, Madrid, Spain. RP Piknova, B (reprint author), NIDDK, Mol Med Branch, NIH, 10 Ctr Dr,9N318, Bethesda, MD 20892 USA. EM piknovab@mail.nih.gov RI Kanias, Tamir/K-2384-2016; OI Kanias, Tamir/0000-0001-6558-0913; Schechter, Alan N/0000-0002-5235-9408 FU NIH [HL058091, HL098032, RO1HL096973, P01HL103455]; Institute for Transfusion Medicine; Hemophilia Center of Western Pennsylvania; US government FX This study was conducted using intramural NIH funds and NIH grants HL058091 (DK-S) and HL098032 (MTG and DKS). MTG also receives research support from NIH grants RO1HL096973, and P01HL103455, the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania. The work by the authors was done as part of US government-funded research; however, the opinions expressed are not necessarily those of the National Institutes of Health. NR 66 TC 4 Z9 4 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD DEC PY 2013 VL 53 IS 12 BP 3149 EP 3163 DI 10.1111/trf.12162 PG 15 WC Hematology SC Hematology GA 265CD UT WOS:000327926400016 PM 23488474 ER PT J AU Cherry, JL AF Cherry, Joshua L. TI Inbreeding and asexuality: a response to Szulkin et al SO TRENDS IN ECOLOGY & EVOLUTION LA English DT Letter C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Cherry, JL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM jcherry@nebi.nlm.nih.gov NR 2 TC 2 Z9 2 U1 2 U2 13 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0169-5347 J9 TRENDS ECOL EVOL JI Trends Ecol. Evol. PD DEC PY 2013 VL 28 IS 12 BP 683 EP 683 DI 10.1016/j.tree.2013.08.001 PG 1 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 270IU UT WOS:000328312900003 PM 24189156 ER PT J AU Yamashita, S Segawa, R Satou, N Hiratsuka, M Leonard, WJ Hirasawa, N AF Yamashita, Saori Segawa, Ryosuke Satou, Nozomi Hiratsuka, Masahiro Leonard, Warren J. Hirasawa, Noriyasu TI Induction of Thymic Stromal Lymphopoietin Production by Nonanoic Acid and Exacerbation of Allergic Inflammation in Mice SO ALLERGOLOGY INTERNATIONAL LA English DT Article DE fatty acid; nonanoic acid; ovalbumin; picryl chloride; thymic stromal lymphopoietin ID ARYL-HYDROCARBON RECEPTOR; IN-VIVO; EXPRESSION; TSLP; SKIN; KERATINOCYTES; DERMATITIS; IRRITANTS; CYTOKINES; LIGANDS AB Background: Thymic stromal lymphopoietin (TSLP) plays critical roles in the induction and exacerbation of allergic diseases. We tested various chemicals in the environment and found that xylene and 1,2,4-trimethylbenzene induced the production of TSLP in vivo. These findings prompted us to search for additional chemicals that induce TSLP production. In this study, we examined whether fatty acids could induce the production of TSLP in vivo and exacerbate allergic inflammation. Methods: Various fatty acids and related compounds were painted on the ear lobes of mice and the amount of TSLP in the homogenate of ear lobe tissue was determined. The effects of nonanoic acid on allergic inflammation were also examined. Results: Octanoic acid, nonanoic acid, and decanoic acid markedly induced TSLP production, while a medium-chain aldehyde and alcohol showed only weak activity. Nonanoic acid induced the production of TSLP with a maximum at 24 h. TSLP production was even observed in nonanoic acid-treated C3H/HeJ mice that lacked functional toll-like receptor 4. The aryl hydrocarbon receptor agonist beta-naphthoflavone did not induce TSLP production. Nonanoic acid promoted sensitization to ovalbumin, resulting in an enhancement in the cutaneous anaphylactic response. In addition, painting of nonanoic acid after the sensitization augmented picryl chloride-induced thickening of the ear, which was reversed in TSLP receptor-deficient mice. Conclusions: Nonanoic acid and certain fatty acids induced TSLP production, resulting in the exacerbation of allergic inflammation. We propose that TSLP-inducing chemical compounds such as nonanoic acid be recognized as chemical allergo-accelerators. C1 [Yamashita, Saori; Segawa, Ryosuke; Satou, Nozomi; Hiratsuka, Masahiro; Hirasawa, Noriyasu] Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi 9808578, Japan. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Hirasawa, N (reprint author), Tohoku Univ, Grad Sch Pharmaceut Sci, Lab Pharmacotherapy Life Style Related Dis, Aoba Ku, 6-3 Aoba Aramaki, Sendai, Miyagi 9808578, Japan. EM hirasawa@m.tohoku.ac.jp FU Long-range Research Initiative (LRI) by the Japan Chemical Industry Association (JCIA); Japan Society for the Promotion of Science [22659025]; Smoking Research Foundation; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institute of Health, USA FX The study was supported in part by a grant from the Long-range Research Initiative (LRI) by the Japan Chemical Industry Association (JCIA), a Grant-in-aid for Challenging Exploratory Research (22659025) from the Japan Society for the Promotion of Science, a grant from the Smoking Research Foundation, and by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institute of Health, USA. NR 33 TC 4 Z9 4 U1 1 U2 5 PU JAPANESE SOCIETY ALLERGOLOGY PI TOKYO PA MY BLDG 4F, 1-13-3, UENO, TAITO-KU, TOKYO, 110-0005, JAPAN SN 1323-8930 EI 1440-1592 J9 ALLERGOL INT JI Allergol. Int. PD DEC PY 2013 VL 62 IS 4 BP 463 EP 471 DI 10.2332/allergolint.13-OA-0552 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 268OE UT WOS:000328179600007 PM 24060765 ER PT J AU Mueller, GA Maleki, SJ Johnson, K Hurlburt, BK Cheng, H Ruan, S Nesbit, JB Pomes, A Edwards, LL Schorzman, A Deterding, LJ Park, H Tomer, KB London, RE Williams, JG AF Mueller, G. A. Maleki, S. J. Johnson, K. Hurlburt, B. K. Cheng, H. Ruan, S. Nesbit, J. B. Pomes, A. Edwards, L. L. Schorzman, A. Deterding, L. J. Park, H. Tomer, K. B. London, R. E. Williams, J. G. TI Identification of Maillard reaction products on peanut allergens that influence binding to the receptor for advanced glycation end products SO ALLERGY LA English DT Article DE advanced glycation end product; allergens; epitopes; peanuts; receptor for AGE ID ARA H 1; PROCESSED PEANUTS; CRYSTAL-STRUCTURE; IGE BINDING; FOOD; ENDPRODUCTS; PREVALENCE; PROTEINS; CACO-2; CELLS AB BackgroundRecent immunological data demonstrated that dendritic cells preferentially recognize advanced glycation end product (AGE)-modified proteins, upregulate expression of the receptor for AGE (RAGE), and consequently bias the immune response toward allergy. MethodsPeanut extract was characterized by mass spectrometry (MS) to elucidate the specific residues and specific AGE modifications found in raw and roasted peanuts and on rAra h 1 that was artificially glycated by incubation with glucose or xylose. The binding of the RAGE-V1C1 domain to peanut allergens was assessed by PAGE and Western analysis with anti-Ara h 1, 2, and 3 antibodies. IgE binding to rAra h 1 was also assessed using the same methods. ResultsAGE modifications were found on Ara h 1 and Ara h 3 in both raw and roasted peanut extract. No AGE modifications were found on Ara h 2. Mass spectrometry and Western blot analysis demonstrated that RAGE binds selectively to Ara h 1 and Ara h 3 derived from peanut extract, whereas the analysis failed to demonstrate Ara h 2 binding to RAGE. rAra h 1 with no AGE modifications did not bind RAGE; however, after AGE modification with xylose, rAra h 1 bound to RAGE. ConclusionsAGE modifications to Ara h 1 and Ara h 3 can be found in both raw and roasted peanuts. Receptor for AGE was demonstrated to selectively interact with AGE-modified rAra h 1. If sensitization to peanut allergens occurs in dendritic cells via RAGE interactions, these cells are likely interacting with modified Ara h 1 and Ara h 3, but not Ara h 2. C1 [Mueller, G. A.; Johnson, K.; Edwards, L. L.; Schorzman, A.; Deterding, L. J.; Tomer, K. B.; London, R. E.; Williams, J. G.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Maleki, S. J.; Hurlburt, B. K.; Cheng, H.; Ruan, S.; Nesbit, J. B.] ARS, USDA, So Reg Res Ctr, New Orleans, LA USA. [Pomes, A.] Indoor Biotechnol Inc, Charlottesville, VA USA. [Park, H.] Scripps Res Inst, Jupiter, FL USA. RP Mueller, GA (reprint author), NIEHS, 111 TW Alexander Dr,MD MR 01, Res Triangle Pk, NC 27709 USA. EM Mueller3@niehs.nih.gov OI Pomes, Anna/0000-0002-8729-1829 FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES102885-01, Z01-ES50161, Z01-ES102488-05]; Agricultural Research Service, U.S. Department of Agriculture FX This research was supported in part by Research Project Number Z01-ES102885-01 to REL, Z01-ES50161 to KBT, and Z01-ES102488-05 to JGW in the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. This work was supported in part by the Agricultural Research Service, U.S. Department of Agriculture. NR 23 TC 17 Z9 17 U1 8 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 EI 1398-9995 J9 ALLERGY JI Allergy PD DEC PY 2013 VL 68 IS 12 BP 1546 EP 1554 DI 10.1111/all.12261 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 263IK UT WOS:000327801600006 PM 24266677 ER PT J AU Freedman, DS Horlick, M Berenson, GS AF Freedman, David S. Horlick, Mary Berenson, Gerald S. TI A comparison of the Slaughter skinfold-thickness equations and BMI in predicting body fatness and cardiovascular disease risk factor levels in children SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID X-RAY ABSORPTIOMETRY; INDEX-FOR-AGE; MASS INDEX; METABOLIC RISK; BLOOD-PRESSURE; FAT MASS; ADOLESCENTS; ADIPOSITY; OBESITY; YOUTH AB Background: Although estimation of percentage body fat with the Slaughter skinfold-thickness equations (PBFSlaughter) is widely used, the accuracy of this method has not been well studied. Objective: The objective was to determine the accuracy of the Slaughter skinfold-thickness equations. Design: We compared agreement between PBFSlaughter and estimations derived from dual-energy X-ray absorptiometry (PBFDXA) in 1169 children in the Pediatric Rosetta Body Composition Project and the relation to cardiovascular disease risk factors, as compared with body mass index (BMI), in 6725 children in the Bogalusa Heart Study. Results: PBFSlaughter was highly correlated (r = 0.90) with PBFDXA, but it markedly overestimated levels of PBFDXA in children with large skinfold thicknesses. In the 65 boys with a sum of skinfold thicknesses (subscapular- plus triceps-skinfold thicknesses) >= 50 mm, PBFSlaughter overestimated PBFDXA by 12 percentage points. The comparable overestimation in girls with a high skinfold sum was 6 percentage points. We also found that, after adjustment for sex and age, BMI showed slightly stronger associations with lipid, lipoprotein, insulin, and blood pressure values than did PBFSlaughter. Conclusions: These results indicate that PBFSlaughter which was developed among a group of much thinner children and adolescents, is fairly accurate among nonobese children, but markedly overestimates the body fatness of children who have thick skinfold thicknesses. Furthermore, PBFSlaughter has no advantage over sex- and age-adjusted BMIs at identifying children who are at increased risk of cardiovascular disease based on lipid, lipoprotein, insulin, and blood pressure values. C1 [Freedman, David S.] CDC, Div Nutr Phys Act & Obes, Atlanta, GA 30333 USA. [Horlick, Mary] NIDDK, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. [Berenson, Gerald S.] Tulane Univ, Sch Publ Hlth & Trop Med, Tulane Ctr Cardiovasc Hlth, New Orleans, LA USA. RP Freedman, DS (reprint author), CDC F77,4770 Buford Highway, Atlanta, GA 30341 USA. EM dxf1@cdc.gov FU NIH [DK37352, AG16592] FX Supported by grants DK37352 and AG16592 from the NIH. NR 49 TC 18 Z9 20 U1 3 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2013 VL 98 IS 6 BP 1417 EP 1424 DI 10.3945/ajcn.113.065961 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 266DG UT WOS:000328002000008 PM 24153344 ER PT J AU Cogswell, ME Wang, CY Chen, TC Pfeiffer, CM Elliott, P Gillespie, CD Carriquiry, AL Sempos, CT Liu, K Perrine, CG Swanson, CA Caldwell, KL Loria, CM AF Cogswell, Mary E. Wang, Chia-Yih Chen, Te-Ching Pfeiffer, Christine M. Elliott, Paul Gillespie, Cathleen D. Carriquiry, Alicia L. Sempos, Christopher T. Liu, Kiang Perrine, Cria G. Swanson, Christine A. Caldwell, Kathleen L. Loria, Catherine M. TI Validity of predictive equations for 24-h urinary sodium excretion in adults aged 18-39 y SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID DAILY SALT INTAKE; POTASSIUM EXCRETION; BLOOD-PRESSURE; CREATININE; COLLECTIONS; VARIABILITY; SPECIMEN; CALCIUM; OUTPUT; MEN AB Background: Collecting a 24-h urine sample is recommended for monitoring the mean population sodium intake, but implementation can be difficult. Objective: The objective was to assess the validity of published equations by using spot urinary sodium concentrations to predict 24-h sodium excretion. Design: This was a cross-sectional study, conducted from June to August 2011 in metropolitan Washington, DC, of 407 adults aged 18-39 y, 48% black, who collected each urine void in a separate container for 24 h. Four timed voids (morning, afternoon, evening, and overnight) were selected from each 24-h collection. Published equations were used to predict 24-h sodium excretion with spot urine by specimen timing and race-sex subgroups. We examined mean differences with measured 24-h sodium excretion (bias) and individual differences with the use of Bland-Altman plots. Results: Across equations and specimens, mean bias in predicting 24-h sodium excretion for all participants ranged from -267 to 1300 mg (Kawasaki equation). Bias was least with International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT) equations with morning (-165 mg; 95% CI: -295, 36 mg), afternoon (-90 mg; -208, 28 mg), and evening (-120 mg; -230, -11 mg) specimens. With overnight specimens, mean bias was least when the Tanaka (-23 mg; 95% CI: -141, 95 mg) or Mage (-145 mg; -314, 25 mg) equations were used but was statistically significant when using the Tanaka equations among females (216 to 243 mg) and the Mage equations among races other than black (-554 to -372 mg). Significant over- and underprediction occurred across individual sodium excretion concentrations. Conclusions: Using a single spot urine, INTERSALT equations may provide the least biased information about population mean sodium intakes among young US adults. None of the equations evaluated provided unbiased estimates of individual 24-h sodium excretion. C1 [Cogswell, Mary E.; Gillespie, Cathleen D.] CDC, Div Heart Dis & Stroke Prevent, Atlanta, GA 30341 USA. [Perrine, Cria G.] CDC, Div Nutr Phys Act & Obes, Atlanta, GA 30341 USA. [Pfeiffer, Christine M.; Caldwell, Kathleen L.] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Pfeiffer, Christine M.; Caldwell, Kathleen L.] CDC, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Wang, Chia-Yih; Chen, Te-Ching] CDC, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Loria, Catherine M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Sempos, Christopher T.; Swanson, Christine A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Elliott, Paul] MRC, Hlth Protect Agcy, Ctr Environm & Hlth, London, England. RP Cogswell, ME (reprint author), CDC, Mailstop F-72,4770 Buford Highway NE, Atlanta, GA 30341 USA. EM mcogswell@cdc.gov FU National Institute for Health Research Biomedical Research Centre; Imperial College Healthcare National Health Service Trust; Imperial College FX The authors' responsibilities were as follows-MEC, C-YW, T-CC, CMP, PE, CDG, ALC, CTS, KL, COP, CAS, KLC, and CML: designed the analysis; MEC, C-YW, T-CC, and CDG: analyzed the data; MEC: wrote the initial draft, which was modified based on critical review from all coauthors, and had primary responsibility for all of the content. All authors read and approved the final manuscript. PE acknowledges support from the National Institute for Health Research Biomedical Research Centre, Imperial College Healthcare National Health Service Trust and Imperial College. PE is a Senior Investigator at the National Institute for Health Research. None of the authors had any conflicts of interest. NR 46 TC 37 Z9 39 U1 1 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2013 VL 98 IS 6 BP 1502 EP 1513 DI 10.3945/ajcn.113.059436 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 266DG UT WOS:000328002000018 PM 24047921 ER PT J AU Steer, CD Lattka, E Koletzko, B Golding, J Hibbeln, JR AF Steer, Colin D. Lattka, Eva Koletzko, Berthold Golding, Jean Hibbeln, Joseph R. TI Maternal fatty acids in pregnancy, FADS polymorphisms, and child intelligence quotient at 8 y of age SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID LINOLEIC-ACID; WHITE-MATTER; FISH INTAKE; BRAIN; SUPPLEMENTATION; ALSPAC; IQ; PHOSPHOLIPIDS; SERUM; DIET AB Background: Brain tissue is selectively enriched with highly unsaturated fatty acids (FAs). Altering the maternal FA status in pregnancy may improve fetal neural development with lasting consequences for child development. Objective: We explored whether maternal FAs in erythrocytes, either measured directly or indirectly by maternal FADS genetic variants, are associated with child intelligence quotient (IQ). Design: Linear regression analyses, adjusted for 18 confounders, were used to investigate the associations in 2839 mother-child pairs from the population-based Avon Longitudinal Study of Parents and Children cohort. Results: Low levels of arachidonic acid (20:4n-6) were associated with lower performance IQ (-2.0 points; 95% CI: -3.5, -0.6 points; P = 0.007, increased R-2 = 0.27%), high levels of osbond acid (22:5n-6) were associated with verbal IQ (-1.8 points; 95% CI: -3.2, -0.4 points; P = 0.014, R-2 = 0.20%), and high levels of adrenic acid (22:4n-6) were associated with verbal IQ (-1.7 points; 95% CI: -3.1, -0.3 points; P = 0.016, R-2 = 0.19%). There was some evidence to support a negative association of low docosahexaenoic acid (DHA; 22:6n-3) with full-scale IQ (R-2 = 0.15%). Novel weak associations were also observed for low levels of osbond acid (R-2 <= 0.29%) and FADS variants with opposite effects for intron variants and variants in the promoter region such as rs3834458 (R-2 <= 0.38%). Conclusions: These results support the positive role of maternal arachidonic acid and DHA on fetal neural development, although the effects on child IQ by 8 y of age were small (0.1 SD), with other factors contributing more substantially. The endogenous synthesis of these FAs by FADS genes, especially FADS2, may also be important. The replication of these results is recommended. C1 [Steer, Colin D.; Golding, Jean] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Lattka, Eva] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany. [Koletzko, Berthold] Univ Munich, Med Ctr, Dept Pediat, Dr von Hauner Childrens Hosp, Munich, Germany. [Hibbeln, Joseph R.] NIAAA, NIH, Bethesda, MD USA. RP Steer, CD (reprint author), Sch Social & Community Med, Ctr Child & Adolescent Hlth, Barley House, Bristol BS8 2BN, Avon, England. EM colin.steer@bristol.ac.uk RI Reischl, Eva/B-9311-2013; OI Reischl, Eva/0000-0003-4055-8060; Golding, Jean/0000-0003-2826-3307 FU Wellcome Trust [092731] FX We are extremely grateful to all families who took part in this study, mid-wives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and the Wellcome Trust (grant 092731) and the University of Bristol currently provide core support for the ALSPAC. NR 51 TC 19 Z9 19 U1 1 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2013 VL 98 IS 6 BP 1575 EP 1582 DI 10.3945/ajcn.112.051524 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 266DG UT WOS:000328002000025 PM 24067669 ER PT J AU Dwyer, JT Peterson, J AF Dwyer, Johanna T. Peterson, Julia TI Tea and flavonoids: where we are, where to go next SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 5th International Scientific Symposium on Tea and Human Health CY SEP 19-19, 2012 CL Washington, DC ID CARDIOVASCULAR-DISEASE MORTALITY; GREEN TEA; DIETARY-SUPPLEMENTS; PROSPECTIVE COHORT; BLOOD-PRESSURE; FOOD SOURCES; BLACK TEA; RISK; METAANALYSIS; CONSUMPTION AB There is a need to evaluate the evidence about the health effects of tea flavonoids and to provide valid, specific, and actionable tea consumption information to consumers. Emerging evidence suggests that the flavonoids in tea may be associated with beneficial health outcomes, whereas the benefits and risks of tea extracts and supplements are less well known. The next steps in developing tea science should include a focus on the most promising leads, such as reducing the risk of cardiovascular disease and stroke, rather than pursuing smaller, more diffuse studies of many different health outcomes. Future tea research should also include the use of common reference standards, better characterization of intervention products, and application of batteries of biomarkers of intakes and outcomes across studies, which will allow a common body of evidence to be developed. Mechanistic studies should determine which tea bioactive constituents have effects, whether they act alone or in combination, and how they influence health. Clinical studies should use well-characterized test products, better descriptions of baseline diets, and validated biomarkers of intake and disease risk reduction. There should be more attention to careful safety monitoring and adverse event reporting. Epidemiologic investigations should be of sufficient size and duration to detect small effects, involve populations most likely to benefit, use more complete tea exposure assessment, and include both intermediary markers of risk as well as morbidity and mortality outcomes. The construction of a strong foundation of scientific evidence on tea and health outcomes is essential for developing more specific and actionable messages on tea for consumers. C1 [Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Dwyer, Johanna T.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Peterson, Julia] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Dwyer, JT (reprint author), NIH, Off Dietary Supplements, Room 3B01,MSC 7517, Bethesda, MD 20892 USA. EM dwyerj1@od.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 FU Tea Council of the USA FX The authors' responsibilities were as follows-JTD: designed the review and had primary responsibility for preparing the final manuscript and for final content; and JTD and JP: collected and analyzed the data and wrote the manuscript. Both authors read and approved the final manuscript. JTD performed this work as a contractor at the Office of Dietary Supplements, NIH. JP received a grant for travel and accommodations to attend the symposium from the Tea Council of the USA. The authors declared no competing financial interests. NR 41 TC 4 Z9 4 U1 0 U2 13 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2013 VL 98 IS 6 SU S BP 1611S EP 1618S DI 10.3945/ajcn.113.059584 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 266DJ UT WOS:000328002400002 PM 24172298 ER PT J AU Vichinsky, E Torres, M Minniti, CP Barrette, S Habr, D Zhang, YY Files, B AF Vichinsky, Elliott Torres, Marcela Minniti, Caterina P. Barrette, Stephane Habr, Dany Zhang, Yiyun Files, Beatrice CA CICL670A2201 Investigators TI Efficacy and safety of deferasirox compared with deferoxamine in sickle cell disease: Two-year results including pharmacokinetics and concomitant hydroxyurea SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID TUMOR-ASSOCIATED MACROPHAGES; ABSOLUTE LYMPHOCYTE COUNT; NON-HODGKINS-LYMPHOMA; B-CELL; R-CHOP; PROGNOSTIC-SIGNIFICANCE; MONOCYTE COUNT; SURVIVAL; RITUXIMAB; CHEMOTHERAPY AB We report a prospective, randomized, Phase II study of deferasirox and deferoxamine (DFO) in sickle cell disease patients with transfusional iron overload, with all patients continuing on deferasirox after 24 weeks, for up to 2 years. The primary objective was to evaluate deferasirox safety compared with DFO; long-term efficacy and safety of deferasirox was also assessed. We also report, for the first time, the safety and pharmacokinetics of deferasirox in patients concomitantly receiving hydroxyurea. Deferasirox (n=135) and DFO (n=68) had comparable safety profiles over 24 weeks. Adverse events (AEs) secondary to drug administration were reported in 26.7% of patients in the deferasirox cohort and 28.6% in the DFO cohort. Gastrointestinal disorders were more common with deferasirox, including diarrhea (10.4% versus 3.6%) and nausea (5.2% versus 3.6%). The most common AE in the DFO group was injection-site pain irritation, which occurred in 7% of patients. Acute renal failure occurred in one patient on deferasirox who was continued on medication despite progressive impairment of renal function parameters. Serum ferritin levels were reduced in both treatment groups. Patients continuing on deferasirox for up to 2 years demonstrated an absolute median serum ferritin decrease of 2614 ng/mL (n=96). Increasing deferasirox dose was associated with improved response and a continued manageable safety profile. Concomitant hydroxyurea administration (n=28) did not appear to influence the efficacy, safety (including liver and kidney function), and pharmacokinetic parameters of deferasirox. Am. J. Hematol. 88: 1068-1073, 2013. (C) 2013 Wiley Periodicals, Inc. C1 [Vichinsky, Elliott] Childrens Hosp & Res Ctr Oakland, Oakland, CA 94609 USA. [Torres, Marcela] Cook Childrens Hosp, Ft Worth, TX USA. [Minniti, Caterina P.] NHLBI, Bethesda, MD 20892 USA. [Barrette, Stephane] St Justine Hosp, Montreal, PQ, Canada. [Habr, Dany; Zhang, Yiyun] Novartis Pharmaceut, E Hanover, NJ USA. [Files, Beatrice] Emory Univ, Atlanta, GA 30322 USA. RP Vichinsky, E (reprint author), Childrens Hosp & Res Ctr Oakland, Hematol Oncol Dept, 747 52nd St, Oakland, CA 94609 USA. EM evichinsky@mail.cho.org FU Novartis Pharma AG; Novartis Pharmaceuticals FX Contract sponsors: Novartis Pharma AG and Novartis Pharmaceuticals. NR 41 TC 7 Z9 7 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2013 VL 88 IS 12 BP 1068 EP 1073 DI 10.1002/ajh.23569 PG 6 WC Hematology SC Hematology GA 255FE UT WOS:000327224000137 PM 23946212 ER PT J AU Stern, W Mathews, D McKew, J Seiler, SR Shen, XG Kato, GJ AF Stern, Warren Mathews, David McKew, John Seiler, Stephen R. Shen, Xiqgiang Kato, Gregory J. TI ASE 1, FIRST-IN-MAN, DOSE-RESPONSE STUDY OF AES-103 (5-HMF), AN ANTI-SICKLING, ALLOSTERIC MODIFIER OF HEMOGLOBIN OXYGEN AFFINITY IN HEALTHY NORMAL VOLUNTEERS SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Stern, Warren; Seiler, Stephen R.] AesRx LLC, Newton, MA USA. [Mathews, David] Quintiles Phase 1 Serv Inc, Durham, NC USA. [McKew, John; Shen, Xiqgiang] NIH, Bethesda, MD USA. [Kato, Gregory J.] NHLBI, Hematol Branch, MD Sickle Cell Vasc Dis Sect, Bethesda, MD USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2013 VL 88 IS 12 BP E79 EP E79 PG 1 WC Hematology SC Hematology GA 255FE UT WOS:000327224000114 ER PT J AU Rice, MB Ljungman, PL Wilker, EH Gold, DR Schwartz, JD Koutrakis, P Washko, GR O'Connor, GT Mittleman, MA AF Rice, Mary B. Ljungman, Petter L. Wilker, Elissa H. Gold, Diane R. Schwartz, Joel D. Koutrakis, Petros Washko, George R. O'Connor, George T. Mittleman, Murray A. TI Short-Term Exposure to Air Pollution and Lung Function in the Framingham Heart Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chronic obstructive pulmonary disease; asthma; air pollutants; US Environmental Protection Agency ID OBSTRUCTIVE PULMONARY-DISEASE; RESPIRATORY HEALTH; OZONE EXPOSURE; DEFICIENT MICE; INFLAMMATION; ADULTS; POLLUTANTS; SMOKERS; ASTHMA; RISK AB Rationale: Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U. S. Environmental Protection Agency (EPA) standards. Objectives: To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study. Methods: We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995-2011) who were not current smokers, with previous-day pollutant levels in compliance with EPA standards. We compared lung function (FEV1 and FVC) after previous-day exposure to particulate matter less than 2.5 mu m in diameter (PM2.5), nitrogen dioxide (NO2), and ozone (O-3) in the "moderate" range of the EPA Air Quality Index to exposure in the "good" range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function. Measurements and Main Results: Exposure to pollutant concentrations in the "moderate" range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV1 for PM2.5 (95% confidence interval [CI], -33.4, -6.9), a 30.6-ml lower FEV1 for NO2 (95% CI, -60.9, -0.2), and a 55.7-ml lower FEV1 for O-3 (95% CI, -100.7, -10.8) compared with the "good" range. The 1- and 2-day moving averages of PM2.5, NO2, and O-3 before testing were negatively associated with FEV1 and FVC. Conclusions: Short-term exposure to PM2.5, NO2, and O-3 within current EPA standards was associated with lower lung function in this cohort of adults. C1 [Rice, Mary B.; Ljungman, Petter L.; Wilker, Elissa H.; Mittleman, Murray A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. [Rice, Mary B.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Ljungman, Petter L.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Gold, Diane R.; Schwartz, Joel D.; Koutrakis, Petros] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Washko, George R.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Washko, George R.; O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. RP Rice, MB (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Bulfinch 148,55 Fruit St, Boston, MA 02114 USA. EM mrice2@partners.org RI Ljungman, Petter/C-6371-2014; OI Ljungman, Petter/0000-0002-7815-2632; O'Connor, George/0000-0002-6476-3926 FU U.S. Environmental Protection Agency [R832416, RD834798]; National Heart, Lung, and Blood Institute [N01-HC 25195, 1R01HL60040, 1R01HL70100, T32HL007374]; National Institute of Environmental Health Sciences [1F32ES023352-01, P30ES000002]; Swedish Heart Lung Foundation; Swedish Council for Working Life and Social Research Marie Curie International Postdoc Fellowship Programme; Swedish Society of Cardiology; Swedish Society for Medical Research FX Supported by U.S. Environmental Protection Agency grants R832416 and RD834798. Further supported by National Heart, Lung, and Blood Institute grants N01-HC 25195, 1R01HL60040, 1R01HL70100, and T32HL007374, and National Institute of Environmental Health Sciences grants 1F32ES023352-01 and P30ES000002. Support from the Swedish Heart Lung Foundation, the Swedish Council for Working Life and Social Research Marie Curie International Postdoc Fellowship Programme, the Swedish Society of Cardiology, and the Swedish Society for Medical Research (P.L.L.). NR 48 TC 37 Z9 39 U1 7 U2 48 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 1 PY 2013 VL 188 IS 11 BP 1351 EP 1357 DI 10.1164/rccm.201308-1414OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 268UY UT WOS:000328197300015 PM 24200465 ER PT J AU Leung, JM Fowler, C Smith, C Adjemian, J Frein, C Claypool, RJ Holland, SM Prevots, RD Olivier, K AF Leung, Janice M. Fowler, Cedar Smith, Caroline Adjemian, Jennifer Frein, Cathleen Claypool, Reginald J. Holland, Steven M. Prevots, Rebecca D. Olivier, Kenneth TI A Familial Syndrome of Pulmonary Nontuberculous Mycobacteria Infections SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID MITRAL-VALVE-PROLAPSE; PECTUS EXCAVATUM; IDIOPATHIC SCOLIOSIS; LUNG-DISEASE; PREVALENCE; CT C1 [Leung, Janice M.; Fowler, Cedar; Smith, Caroline; Adjemian, Jennifer; Frein, Cathleen; Claypool, Reginald J.; Holland, Steven M.; Prevots, Rebecca D.; Olivier, Kenneth] NIH, Bethesda, MD 20892 USA. RP Leung, JM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 20 TC 6 Z9 6 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 1 PY 2013 VL 188 IS 11 BP 1373 EP 1376 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 268UY UT WOS:000328197300026 PM 24289782 ER PT J AU Yao, XL Gao, MX Dai, CL Meyer, KS Chen, JC Keeran, KJ Nugent, GZ Qu, X Yu, ZX Dagur, PK Mccoy, JP Levine, SJ AF Yao, Xianglan Gao, Meixia Dai, Cuilian Meyer, Katharine S. Chen, Jichun Keeran, Karen J. Nugent, Gayle Z. Qu, Xuan Yu, Zu-Xi Dagur, Pradeep K. Mccoy, J. Philip Levine, Stewart J. TI Peptidoglycan Recognition Protein 1 Promotes House Dust Mite-Induced Airway Inflammation in Mice SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE asthma; house dust mite; innate immunity; pattern recognition proteins; peptidoglycan recognition protein 1 ID ALLERGIC-ASTHMA; T-CELLS; RESPONSES; CHEMOKINE; INNATE; HYPERRESPONSIVENESS; LYMPHOCYTES; CHALLENGE; EOTAXIN-2; DISEASE AB Peptidoglycan recognition protein (Pglyrp) 1 is a pattern-recognition protein that mediates antibacterial host defense. Because we had previously shown that Pglyrp1 expression is increased in the lungs of house dust mite (HDM)-challenged mice, we hypothesized that it might modulate the pathogenesis of asthma. Wild-type and Pglyrp1(-/-) mice on a BALB/c background received intranasal HDM or saline, 5 days/week for 3 weeks. HDM-challenged Pglyrp1(-/-) mice showed decreases in bronchoalveolar lavage fluid eosinophils and lymphocytes, serum IgE, and mucous cell metaplasia, whereas airway hyperresponsiveness was not changed when compared with wild-type mice. T helper type 2 (Th2) cytokines were reduced in the lungs of HDM-challenged Pglyrp1(-/-) mice, which reflected a decreased number of CD4(+) Th2 cells. There was also a reduction in C-C chemokines in bronchoalveolar lavage fluid and lung homogenates from HDM-challenged Pglyrp1(-/-) mice. Furthermore, secretion of CCL17, CCL22, and CCL24 by alveolar macrophages from HDM-challenged Pglyrp1(-/-) mice was markedly reduced. As both inflammatory cells and airway epithelial cells express Pglyrp1, bone marrow transplantation was performed to generate chimeric mice and assess which cell type promotes HDM-induced airway inflammation. Chimeric mice lacking Pglyrp1 on hematopoietic cells, not structural cells, showed a reduction in HDM-induced eosinophilic and lymphocytic airway inflammation. We conclude that Pglyrp1 expressed by hematopoietic cells, such as alveolar macrophages, mediates HDM-induced airway inflammation by up-regulating the production of C-C chemokines that recruit eosinophils and Th2 cells to the lung. This identifies a new family of innate immune response proteins that promotes HDM-induced airway inflammation in asthma. C1 [Yao, Xianglan; Gao, Meixia; Dai, Cuilian; Meyer, Katharine S.; Levine, Stewart J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Chen, Jichun] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Keeran, Karen J.; Nugent, Gayle Z.] NHLBI, Lab Anim Surg, NIH, Bethesda, MD 20892 USA. [Keeran, Karen J.; Nugent, Gayle Z.] NHLBI, Resources Core Facil, NIH, Bethesda, MD 20892 USA. [Qu, Xuan; Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. [Dagur, Pradeep K.; Mccoy, J. Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute FX This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute. NR 35 TC 4 Z9 5 U1 0 U2 8 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD DEC PY 2013 VL 49 IS 6 BP 902 EP 911 DI 10.1165/rcmb.2013-0001OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 269SI UT WOS:000328261800004 PM 23808363 ER PT J AU Yin, HE Cabrera-Perez, J Lai, ZA Michael, D Weller, M Swaim, WD Liu, XB Catalan, MA Rocha, EM Ismail, N Afione, S Rana, NA Di Pasquale, G Alevizos, I Ambudkar, I Illei, GG Chiorini, JA AF Yin, Hongen Cabrera-Perez, Javier Lai, Zhenan Michael, Drew Weller, Melodie Swaim, William D. Liu, Xibao Catalan, Marcelo A. Rocha, Eduardo M. Ismail, Nevien Afione, Sandra Rana, Noreen A. Di Pasquale, Giovanni Alevizos, Ilias Ambudkar, Indu Illei, Gabor G. Chiorini, John A. TI Association of Bone Morphogenetic Protein 6 With Exocrine Gland Dysfunction in Patients With Sjogren's Syndrome and in Mice SO ARTHRITIS AND RHEUMATISM LA English DT Article ID TRANSGENIC MICE; SALIVARY-GLANDS; MICROARRAY DATA; MOUSE MODEL; EXPRESSION; CELLS; IRON; OVEREXPRESSION; SECRETION; INFECTION AB ObjectivePrimary Sjogren's syndrome (SS) is characterized by autoimmune activation and loss of function in secretory epithelia. The present study was undertaken to investigate and characterize changes in the epithelia associated with the loss of gland function in primary SS. MethodsTo identify changes in epithelial gene expression, custom microarrays were probed with complementary RNA (cRNA) isolated from minor salivary glands (MSGs) of female patients with primary SS who had low focus scores and low salivary flow rates, and the results were compared with those obtained using cRNA from the MSGs of sex-matched healthy volunteers. The effect of bone morphogenetic protein 6 (BMP-6) on salivary gland function was tested using adeno-associated virus-mediated gene transfer to the salivary glands of C57BL/6 mice. ResultsA significant increase in expression of BMP-6 was observed in RNA isolated from SS patients compared with healthy volunteers. Overexpression of BMP-6 locally in the salivary or lacrimal glands of mice resulted in the loss of fluid secretion as well as changes in the connective tissue of the salivary gland. Assessment of the fluid movement in either isolated acinar cells from mice overexpressing BMP-6 or a human salivary gland cell line cultured with BMP-6 revealed a loss in volume regulation in these cells. Lymphocytic infiltration in the submandibular gland of BMP-6 vector-treated mice was increased. No significant changes in the production of proinflammatory cytokines or autoantibodies associated with SS (anti-Ro/SSA and anti-La/SSB) were found after BMP-6 overexpression. ConclusionIn addition to identifying BMP-6 expression in association with xerostomia and xerophthalmia in primary SS, the present results suggest that BMP-6-induced salivary and lacrimal gland dysfunction in primary SS is independent of the autoantibodies and immune activation associated with the disease. C1 [Yin, Hongen; Cabrera-Perez, Javier; Lai, Zhenan; Michael, Drew; Weller, Melodie; Swaim, William D.; Liu, Xibao; Catalan, Marcelo A.; Rocha, Eduardo M.; Ismail, Nevien; Afione, Sandra; Rana, Noreen A.; Di Pasquale, Giovanni; Alevizos, Ilias; Ambudkar, Indu; Illei, Gabor G.; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, 10-1A21,10 Ctr Dr,MSC1190, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov RI Rocha, Eduardo/D-6002-2011; OI Rocha, Eduardo/0000-0001-9888-7313; Catalan, Marcelo/0000-0003-3544-2821 FU NIH (National Institute of Dental and Craniofacial Research) FX Supported by the NIH (National Institute of Dental and Craniofacial Research intramural grants to Dr. Chiorini). NR 43 TC 6 Z9 6 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 EI 1529-0131 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD DEC PY 2013 VL 65 IS 12 BP 3228 EP 3238 DI 10.1002/art.38123 PG 11 WC Rheumatology SC Rheumatology GA 261VL UT WOS:000327692600026 PM 23982860 ER PT J AU Miller, FW Cooper, RG Vencovsky, J Rider, LG Danko, K Wedderburn, LR Lundberg, IE Pachman, LM Reed, AM Ytterberg, SR Padyukov, L Selva-O'Callaghan, A Radstake, TRDJ Isenberg, DA Chinoy, H Ollier, WER O'Hanlon, TP Peng, B Lee, A Lamb, JA Chen, W Amos, CI Gregersen, PK AF Miller, Frederick W. Cooper, Robert G. Vencovsky, Jiri Rider, Lisa G. Danko, Katalin Wedderburn, Lucy R. Lundberg, Ingrid E. Pachman, Lauren M. Reed, Ann M. Ytterberg, Steven R. Padyukov, Leonid Selva-O'Callaghan, Albert Radstake, Timothy R. D. J. Isenberg, David A. Chinoy, Hector Ollier, William E. R. O'Hanlon, Terrance P. Peng, Bo Lee, Annette Lamb, Janine A. Chen, Wei Amos, Christopher I. Gregersen, Peter K. CA Myositis Genetics Consortium TI Genome-Wide Association Study of Dermatomyositis Reveals Genetic Overlap With Other Autoimmune Disorders SO ARTHRITIS AND RHEUMATISM LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; JUVENILE DERMATOMYOSITIS; SUSCEPTIBILITY LOCI; CROHNS-DISEASE; RISK LOCUS; METAANALYSIS; PATHOGENESIS; EXPRESSION AB ObjectiveTo identify new genetic associations with juvenile and adult dermatomyositis (DM). MethodsWe performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. ResultsCompared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 x 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. ConclusionOur findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. C1 [Miller, Frederick W.; Rider, Lisa G.; O'Hanlon, Terrance P.] NIEHS, NIH, Bethesda, MD 20892 USA. [Cooper, Robert G.] Univ Manchester, Manchester, Lancs, England. [Cooper, Robert G.] Salford Royal Natl Hlth Serv Fdn Trust, Salford, Lancs, England. [Vencovsky, Jiri] Inst Rheumatol, Prague, Czech Republic. [Danko, Katalin] Univ Debrecen, H-4012 Debrecen, Hungary. [Wedderburn, Lucy R.; Isenberg, David A.] UCL, London, England. [Lundberg, Ingrid E.; Padyukov, Leonid] Karolinska Univ Hosp, Solna, Sweden. [Lundberg, Ingrid E.; Padyukov, Leonid] Karolinska Inst, Stockholm, Sweden. [Pachman, Lauren M.] Childrens Hosp Chicago, Chicago, IL USA. [Pachman, Lauren M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Reed, Ann M.; Ytterberg, Steven R.] Mayo Clin, Rochester, MN USA. [Selva-O'Callaghan, Albert] Hosp Gen Valle Hebron, Barcelona, Spain. [Radstake, Timothy R. D. J.] Univ Utrecht, Med Ctr, Utrecht, Netherlands. [Radstake, Timothy R. D. J.] Nijmegen Ctr Mol Life Sci, Nijmegen, Netherlands. [Chinoy, Hector; Ollier, William E. R.; Lamb, Janine A.] Univ Manchester, Manchester, NH USA. [Peng, Bo; Chen, Wei; Amos, Christopher I.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lee, Annette; Gregersen, Peter K.] North Shore LIJ Hlth Syst, New York, NY USA. [Lee, Annette; Gregersen, Peter K.] Feinstein Inst Med Res, New York, NY USA. RP Miller, FW (reprint author), NIEHS, NIH Clin Res Ctr, NIH 10,Room 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov OI Miller, Frederick/0000-0003-2831-9593; Chinoy, Hector/0000-0001-6492-1288; Padyukov, Leonid/0000-0003-2950-5670; Isenberg, David/0000-0001-9514-2455; Peng, Bo/0000-0001-8225-2284; Lundberg, Ingrid/0000-0002-6068-9212; Rider, Lisa/0000-0002-6912-2458 FU NIH (Intramural Program, National Institute of Environmental Health Sciences) [Z01-ES-101074]; European Union [LSHB CT-2006-018661]; UK Myositis Support Group; Arthritis Research UK [18474]; Cure JM Foundation; European Science Foundation; Wellcome Trust; Henry Smith Charity (UK); Action Medical Research (UK); Swedish Research Council; Ministry of Health, Czech Republic [00023728] FX Supported in part by the NIH (Intramural Program, National Institute of Environmental Health Sciences grant Z01-ES-101074), the European Union Sixth Framework Programme (project AutoCure; LSHB CT-2006-018661), the UK Myositis Support Group, Arthritis Research UK (grant 18474), the Cure JM Foundation, the European Science Foundation, the Wellcome Trust, the Henry Smith Charity (UK), Action Medical Research (UK), and the Swedish Research Council. The Czech cohort was supported in part by the Ministry of Health, Czech Republic (grant 00023728). NR 39 TC 36 Z9 37 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 EI 1529-0131 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD DEC PY 2013 VL 65 IS 12 BP 3239 EP 3247 DI 10.1002/art.38137 PG 9 WC Rheumatology SC Rheumatology GA 261VL UT WOS:000327692600027 PM 23983088 ER PT J AU Nordstrom, R Cherry, S Azhdarinia, A Sevick-Muraca, E VanBrocklin, H AF Nordstrom, Robert Cherry, Simon Azhdarinia, Ali Sevick-Muraca, Eva VanBrocklin, Henry TI Photons across medicine: relating optical and nuclear imaging SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID TRANSLATIONAL RESEARCH; INDOCYANINE GREEN; CLINICAL-USE; SYSTEM; TOMOGRAPHY; SURGERY; CANCER; PET; RECONSTRUCTION; LOCALIZATION AB The Optics in the Life Sciences conference sponsored by the Optical Society of America was held in Waikoloa Beach, HI on April 14 18, 2013. Papers were presented in the areas of Bio-Optics: Design & Application, Novel Techniques in Microscopy, Optical Molecular Probes, Imaging & Drug Delivery, and Optical Trapping Applications. A focal point of the meeting was a special symposium entitled "Photons Across Medicine", organized by Adam Wax, Duke University, highlighting activities of joint interest between the Optical Society of America (OSA) and the Society for Nuclear Medicine and Molecular Imaging (SNMMI). This paper is a synopsis of the presentations made at this joint symposium. Central to the special symposium presentations was the fact that the optical and nuclear imaging communities share common interests and challenges. These are highlighted in this article. Also discussed was the fact that the nuclear technologies in imaging have found their way into general clinical utility, a feat that has yet to be achieved by optical methods. Because of the common ground shared by the two technologies, coordination between the two societies should be planned. (C) 2013 Optical Society of America C1 [Nordstrom, Robert] NCI, NIH, Bethesda, MD 20892 USA. [Cherry, Simon] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Azhdarinia, Ali; Sevick-Muraca, Eva] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [VanBrocklin, Henry] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. RP Nordstrom, R (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM nordstrr@mail.nih.gov RI Sevick-Muraca, Eva/A-4152-2017 OI Sevick-Muraca, Eva/0000-0002-8152-4847 NR 42 TC 1 Z9 1 U1 3 U2 15 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD DEC 1 PY 2013 VL 4 IS 12 BP 2751 EP 2762 DI 10.1364/BOE.4.002751 PG 12 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 267EA UT WOS:000328078300003 PM 24409377 ER PT J AU Hourigan, CS Karp, JE AF Hourigan, Christopher S. Karp, Judith E. TI Personalized Therapy for Acute Myeloid Leukemia SO CANCER DISCOVERY LA English DT Editorial Material ID EVOLUTION AB Patient-specific ex vivo drug sensitivity and resistance screening can identify rational drug candidates for the testing of personalized targeted therapy. An iterative approach of genomic and drug susceptibility characterization at sequential time points during clinical trials of targeted therapy in acute myeloid leukemia may be useful both for characterizing mechanisms of resistance and clonal evolution and also for identification of novel therapeutic targets and drug combinations. (C) 2013 AACR. C1 [Hourigan, Christopher S.] NHLBI, Myeloid Malignancies Sect, Hematol Branch, Bethesda, MD 20892 USA. [Karp, Judith E.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. RP Hourigan, CS (reprint author), NHLBI, Myeloid Malignancies Sect, Room 6C-103C,10 Ctr Dr, Bethesda, MD 20892 USA. EM hourigan@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU Intramural NIH HHS [ZIA HL006163-01] NR 11 TC 3 Z9 3 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2013 VL 3 IS 12 BP 1336 EP 1338 DI 10.1158/2159-8290.CD-13-0832 PG 3 WC Oncology SC Oncology GA 269QR UT WOS:000328257500019 PM 24327695 ER PT J AU O'Connell, MP Marchbank, K Webster, MR Valiga, AA Kaur, A Vultur, A Li, L Herlyn, M Villanueva, J Liu, Q Yin, XF Widura, S Nelson, J Ruiz, N Camilli, TC Indig, FE Flaherty, KT Wargo, JA Frederick, DT Cooper, ZA Nair, S Amaravadi, RK Schuchter, LM Karakousis, GC Xu, W Xu, XW Weeraratna, AT AF O'Connell, Michael P. Marchbank, Katie Webster, Marie R. Valiga, Alexander A. Kaur, Amanpreet Vultur, Adina Li, Ling Herlyn, Meenhard Villanueva, Jessie Liu, Qin Yin, Xiangfan Widura, Sandy Nelson, Janelle Ruiz, Nivia Camilli, Tura C. Indig, Fred E. Flaherty, Keith T. Wargo, Jennifer A. Frederick, Dennie T. Cooper, Zachary A. Nair, Suresh Amaravadi, Ravi K. Schuchter, Lynn M. Karakousis, Giorgos C. Xu, Wei Xu, Xiaowei Weeraratna, Ashani T. TI Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2 SO CANCER DISCOVERY LA English DT Article ID UBIQUITIN LIGASE SIAH2; BETA-CATENIN; MESENCHYMAL TRANSITION; MALIGNANT-MELANOMA; EXPRESSION; METASTASIS; CELLS; INVASION; INHIBITION; PATHWAY AB An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the noncanonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Furthermore, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In patients with melanoma treated with the BRAF inhibitor vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance. SIGNIFICANCE: These data show for the first time that a single signaling pathway, the Wnt signaling pathway, can effectively guide the phenotypic plasticity of tumor cells, when primed to do so by a hypoxic microenvironment. Importantly, this increased Wnt5A signaling can give rise to a subpopulation of highly invasive cells that are intrinsically less sensitive to novel therapies for melanoma, and targeting the Wnt5A/ROR2 axis could improve the efficacy and duration of response for patients with melanoma on vemurafenib. (C) 2013 AACR. C1 [O'Connell, Michael P.; Marchbank, Katie; Webster, Marie R.; Valiga, Alexander A.; Kaur, Amanpreet; Vultur, Adina; Li, Ling; Herlyn, Meenhard; Widura, Sandy; Nelson, Janelle; Ruiz, Nivia; Weeraratna, Ashani T.] Wistar Inst Anat & Biol, Tumor Microenvironm & Metastasis Program, Philadelphia, PA 19104 USA. [Villanueva, Jessie; Liu, Qin; Yin, Xiangfan] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA. [Amaravadi, Ravi K.; Schuchter, Lynn M.; Karakousis, Giorgos C.; Xu, Wei; Xu, Xiaowei] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Nair, Suresh] Lehigh Valley Hlth Network, Allentown, PA USA. [Camilli, Tura C.; Indig, Fred E.] NIA, NIH, Baltimore, MD 21224 USA. [Flaherty, Keith T.; Wargo, Jennifer A.; Frederick, Dennie T.; Cooper, Zachary A.] Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Weeraratna, AT (reprint author), Wistar Inst Anat & Biol, Tumor Microenvironm & Metastasis Program, 3601 Spruce St, Philadelphia, PA 19104 USA. EM aweeraratna@wistar.org OI Cooper, Zachary/0000-0003-1059-0940 FU National Institute on Aging Intramural Research Program; PA Department of Health (CURE) funding; Joanna M Nicolay Foundation; PHS [2 T32 CA 9171-36, 1K23CA120862, CA25874] FX This work was supported in part by funds from the National Institute on Aging Intramural Research Program (to F.E. Indig and T.C. Camilli), PA Department of Health (CURE) funding (to A.T. Weeraratna, M.P. O'Connell, K. Marchbank, A. Vultur, N. Ruiz, Q. Liu, X. Yin, and S. Widura), and the Joanna M Nicolay Foundation (to A. Kaur). Additional support for other authors comes from PHS 2 T32 CA 9171-36 (to M. R. Webster), 1K23CA120862 (to R.K. Amaravadi), and CA25874 (to M. Herlyn). NR 51 TC 64 Z9 65 U1 0 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2013 VL 3 IS 12 BP 1378 EP 1393 DI 10.1158/2159-8290.CD-13-0005 PG 16 WC Oncology SC Oncology GA 269QR UT WOS:000328257500024 PM 24104062 ER PT J AU Walter, AO Sjin, RTT Haringsma, HJ Ohashi, K Sun, J Lee, K Dubrovskiy, A Labenski, M Zhu, ZD Wang, ZG Sheets, M St Martin, T Karp, R van Kalken, D Chaturvedi, P Niu, DQ Nacht, M Petter, RC Westlin, W Lin, K Jaw-Tsai, S Raponi, M Van Dyke, T Etter, J Weaver, Z Pao, W Singh, J Simmons, AD Harding, TC Allen, A AF Walter, Annette O. Sjin, Robert Tjin Tham Haringsma, Henry J. Ohashi, Kadoaki Sun, Jing Lee, Kwangho Dubrovskiy, Aleksandr Labenski, Matthew Zhu, Zhendong Wang, Zhigang Sheets, Michael St Martin, Thia Karp, Russell van Kalken, Dan Chaturvedi, Prasoon Niu, Deqiang Nacht, Mariana Petter, Russell C. Westlin, William Lin, Kevin Jaw-Tsai, Sarah Raponi, Mitch Van Dyke, Terry Etter, Jeff Weaver, Zoe Pao, William Singh, Juswinder Simmons, Andrew D. Harding, Thomas C. Allen, Andrew TI Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC SO CANCER DISCOVERY LA English DT Article ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITOR; FACTOR RECEPTOR MUTATIONS; ACQUIRED-RESISTANCE; T790M MUTATION; GEFITINIB RESISTANCE; MET AMPLIFICATION; AKT INHIBITOR; AXL KINASE; OPEN-LABEL AB Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC. SIGNIFICANCE: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the first drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR. (C) 2013 AACR. C1 [Walter, Annette O.; Haringsma, Henry J.; Lin, Kevin; Jaw-Tsai, Sarah; Raponi, Mitch; Etter, Jeff; Simmons, Andrew D.; Harding, Thomas C.; Allen, Andrew] Clovis Oncol Inc, San Francisco, CA 94158 USA. [Sjin, Robert Tjin Tham; Lee, Kwangho; Dubrovskiy, Aleksandr; Labenski, Matthew; Zhu, Zhendong; Wang, Zhigang; Sheets, Michael; St Martin, Thia; Karp, Russell; van Kalken, Dan; Chaturvedi, Prasoon; Niu, Deqiang; Nacht, Mariana; Petter, Russell C.; Westlin, William; Singh, Juswinder] Celgene Avil Res, Bedford, MA USA. [Ohashi, Kadoaki; Sun, Jing; Pao, William] Vanderbilt Univ, Sch Med, Dept Med, Div Hematol Oncol, Nashville, TN 37212 USA. [Van Dyke, Terry] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. [Van Dyke, Terry; Weaver, Zoe] NCI, Ctr Adv Preclin Res, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. RP Harding, TC (reprint author), Clovis Oncol Inc, 1700 Owens St,Suite 205, San Francisco, CA 94158 USA. EM tharding@clovisoncology.com FU National Cancer Institute, NIH [HHSN261200800001E]; NIH NCI [R01CA121210, P01CA129243, U54CA143798, P30CA68485] FX This project was funded in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. W. Pao received additional funding from NIH NCI grants R01CA121210, P01CA129243, U54CA143798, and P30CA68485. NR 43 TC 203 Z9 210 U1 8 U2 51 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2013 VL 3 IS 12 BP 1404 EP 1415 DI 10.1158/2159-8290.CD-13-0314 PG 12 WC Oncology SC Oncology GA 269QR UT WOS:000328257500026 PM 24065731 ER PT J AU Walcott, F Rajaraman, P Gadalla, SM Inskip, PD Purdue, MP Albanes, D Orr, E De Vivo, I Savage, SA AF Walcott, Farzana Rajaraman, Preetha Gadalla, Shahinaz M. Inskip, Peter D. Purdue, Mark P. Albanes, Demetrius Orr, Esther De Vivo, Immaculata Savage, Sharon A. TI Telomere length and risk of glioma SO CANCER EPIDEMIOLOGY LA English DT Article DE Telomere length; Glioma; Epidemiology; Cancer risk ID UNITED-STATES; CANCER-RISK; VARIANTS; TUMORS; METAANALYSIS; ASSOCIATION; SURVIVAL; TISSUES; BRAIN; RATES AB Background: Telomere length in blood or buccal cell DNA has been associated with risk of various cancers. Glioma can be a highly malignant brain tumor and has few known risk factors. Genetic variants in or near RTEL1 and TERT, key components of telomere biology, are associated with glioma risk. Therefore, we evaluated the association between relative telomere length (RTL) and glioma in a prospective study. Materials and methods: We performed a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. RTL was determined by quantitative PCR on blood or buccal cell DNA obtained at least 2 years prior to diagnosis from 101 individuals with glioma cases. Healthy controls (n = 198) were matched to cases (2:1) on age, gender, smoking status, calendar year, and DNA source. Conditional logistic regression was used to investigate the association between RTL and glioma. Results: As expected, RTL declined with increasing age in both cases and controls. There was no statistically significant association between RTL and glioma overall. An analysis stratified by gender suggested that short RTL (1st tertile) in males was associated with glioma (odds ratio, [ OR] = 2.29, 95% confidence interval [CI] 1.02-5.11); this association was not observed for females (OR = 0.41, 95% CI 0.14-1.17). Conclusions: This prospective study did not identify significant associations between RTL and glioma risk, but there may be gender-specific differences. Larger, prospective studies are needed to evaluate these findings. Published by Elsevier Ltd. C1 [Walcott, Farzana] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Rajaraman, Preetha] NCI, Ctr Global Hlth, NIH, Bethesda, MD 20892 USA. [Rajaraman, Preetha; Inskip, Peter D.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gadalla, Shahinaz M.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Purdue, Mark P.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Orr, Esther; De Vivo, Immaculata] Harvard Univ, Dept Med, Brigham & Womens Hosp, Channing Lab,Med Sch, Boston, MA 02115 USA. [De Vivo, Immaculata] Harvard Univ, Sch Med, Dept Epidemiol, Boston, MA 02115 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E454,MSC 9772, Rockville, MD 20850 USA. EM savagesh@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Purdue, Mark/C-9228-2016; Savage, Sharon/B-9747-2015 OI Purdue, Mark/0000-0003-1177-3108; Savage, Sharon/0000-0001-6006-0740 FU intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This study was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 27 TC 13 Z9 13 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD DEC PY 2013 VL 37 IS 6 BP 935 EP 938 DI 10.1016/j.canep.2013.10.002 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 269OO UT WOS:000328251000027 PM 24231251 ER PT J AU Murthy, SRK Dupart, E Al-Sweel, N Chen, A Cawley, NX Loh, YP AF Murthy, Saravana R. K. Dupart, Evan Al-Sweel, Najla Chen, Alexander Cawley, Niamh X. Loh, Y. Peng TI Carboxypeptidase E promotes cancer cell survival, but inhibits migration and invasion SO CANCER LETTERS LA English DT Article DE Pheochromocytoma; Hepatocellular carcinoma; Fibrosarcoma; Cell survival; Cell invasion ID NF-KAPPA-B; BETA-CATENIN; PATHWAY; PROTEIN; BCL-2; PHEOCHROMOCYTOMA; PROLIFERATION; ACTIVATION; EXPRESSION; MUTATIONS AB Carboxypeptidase E (CPE), a prohormone processing enzyme is highly expressed and secreted from (neuro)endocrine tumors and gliomas, and has been implicated in cancer progression by promoting tumor growth. Our study demonstrates that secreted or exogenously applied CPE promotes survival of pheochromocytoma (PC12) and hepatocellular carcinoma (MHCC97H) cells under nutrient starvation and hypoxic conditions, but had no effect on their proliferation. CPE also reduced migration and invasion of fibrosarcoma (HT1080) cells. We show that CPE treatment mediates survival of MHCC97H cells during metabolic stress by up-regulating the expression of anti-apoptotic protein BCL-2, and other pro-survival genes, via activation of the ERK1/2 pathway. Published by Elsevier Ireland Ltd. C1 [Murthy, Saravana R. K.; Dupart, Evan; Al-Sweel, Najla; Chen, Alexander; Cawley, Niamh X.; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Biol, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), 49,Convent Dr,Bldg 49,Rm 5A22, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA 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, USA, NR 43 TC 10 Z9 10 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD DEC 1 PY 2013 VL 341 IS 2 BP 204 EP 213 DI 10.1016/j.canlet.2013.08.011 PG 10 WC Oncology SC Oncology GA 267KK UT WOS:000328096300011 PM 23941827 ER PT J AU Janakiram, NB Mohammed, A Zhang, YT Brewer, M Bryant, T Lightfoot, S Steele, VE Rao, CV AF Janakiram, Naveena B. Mohammed, Altaf Zhang, Yuting Brewer, Misty Bryant, Taylor Lightfoot, Stan Steele, Vernon E. Rao, Chinthalapally V. TI Chemopreventive Efficacy of Raloxifene, Bexarotene, and Their Combination on the Progression of Chemically Induced Colon Adenomas to Adenocarcinomas in Rats SO CANCER PREVENTION RESEARCH LA English DT Article ID ESTROGEN-RECEPTOR-BETA; HORMONE REPLACEMENT THERAPY; COLORECTAL-CANCER INCIDENCE; RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; BREAST-CANCER; MAMMARY-CARCINOMA; LGD1069 TARGRETIN; SELECTIVE LIGAND; TRANSGENIC MICE AB Estrogen receptor (ER)-beta signaling is associated positively in colon tumor progression, whereas down-regulation or loss of function of retinoid X receptor (RXR)-alpha occurs in colon tumors. The chemopreventive efficacies of the estrogen antagonist raloxifene and the selective RXR agonist bexarotene were tested individually and in combination, during promotion and progression stages of colon tumorigenesis. Colon tumors were induced in male F344 rats with azoxymethane and at early adenoma stage, groups of rats (36 or 45 per group) were fed diets containing raloxifene (1.5 or 3 ppm), bexarotene (50 or 100 ppm), or their low-dose combinations for 40 weeks. Raloxifene or bexarotene alone significantly suppressed colon adenocarcinoma formation in terms of multiplicities (mean +/- SE): control, 3.59 +/- 0.25; 1.5 ppm raloxifene, 2.51 +/- 0.29 (P < 0.004); 3 ppm raloxifene, 2.14 +/- 0.28 (P < 0.0001); 50 ppm bexarotene, 2.25 +/- 0.32 (P < 0.001); 100 ppm bexarotene, 2.1 +/- 0.27 (P < 0.0001); and 1.5 ppm raloxifene + 50 ppm bexarotene, 1.57 +/- 0.21 (P < 0.0001). The low-dose combination caused significant (56%) inhibition of adenocarcinomas as compared with control diet fed rats. Tumors exposed to raloxifene, bexarotene and/or the combination showed significant suppression of proliferating cell nuclear antigen, cyclin D1, and beta-catenin with an increased apoptotic cells (3-fold) and p21 expression (3.8-fold) as compared tumors of rats fed control diet. The combination of low doses of raloxifene and bexarotene significantly suppressed the progression of colonic adenomas to adenocarcinomas and may be useful for colon cancer prevention and/or treatment in high-risk individuals. (C) 2013 AACR. C1 [Janakiram, Naveena B.; Mohammed, Altaf; Zhang, Yuting; Brewer, Misty; Bryant, Taylor; Rao, Chinthalapally V.] Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, Hematol Oncol Sect,Dept Med,PCS Canc Ctr, Oklahoma City, OK 73104 USA. [Lightfoot, Stan] Univ Oklahoma, Hlth Sci Ctr, VA Med Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Ctr Canc Prevent & Drug Dev, 975 NE 10th St,BRC 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU National Cancer Institute [NCI-N01 CN-53300] FX This investigation was supported by Grant NCI-N01 CN-53300 from the National Cancer Institute to C.V. Rao. NR 48 TC 5 Z9 5 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD DEC PY 2013 VL 6 IS 12 BP 1251 EP 1261 DI 10.1158/1940-6207.CAPR-13-0249 PG 11 WC Oncology SC Oncology GA 268SL UT WOS:000328190700001 PM 24080207 ER PT J AU Disis, ML Gad, E Herendeen, DR Vy, PL Park, KH Cecil, DL O'Meara, MM Treuting, PM Lubet, RA AF Disis, Mary L. Gad, Ekram Herendeen, Daniel R. Vy Phan-Lai Park, Kyong Hwa Cecil, Denise L. O'Meara, Megan M. Treuting, Piper M. Lubet, Ronald A. TI A Multiantigen Vaccine Targeting Neu, IGFBP-2, and IGF-IR Prevents Tumor Progression in Mice with Preinvasive Breast Disease SO CANCER PREVENTION RESEARCH LA English DT Article ID CARCINOMA IN-SITU; FACTOR-BINDING PROTEIN-2; GROWTH-FACTOR-I; TRANSGENIC MICE; PREMALIGNANT LESIONS; MAMMARY-TUMORS; CANCER; EXPRESSION; IMMUNITY; RECEPTOR AB A multiantigen multipeptide vaccine, targeting proteins expressed in preinvasive breast lesions, can stimulate type I CD4(+) T cells which have been shown to be deficient in both patients with breast cancer and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multiantigen peptide vaccine specific for neu, insulin-like growth factor-binding protein 2 and insulin-like growth factor receptor-I at a time when some of the animals already had preinvasive lesions (18 weeks of age). Although immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multiantigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors, which did arise. Protection was mediated by CD4(+) T cells, and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8(+) T cells as compared with controls (P = 0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. Although the combination of lapatinib and vaccination performed similarly to vaccination alone (P = 0.735), bexarotene and vaccination significantly enhanced disease-free survival (P < 0.0001), and approximately 90% of the mice showed no pathologic evidence of carcinomas at one year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemoimmunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease. (C) 2013 AACR. C1 [Disis, Mary L.; Gad, Ekram; Herendeen, Daniel R.; Vy Phan-Lai; Cecil, Denise L.; O'Meara, Megan M.] Univ Washington, Tumor Vaccine Grp, Ctr Translat Med Womens Hlth, Seattle, WA 98109 USA. [Treuting, Piper M.] Univ Washington, Dept Comparat Med, Seattle, WA 98109 USA. [Park, Kyong Hwa] Korea Univ, Dept Internal Med, Div Oncol Hematol, Seoul, South Korea. [Lubet, Ronald A.] NCI, Canc Chemoprevent Branch, Bethesda, MD 20892 USA. RP Disis, ML (reprint author), Univ Washington, Tumor Vaccine Grp, Ctr Translat Med Womens Hlth, 850 Republican St,Box 358050, Seattle, WA 98109 USA. EM ndisis@uw.edu FU National Cancer Institute [N01-CN-53300/WA10, U01 CA141539, P50 CA083636]; Ovarian Cancer Research Fund; Athena Distinguished Professorship of Breast Cancer Research FX M.L. Disis was supported by a National Cancer Institute grant (N01-CN-53300/WA#10, U01 CA141539, P50 CA083636), the Ovarian Cancer Research Fund, and by the Athena Distinguished Professorship of Breast Cancer Research. NR 39 TC 23 Z9 23 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD DEC PY 2013 VL 6 IS 12 BP 1273 EP 1282 DI 10.1158/1940-6207.CAPR-13-0182 PG 10 WC Oncology SC Oncology GA 268SL UT WOS:000328190700003 PM 24154719 ER PT J AU DeCicco-Skinner, KL Jung, SA Tabib, T Gwilliam, JC Alexander, H Goodheart, SE Merchant, AS Shan, MG Garber, C Wiest, JS AF DeCicco-Skinner, Kathleen L. Jung, Sarah A. Tabib, Tracy Gwilliam, J. Curtis Alexander, Hepzibha Goodheart, Sarah E. Merchant, Anand S. Shan, Mengge Garber, Caroline Wiest, Jonathan S. TI Tpl2 knockout keratinocytes have increased biomarkers for invasion and metastasis SO CARCINOGENESIS LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; SQUAMOUS-CELL CARCINOMA; ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION ANALYSIS; MATRIX METALLOPROTEINASES; TUMOR PROGRESSION; BREAST-CANCER; IN-VITRO; PANCREATIC ADENOCARCINOMAS; MALIGNANT CONVERSION AB Skin cancer is the most common form of cancer in the USA, with an estimated two million cases diagnosed annually. Tumor progression locus 2 (Tpl2), also known as MAP3K8, is a serine/threonine protein kinase in the mitogen-activated protein kinase signal transduction cascade. Tpl2 was identified by our laboratory as having a tumor suppressor function in skin carcinogenesis, with the absence of this gene contributing to heightened inflammation and increased skin carcinogenesis. In this study, we used gene expression profiling to compare expression levels between Tpl2+/+ and Tpl2-/- keratinocytes. We identified over 2000 genes as being differentially expressed between genotypes. Functional annotation analysis identified cancer, cell growth/proliferation, cell death, cell development, cell movement and cell signaling as the top biological processes to be differentially regulated between genotypes. Further microarray analysis identified several candidate genes, including Mmp1b, Mmp2, Mmp9 and Mmp13, involved in migration and invasion to be upregulated in Tpl2-/- keratinocytes. Moreover, Tpl2-/- keratinocytes had a significant downregulation in the matrix metalloproteinase (MMP) inhibitor Timp3. Real-time PCR validated the upregulation of the MMPs in Tpl2-/- keratinocytes and zymography confirmed that MMP2 and MMP9 activity was higher in conditioned media from Tpl2-/- keratinocytes. Immunohistochemistry confirmed higher MMP9 staining in 12-O-tetradecanoylphorbol-13-acetate-treated skin from Tpl2-/- mice and grafted tumors formed from v-ras(Ha) retrovirus-infected Tpl2-/- keratinocytes. Additionally, Tpl2-/- keratinocytes had significantly higher invasion, malignant conversion rates and increased endothelial cell tube formation when compared with Tpl2+/+ keratinocytes. In summary, our studies reveal that keratinocytes from Tpl2-/- mice demonstrate a higher potential to be invasive and metastatic. C1 [DeCicco-Skinner, Kathleen L.; Jung, Sarah A.; Tabib, Tracy; Gwilliam, J. Curtis; Alexander, Hepzibha; Goodheart, Sarah E.] Amer Univ, Dept Biol, Washington, DC 20016 USA. [Merchant, Anand S.] NCI, CCRIFX Bioinformat Core, NIH, Bethesda, MD 20892 USA. [Shan, Mengge] NCI, Off Sci & Technol Partnerships, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Garber, Caroline; Wiest, Jonathan S.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP DeCicco-Skinner, KL (reprint author), Amer Univ, Dept Biol, Washington, DC 20016 USA. EM decicco@american.edu FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; National Cancer Institute grant [UA5CA152907] FX Intramural Research Program of the National Cancer Institute at the National Institutes of Health; National Cancer Institute grant (UA5CA152907). NR 66 TC 3 Z9 3 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 2013 VL 34 IS 12 BP 2789 EP 2798 DI 10.1093/carcin/bgt319 PG 10 WC Oncology SC Oncology GA 269XX UT WOS:000328278900012 PM 24067898 ER PT J AU Bates, SE AF Bates, Susan E. TI On Masterpieces and Breast Cancer Research SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2013 VL 19 IS 23 BP 6352 EP 6352 DI 10.1158/1078-0432.CCR-13-2847 PG 1 WC Oncology SC Oncology GA 263PE UT WOS:000327819700004 PM 24298064 ER PT J AU Lin, NU Amiri-Kordestani, L Palmieri, D Liewehr, DJ Steeg, PS AF Lin, Nancy U. Amiri-Kordestani, Laleh Palmieri, Diane Liewehr, David J. Steeg, Patricia S. TI CNS Metastases in Breast Cancer: Old Challenge, New Frontiers SO CLINICAL CANCER RESEARCH LA English DT Article ID NERVOUS-SYSTEM METASTASES; POSITRON-EMISSION-TOMOGRAPHY; BLOOD-BRAIN-BARRIER; LAPATINIB PLUS CAPECITABINE; TYROSINE KINASE INHIBITOR; ADVANCED SOLID TUMORS; PHASE-II; INTRATHECAL TRASTUZUMAB; CLINICAL-OUTCOMES; MENINGEAL CARCINOMATOSIS AB Despite major therapeutic advances in the management of patients with breast cancer, central nervous system (CNS) metastases remain an intractable problem, particularly in patients with metastatic HER2-positive and triple-negative breast cancer. As systemic therapies to treat extracranial disease improve, some patients are surviving longer, and the frequency of CNS involvement seems to be increasing. Furthermore, in the early-stage setting, the CNS remains a potential sanctuary site for relapse. This review highlights advances in the development of biologically relevant preclinical models, including the development of brain-tropic cell lines for testing of agents to prevent and treat brain metastases, and summarizes our current understanding of the biology of CNS relapse. From a clinical perspective, a variety of therapeutic approaches are discussed, including methods to improve drug delivery, novel cytotoxic agents, and targeted therapies. Challenges in current trial design and endpoints are reviewed. Finally, we discuss promising new directions, including novel trial designs, correlative imaging techniques, and enhanced translational opportunities. Clin Cancer Res; 19(23); 6404-18. (C) 2013 AACR. C1 [Lin, Nancy U.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Amiri-Kordestani, Laleh] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Palmieri, Diane; Steeg, Patricia S.] NCI, Womens Canc Sect, Lab Mol Pharmacol, Bethesda, MD 20892 USA. [Liewehr, David J.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Lin, NU (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM nlin@partners.org RI Palmieri, Diane/B-4258-2015 FU Intramural Program of the National Cancer Institute; DOD Breast Cancer Research Program [W81XWH-062-0033]; Breast Cancer Research Foundation FX The statistical assistance of S. Steinberg, Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD, is appreciated. The authors thank the following individuals for providing figures: National Cancer Institute Molecular Imaging Program Staff (M. Liza Lindenberg, MD, Esther Mena Gonzalex, PhD, Peter L. Choyke, MD, Karen A. Kurdziel, MD), Kyrre E. Emblem, PhD (Massachusetts General Hospital, Boston, MA), Elizabeth Gerstner, MD (Massachusetts General Hospital, Boston, MA), and Professor E. G. Elisabeth de Vries, MD, PhD (University Medical Centre, Groningen, the Netherlands). This work was funded, in part, by the Intramural Program of the National Cancer Institute, DOD Breast Cancer Research Program grant W81XWH-062-0033 (P.S. Steeg, D. Palmieri), and the Breast Cancer Research Foundation (N.U. Lin). NR 108 TC 42 Z9 43 U1 1 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2013 VL 19 IS 23 BP 6404 EP 6418 DI 10.1158/1078-0432.CCR-13-0790 PG 15 WC Oncology SC Oncology GA 263PE UT WOS:000327819700011 PM 24298071 ER PT J AU Dynkevich, Y Rother, KI Whitford, I Qureshi, S Galiveeti, S Szulc, AL Danoff, A Breen, TL Kaviani, N Shanik, MH LeRoith, D Vigneri, R Koch, CA Roth, J AF Dynkevich, Yevgeniya Rother, Kristina I. Whitford, Ian Qureshi, Sana Galiveeti, Sneha Szulc, Alessandra L. Danoff, Ann Breen, Tracy L. Kaviani, Nargess Shanik, Michael H. LeRoith, Derek Vigneri, Riccardo Koch, Christian A. Roth, Jesse TI Tumors, IGF-2, and Hypoglycemia: Insights From the Clinic, the Laboratory, and the Historical Archive SO ENDOCRINE REVIEWS LA English DT Review ID GROWTH-FACTOR-II; ISLET-CELL TUMOR; SOLITARY FIBROUS TUMOR; FACTOR-BINDING-PROTEINS; NONSUPPRESSIBLE INSULIN-LIKE; GASTROINTESTINAL STROMAL TUMOR; II/MANNOSE 6-PHOSPHATE RECEPTOR; HYPERINSULINEMIC HYPOGLYCEMIA; GASTRIC-BYPASS; NSILA-S AB Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non-islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors. C1 [Dynkevich, Yevgeniya] North Shore Long Isl Jewish NS LIJ Hlth Syst, Queens Long Isl Med Grp, Hicksville, NY 11801 USA. [Rother, Kristina I.] NIDDK, Bethesda, MD 20892 USA. [Whitford, Ian; Qureshi, Sana; Galiveeti, Sneha; Roth, Jesse] NS LIJ Hlth Syst, Lab Diabet & Diabet Related Res, Feinstein Inst Med Res, Manhasset, NY 11030 USA. [Szulc, Alessandra L.; Roth, Jesse] Yeshiva Univ, Albert Einstein Coll Med, Bronx, NY 10461 USA. [Danoff, Ann] NYU, Sch Med, Div Endocrinol Diabet & Metab, New York, NY 10016 USA. [Danoff, Ann] Vet Adm New York Harbor Healthcare Syst, New York, NY 10010 USA. [Breen, Tracy L.] NS LIJ Hlth Syst, Div Endocrinol, Great Neck, NY 11021 USA. [Breen, Tracy L.; Roth, Jesse] NS LIJ Hlth Syst, Hofstra NS LIJ Sch Med, Manhasset, NY 11549 USA. [Kaviani, Nargess] Geisinger Hlth Syst, Endocrinol & Metab, State Coll, PA 16801 USA. [Shanik, Michael H.] Endocrine Associates Long Isl PC, Smithtown, NY 11787 USA. [Shanik, Michael H.] Stony Brook Univ Hosp, Stony Brook, NY 11794 USA. [LeRoith, Derek] Mt Sinai Sch Med, Div Endocrinol Diabet & Bone Dis, Samuel Bronfman Dept Med, New York, NY 10029 USA. [LeRoith, Derek] Clin Res Inst Rambam, Diabet & Metab Clin Res Ctr Excellence, IL-31096 Haifa, Israel. [Vigneri, Riccardo] Univ Catania, Endocrine Unit, Dept Clin & Mol Biomed, Garibaldi Nesima Hosp, Catania, Italy. Consilgio Nazl Richerche Catania Sect, Ist Biostrutture & Bioimmagini, I-95131 Catania, Italy. [Koch, Christian A.] Univ Mississippi, Sch Med, Div Endocrinol, Dept Med, Jackson, MS 39216 USA. RP Roth, J (reprint author), Feinstein Inst Med Res, Lab Diabet & Diabet Related Res, 350 Community Dr, Manhasset, NY 11030 USA. EM jesserothmd@hotmail.com OI Koch, Christian/0000-0003-0678-1242 FU Feinstein Institute for Medical Research, Manhasset, New York FX This work was funded by the Feinstein Institute for Medical Research, Manhasset, New York. NR 287 TC 20 Z9 20 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0163-769X EI 1945-7189 J9 ENDOCR REV JI Endocr. Rev. PD DEC PY 2013 VL 34 IS 6 BP 798 EP 826 DI 10.1210/er.2012-1033 PG 29 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 267FU UT WOS:000328082900004 PM 23671155 ER PT J AU Kistemaker, LEM Bos, IST Hylkema, MN Nawijn, MC Hiemstra, PS Wess, J Meurs, H Kerstjens, HAM Gosens, R AF Kistemaker, Loes E. M. Bos, I. S. T. Hylkema, Machteld N. Nawijn, Martijn C. Hiemstra, Pieter S. Wess, Juergen Meurs, Herman Kerstjens, Huib A. M. Gosens, Reinoud TI Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; NONNEURONAL CHOLINERGIC SYSTEM; BRONCHIAL EPITHELIAL-CELLS; AIRWAY SMOOTH-MUSCLE; PHARMACOLOGICAL-PROPERTIES; ACETYLCHOLINE-RECEPTOR; CHEMOTACTIC ACTIVITY; TIOTROPIUM BROMIDE; MURINE AIRWAYS; IN-VITRO AB Cholinergic tone contributes to airflow obstruction in chronic obstructive pulmonary disease. Accordingly, anticholinergics are effective bronchodilators by blocking the muscarinic M-3 receptor on airway smooth muscle. Recent evidence indicates that acetylcholine also contributes to airway inflammation. However, which muscarinic receptor subtype(s) regulates this process is unknown. In this study, the contribution of the M-1, M-2 and M-3 receptor subtypes to cigarette smoke-induced airway inflammation was investigated by exposing muscarinic receptor subtype deficient mice to cigarette smoke for 4 days. In wild-type mice, cigarette smoke induced an increase in macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid. Neutrophilic inflammation was higher in M-1(-/-) and M-2(-/-) mice compared to wild-type mice, but lower in M-3(-/-) mice. Accordingly, the release of keratinocyte-derived chemokine (KC), monocyte chemotactic protein-1 and interleukin-6 was higher in M-1(-/-) and M-2(-/-) mice, and reduced in M-3(-/-) mice. Markers of remodelling were not increased after cigarette smoke exposure. However, M-3(-/-) mice had reduced expression of transforming growth factor-beta 1 and matrix proteins. Cigarette smoke-induced inflammatory cell recruitment and KC release were also prevented by the M-3-receptor selective antagonist 1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) in wild-type mice. Collectively, our data indicate a pro-inflammatory role for the M-3 receptor in cigarette smoke-induced neutrophilia and cytokine release, yet an anti-inflammatory role for M-1 and M-2 receptors. C1 [Kistemaker, Loes E. M.; Bos, I. S. T.; Meurs, Herman; Gosens, Reinoud] Univ Groningen, Dept Mol Pharmacol, NL-9713 AV Groningen, Netherlands. [Kistemaker, Loes E. M.; Bos, I. S. T.; Hylkema, Machteld N.; Nawijn, Martijn C.; Meurs, Herman; Kerstjens, Huib A. M.; Gosens, Reinoud] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, NL-9713 AV Groningen, Netherlands. [Hylkema, Machteld N.; Nawijn, Martijn C.] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, NL-9713 AV Groningen, Netherlands. [Hiemstra, Pieter S.] Leiden Univ, Med Ctr, Dept Pulmonol, Leiden, Netherlands. [Kerstjens, Huib A. M.] Univ Groningen, Univ Med Ctr Groningen, Dept Resp Med, NL-9713 AV Groningen, Netherlands. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kistemaker, LEM (reprint author), Univ Groningen, Dept Mol Pharmacol, A Deusinglaan 1, NL-9713 AV Groningen, Netherlands. EM l.e.m.kistemaker@rug.nl FU Netherlands Asthma Foundation [3.2.08.014] FX We would like to thank the Netherlands Asthma Foundation for financial support (grant 3.2.08.014). NR 41 TC 12 Z9 13 U1 1 U2 7 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 DEC PY 2013 VL 42 IS 6 BP 1677 EP 1688 DI 10.1183/09031936.00112412 PG 12 WC Respiratory System SC Respiratory System GA 264ZQ UT WOS:000327919900031 PM 23397297 ER PT J AU Gabitzsch, EK Hashmi, SS Koenig, MK Raia, MH Whittemore, VH Northrup, H Nader, S Gambello, MJ AF Gabitzsch, Emily K. Hashmi, Syed S. Koenig, Mary Kay Raia, Marianna H. Whittemore, Vicky H. Northrup, Hope Nader, Shahla Gambello, Michael J. TI Self- reported reproductive health in women with tuberous sclerosis complex SO GENETICS IN MEDICINE LA English DT Article DE reproductive health; tuberous sclerosis complex ID PREMATURE OVARIAN FAILURE; PRIMORDIAL FOLLICLES; TSC2; ACTIVATION; GENE; LYMPHANGIOLEIOMYOMATOSIS; IDENTIFICATION; MISCARRIAGE; PREVALENCE; PATHWAY AB Purpose: Little is known about sex-specific manifestations of tuberous sclerosis complex. Inactivating mutations in the TSC1 and TSC2 genes cause tuberous sclerosis complex, and recent evidence points to a crucial role for these genes in maintaining appropriate ovarian function. The main objective of this study was to estimate reproductive dysfunction in a sample of women with tuberous sclerosis complex. Methods: We designed a three-part questionnaire that included demographic information, reproductive history, and tuberous sclerosis complex history, and developed strict criteria to assess patterns in menstrual cyclicity; we analyzed 182 responses from female adult members of the Tuberous Sclerosis Alliance. Results: More than one-third of women in our sample displayed some degree of menstrual irregularity, and their reported miscarriage rate was 41%. More than 4% of women had reproductive histories suggestive of premature ovarian insufficiency, higher than the general population estimate of 1%. Conclusion: Our data reveal an underappreciated aspect of tuberous sclerosis complex in affected women, suggesting that a further exploration of the role the tuberous sclerosis complex genes play in reproductive function is warranted. C1 [Gabitzsch, Emily K.; Gambello, Michael J.] Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Genet Counseling Program, Houston, TX 77030 USA. [Hashmi, Syed S.; Koenig, Mary Kay; Raia, Marianna H.; Northrup, Hope] Univ Texas Hlth Sci Ctr Houston, Dept Pediat, Houston, TX 77030 USA. [Whittemore, Vicky H.] NINDS, NIH, Rockville, MD USA. [Nader, Shahla] Univ Texas Hlth Sci Ctr Houston, Dept Obstet Gynecol & Reprod Sci, Houston, TX 77030 USA. RP Gambello, MJ (reprint author), Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. EM Michael.j.gambello@emory.edu OI Hashmi, S. Shahrukh/0000-0001-8758-8254 FU University of Texas-Memorial Hermann Hospital TSC Center of Excellence FX We sincerely thank the respondents and members of the Tuberous Sclerosis Alliance organization for their participation, and the Alliance staff for assisting in the distribution of these surveys. The University of Texas-Memorial Hermann Hospital TSC Center of Excellence generously provided financial support for the development of this survey. NR 24 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 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2013 VL 15 IS 12 BP 966 EP 971 DI 10.1038/gim.2013.60 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 266XI UT WOS:000328056900009 PM 23660529 ER PT J AU Berry, SA Kenney, MK Harris, KB Singh, RH Cameron, CA Kraszewski, JN Levy-Fisch, J Shuger, JF Greene, CL Lloyd-Puryear, MA Boyle, CA AF Berry, Susan A. Kenney, Mary Kay Harris, Katharine B. Singh, Rani H. Cameron, Cynthia A. Kraszewski, Jennifer N. Levy-Fisch, Jill Shuger, Jill F. Greene, Carol L. Lloyd-Puryear, Michele A. Boyle, Coleen A. TI Insurance coverage of medical foods for treatment of inherited metabolic disorders SO GENETICS IN MEDICINE LA English DT Article DE diet therapy; inborn errors of metabolism; insurance coverage; neonatal screening AB Purpose: Treatment of inherited metabolic disorders is accomplished by use of specialized diets employing medical foods and medically necessary supplements. Families seeking insurance coverage for these products express concern that coverage is often limited; the extent of this challenge is not well defined. Methods: To learn about limitations in insurance coverage, parents of 305 children with inherited metabolic disorders completed a paper survey providing information about their use of medical foods, modified low-protein foods, prescribed dietary supplements, and medical feeding equipment and supplies for treatment of their child's disorder as well as details about payment sources for these products. Results: Although nearly all children with inherited metabolic disorders had medical coverage of some type, families paid "out of pocket" for all types of products. Uncovered spending was reported for 11% of families purchasing medical foods, 26% purchasing supplements, 33% of those needing medical feeding supplies, and 59% of families requiring modified low-protein foods. Forty-two percent of families using modified low-protein foods and 21% of families using medical foods reported additional treatment-related expenses of $ 100 or more per month for these products. Conclusion: Costs of medical foods used to treat inherited metabolic disorders are not completely covered by insurance or other resources. C1 [Berry, Susan A.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Kenney, Mary Kay] US Hlth Resources & Serv Adm, Off Epidemiol Policy & Evaluat, Rockville, MD 20857 USA. [Harris, Katharine B.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Singh, Rani H.] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Cameron, Cynthia A.] Michigan Publ Hlth Inst, Okemos, MI USA. [Kraszewski, Jennifer N.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Levy-Fisch, Jill] Save Babies Screening Fdn Inc, Cincinnati, OH USA. [Shuger, Jill F.] US Hlth Resources & Serv Adm, Maternal & Child Hlth Bur, Rockville, MD 20857 USA. [Greene, Carol L.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Lloyd-Puryear, Michele A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Boyle, Coleen A.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. RP Berry, SA (reprint author), Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. EM berry002@umn.edu OI Berry, Susan/0000-0001-7970-688X FU Cooperative Agreement between the Maternal and Child Health Bureau (MCHB); Genetic Services Branch, and the University of Texas Health Science Center at San Antonio; National Newborn Screening and Genetics Resource Center; Health Resources and Services Administration (HRSA) [U32MC00148]; HRSA-MCHB Regional Genetic and Newborn Screening Services Collaboratives; Heritable Disorders Program: Region 2 New York-Mid-Atlantic Consortium for Genetic and Newborn Screening Services [U22MC03956]; Region 3 Southeast Newborn Screening and Genetics Collaborative [U22MC10979]; Region 4 Midwest Genetics Collaborative [U22MC03963] FX The project was supported through a Cooperative Agreement between the Maternal and Child Health Bureau (MCHB), Genetic Services Branch, and the University of Texas Health Science Center at San Antonio, National Newborn Screening and Genetics Resource Center, Health Resources and Services Administration (HRSA) grant no. U32MC00148 and by HRSA-MCHB Regional Genetic and Newborn Screening Services Collaboratives, Heritable Disorders Program: Region 2 New York-Mid-AtlantiConsortium for Genetic and Newborn Screening Services, Cooperative Agreement No. U22MC03956; Region 3 Southeast Newborn Screening and Genetics Collaborative, Cooperative Agreement No. U22MC10979; and Region 4 Midwest Genetics Collaborative, Cooperative Agreement No. U22MC03963. The authors thank the investigators at the following institutions: - University of - Minnesota Amplatz Children's Hospital (Kristi Bentler); - Cincinnati Children's Hospital Medical Center (Nancy Leslie); Emory - University (Mary Brauchla); Greenwood Genetics Center (Melinda Whetsell and Neena Champaigne); University of Florida (Helen McCune and Robert Zori); University of North - Carolina-Chapel Hill (Dianne - Frazier); University of Tennessee (Darla Henderson Smith); Vanderbilt University Medical Center (Gina Wey); Mount Sinai Medical Center (Roberta Salveson); Children's Hospital at Albany Medical Center (Katherine Marra); Children's Hospital of Pittsburgh (Judith Henry); Golisano Children's Hospital at Strong (Eileen Blakely); Maria Fareri Children's Hospital at Westchester Medical Center (Shideh Mofidi); University of Maryland Hospital for Children (Megan Skinner). NR 8 TC 5 Z9 5 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2013 VL 15 IS 12 BP 978 EP 982 DI 10.1038/gim.2013.46 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 266XI UT WOS:000328056900011 PM 23598714 ER PT J AU Kruszka, PS Manoli, I Sloan, JL Kopp, JB Venditti, CP AF Kruszka, Paul S. Manoli, Irini Sloan, Jennifer L. Kopp, Jeffrey B. Venditti, Charles P. TI Renal growth in isolated methylmalonic acidemia SO GENETICS IN MEDICINE LA English DT Article DE chronic kidney disease; cystatin C; isolated methylmalonic acidemia; methylmalonyl-CoA mutase; renal growth; renal ultrasound; vitamin B12 ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE; CYSTATIN-C; SONOGRAPHIC ASSESSMENT; HEALTHY-CHILDREN; LENGTH; MANAGEMENT; ACIDURIAS; TRANSPLANTATION; NOMOGRAM AB Purpose: We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic acidemia, a group of disorders associated with chronic kidney disease. Methods: Fifty patients with methylmalonic acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses. Results: Comparisons with age-matched controls showed that renal length in subjects with methylmalonic acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 x age for the controls and 6.80 + 0.09 x age for the methylmalonic acidemia cohort (P < 0.001; constant and slope). Conclusion: Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population. C1 [Kruszka, Paul S.; Manoli, Irini; Sloan, Jennifer L.; Venditti, Charles P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Kopp, Jeffrey B.] Natl Inst Diabet & Digest & Kidney Dis, Kidney Dis Sect, NIH, Bethesda, MD USA. RP Venditti, CP (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941; Kopp, Jeffrey/0000-0001-9052-186X FU National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the intramural research programs of the National Human Genome Research Institute and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 37 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2013 VL 15 IS 12 BP 990 EP 996 DI 10.1038/gim.2013.42 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 266XI UT WOS:000328056900013 PM 23639900 ER PT J AU Weil, CJ Mechanic, LE Green, T Kinsinger, C Lockhart, NC Nelson, SA Rodriguez, LL Buccini, LD AF Weil, Carol J. Mechanic, Leah E. Green, Tiffany Kinsinger, Christopher Lockhart, Nicole C. Nelson, Stefanie A. Rodriguez, Laura L. Buccini, Laura D. TI NCI think tank concerning the identifiability of biospecimens and "omic" data SO GENETICS IN MEDICINE LA English DT Article DE biospecimens; data sharing; identifiability; research participant engagement ID GENOMIC RESEARCH; PRIVACY; PARTICIPANTS AB Purpose: On 11 and 12 June 2012, the National Cancer Institute hosted a think tank concerning the identifiability of biospecimens and "omic" data in order to explore challenges surrounding this complex and multifaceted topic. Methods: The think tank brought together 46 leaders from several fields, including cancer genomics, bioinformatics, human subject protection, patient advocacy, and commercial genetics. Results: The first day involved presentations regarding the state of the science of reidentification; current and proposed regulatory frameworks for assessing identifiability; developments in law, industry, and biotechnology; and the expectations of patients and research participants. The second day was spent by think tank participants in small breakout groups designed to address specific subtopics under the umbrella issue of identifiability, including considerations for the development of best practices for data sharing and consent, and targeted opportunities for further empirical research. Conclusion: We describe the outcomes of this 2-day meeting, including two complementary themes that emerged from moderated discussions following the presentations on day 1, and ideas presented for further empirical research to discern the preferences and concerns of research participants about data sharing and individual identifiability. C1 [Weil, Carol J.] NCI, Diagnost Evaluat Branch, Canc Diag Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. [Mechanic, Leah E.; Green, Tiffany; Nelson, Stefanie A.; Buccini, Laura D.] NCI, Host Susceptibil Factors Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20892 USA. [Kinsinger, Christopher] NCI, Off Canc Clin Prote Res, Ctr Strateg & Sci Initiat, NIH, Bethesda, MD 20892 USA. [Lockhart, Nicole C.] NHGRI, Div Genom & Soc, NIH, Bethesda, MD 20892 USA. [Rodriguez, Laura L.] NHGRI, Div Policy Commun & Educ, NIH, Bethesda, MD 20892 USA. [Buccini, Laura D.] Cleveland Clin, Digest Dis Inst, Cleveland, OH 44106 USA. RP Weil, CJ (reprint author), NCI, Diagnost Evaluat Branch, Canc Diag Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. EM carol.weil@nih.gov FU Host Susceptibility Factors Branch (HSFB); Epidemiology and Genomics Research Program (EGRP) in the Division of Cancer Control and Population Sciences, NCI; Biorepositories and Biospecimen Research Branch (BBRB), Division of Cancer Treatment and Diagnosis, NCI FX Funds for the National Cancer Institute (NCI) think tank were provided by the Host Susceptibility Factors Branch (HSFB) and the Epidemiology and Genomics Research Program (EGRP) in the Division of Cancer Control and Population Sciences, NCI and the Biorepositories and Biospecimen Research Branch (BBRB), Division of Cancer Treatment and Diagnosis, NCI. The authors acknowledge the assistance with meeting planning of Elizabeth Gillanders (HSFB) and Jim Vaught (BBRB). The authors thank all of the participants of the NCI Identifiability think tank listed in Supplementary Appendix S2 online for their intellectual contributions throughout the meeting. NR 18 TC 5 Z9 5 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2013 VL 15 IS 12 BP 997 EP 1003 DI 10.1038/gim.2013.40 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 266XI UT WOS:000328056900014 PM 23579437 ER PT J AU Sacks, DL Ribeiro-Gomes, FL Peters, NC AF Sacks, D. L. Ribeiro-Gomes, F. L. Peters, N. C. TI The influence of vector transmission and neutrophils on the immune response to Leishmania major SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 02-05, 2013 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Sacks, D. L.; Peters, N. C.] NIH, Bethesda, MD 20892 USA. [Ribeiro-Gomes, F. L.] NIAID, NIH, Bethesda, MD 20892 USA. RI Ribeiro-Gomes, Flavia/F-7609-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD DEC PY 2013 VL 140 SU 1 SI SI BP 12 EP 12 PG 1 WC Immunology SC Immunology GA 258VV UT WOS:000327487700024 ER PT J AU Roychoudhuri, R Hirahara, K Mousavi, K Clever, D Bonelli, M Sciume, G Zare, H Vahedi, G Klebanoff, C Sartorelli, V Kanno, Y Gattinoni, L Nakamura, A Muto, A O'Shea, J Restifo, N AF Roychoudhuri, R. Hirahara, K. Mousavi, K. Clever, D. Bonelli, M. Sciume, G. Zare, H. Vahedi, G. Klebanoff, C. Sartorelli, V. Kanno, Y. Gattinoni, L. Nakamura, A. Muto, A. O'Shea, J. Restifo, N. TI BACH2 represses effector programmes to stabilize T-reg-mediated immune homeostasis SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 02-05, 2013 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Roychoudhuri, R.; Clever, D.; Klebanoff, C.; Gattinoni, L.; Restifo, N.] NCI, NIH, Bethesda, MD 20892 USA. [Hirahara, K.; Mousavi, K.; Bonelli, M.; Sciume, G.; Zare, H.; Vahedi, G.; Sartorelli, V.; Kanno, Y.; O'Shea, J.] NIAMSD, Bethesda, MD 20892 USA. [Nakamura, A.; Muto, A.] Tohoku Univ, Sendai, Miyagi 980, Japan. RI Roychoudhuri, Rahul/A-7442-2010; Hirahara, Kiyoshi/E-2460-2017 OI Roychoudhuri, Rahul/0000-0002-5392-1853; Hirahara, Kiyoshi/0000-0002-9128-9449 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD DEC PY 2013 VL 140 SU 1 SI SI BP 43 EP 43 PG 1 WC Immunology SC Immunology GA 258VV UT WOS:000327487700086 ER PT J AU Tregoning, JS Wang, B McDonald, JU Yamaguchi, Y Harker, JA Goritzka, M Johansson, C Bukreyev, A Collins, PL Openshaw, PJ AF Tregoning, J. S. Wang, B. McDonald, J. U. Yamaguchi, Y. Harker, J. A. Goritzka, M. Johansson, C. Bukreyev, A. Collins, P. L. Openshaw, P. J. TI Respiratory syncytial virus (RSV) infection during early life suppresses antibody responses by the induction of interferon gamma SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 02-05, 2013 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Tregoning, J. S.; McDonald, J. U.] Univ London Imperial Coll Sci Technol & Med, Infect Dis Sect, London, England. [Wang, B.; Yamaguchi, Y.; Harker, J. A.; Goritzka, M.; Johansson, C.; Openshaw, P. J.] Univ London Imperial Coll Sci Technol & Med, Dept Resp Med, London, England. [Bukreyev, A.; Collins, P. L.] NIH, Infect Dis Lab, 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 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD DEC PY 2013 VL 140 SU 1 SI SI BP 104 EP 104 PG 1 WC Immunology SC Immunology GA 258VV UT WOS:000327487700260 ER PT J AU Dhanda, AD Liu, B Lait, P Schewitz-Bowers, L Collins, PL Dick, AD Nussenblatt, R Lee, RW AF Dhanda, A. D. Liu, B. Lait, P. Schewitz-Bowers, L. Collins, P. L. Dick, A. D. Nussenblatt, R. Lee, R. W. TI CD14(++)CD16(-) monocytes polarise memory T cells to a Th17 phenotype which is refractory to glucocorticoid treatment SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 02-05, 2013 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Dhanda, A. D.; Lait, P.; Schewitz-Bowers, L.; Dick, A. D.; Lee, R. W.] Univ Bristol, Sch Clin Sci, Bristol, Avon, England. [Dhanda, A. D.; Collins, P. L.] Univ Hosp Bristol NHS Fdn Trust, Dept Liver Med, Bristol, Avon, England. [Liu, B.; Nussenblatt, R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Dick, A. D.] Univ Hosp Bristol NHS Fdn Trust, Acad Unit Ophthalmol, Bristol, Avon, England. [Dick, A. D.; Lee, R. W.] Moorfields Eye Hosp NHS Fdn Trust, Natl Inst Hlth Res Biomed Res Ctr, Bristol, Avon, England. [Dick, A. D.; Lee, R. W.] Univ Hosp Bristol NHS Fdn Trust, UCL Inst Ophthalmol, Bristol, Avon, England. [Dick, A. D.; Lee, R. W.] Univ Bristol, Bristol, Avon, England. RI Lee, Richard/A-3116-2017 OI Lee, Richard/0000-0002-9480-6843 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 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD DEC PY 2013 VL 140 SU 1 SI SI BP 154 EP 154 PG 1 WC Immunology SC Immunology GA 258VV UT WOS:000327487700400 ER PT J AU Gabay, O Zaal, KJ Sanchez, C Dvir-Ginzberg, M Gagarina, V Song, YJ He, XH McBurney, MW AF Gabay, Odile Zaal, Kristien J. Sanchez, Christelle Dvir-Ginzberg, Mona Gagarina, Viktoria Song, Yingjie He, Xiao Hong McBurney, Michael W. TI Sirt1-deficient mice exhibit an altered cartilage phenotype SO JOINT BONE SPINE LA English DT Article DE Sirtuin 1; Cartilage; Osteoarthritis; Animal models ID HUMAN OSTEOARTHRITIC CHONDROCYTES; SIR2-ALPHA PROTEIN; STEM-CELLS; SIRTUIN 1; APOPTOSIS; MAMMALS; PATHWAY; MOUSE AB Objective: We previously demonstrated that Sirt1 regulates apoptosis in cartilage in vitro. Here we attempt to examine in vivo cartilage homeostasis, using Sirt1 total body knockout (KO) mice. Method: Articular cartilage was harvested from hind paws of 1-week and 3-week-old mice carrying wild type (WT) or null Sirt1 gene. Knees of Sirt1 haploinsufficient mice also were examined, at 6 months. Joint cartilage was processed for histologic examination or biochemical analyses of chondrocyte cultures. Results: We found that articular cartilage tissue sections from Sirt1 KO mice up to 3 weeks of age exhibited low levels of type 2 collagen, aggrecan, and glycosaminoglycan content. In contrast, protein levels of MMP-13 were elevated in the Sirt1 KO mice, leading to a potential increase of cartilage breakdown, already shown in the heterozygous mice. Additional results showed elevated chondrocyte apoptosis in Sirt1 KO mice, as compared to WT controls. In addition to these observations, PTP1b (protein tyrosine phosphatase b) was elevated in the Sirt1 KO mice, in line with previous reports. Conclusion: The findings from this animal model demonstrated that Sirt1 KO mice presented an altered cartilage phenotype, with an elevated apoptotic process and a potential degradative cartilage process. Published by Elsevier Masson SAS. C1 [Gabay, Odile; Gagarina, Viktoria] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. [Zaal, Kristien J.] NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. [Sanchez, Christelle] Univ Liege, Bone & Cartilage Res Unit, Inst Pathol B23, Liege, Belgium. [Dvir-Ginzberg, Mona] Hebrew Univ Hadassah Ein Kerem, Fac Med Dent, Inst Dent Sci, Lab Cartilage Biol, Jerusalem, Israel. [Song, Yingjie] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. [He, Xiao Hong; McBurney, Michael W.] Ottawa Hosp Res Inst, Ottawa, ON K1H 8L6, Canada. RP Gabay, O (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM gabayo@mail.nih.gov OI Dvir-Ginzberg, Mona/0000-0003-3089-6875 FU National Institutes of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 26 TC 18 Z9 20 U1 2 U2 8 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1297-319X EI 1778-7254 J9 JOINT BONE SPINE JI Joint Bone Spine PD DEC PY 2013 VL 80 IS 6 BP 613 EP 620 DI 10.1016/j.jbspin.2013.01.001 PG 8 WC Rheumatology SC Rheumatology GA 262XD UT WOS:000327770300011 PM 23587642 ER PT J AU McCrae, RR Chan, W Jussim, L De Fruyt, F Lockenhoff, CE De Bolle, M Costa, PT Hrebickova, M Graf, S Realo, A Allik, J Nakazato, K Shimonaka, Y Yik, M Fickova, E Brunner-Sciarra, M Reatigui, N de Figueora, NL Schmidt, V Ahn, CK Ahn, HN Aguilar-Vafaie, ME Siuta, J Szmigielska, B Cain, TR Crawford, JT Mastor, KA Rolland, JP Nansubuga, F Miramontez, DR Benet-Martinez, V Rossier, J Bratko, D Marusic, I Halberstadt, J Yamaguchi, M Knezevic, G Puric, D Martin, TA Gheorghiu, M Smith, PB Barbaranelli, C Wang, L Shakespeare-Finch, J Lima, MP Klinkosz, W Sekowski, A Alcalay, L Simonetti, F Avdeyeva, TV Pramila, VS Terracciano, A AF McCrae, Robert R. Chan, Wayne Jussim, Lee De Fruyt, Filip Loeckenhoff, Corinna E. De Bolle, Marleen Costa, Paul T., Jr. Hrebickova, Martina Graf, Sylvie Realo, Anu Allik, Jueri Nakazato, Katsuharu Shimonaka, Yoshiko Yik, Michelle Fickova, Emilia Brunner-Sciarra, Marina Reatigui, Norma Leibovich de Figueora, Nora Schmidt, Vanina Ahn, Chang-Kyu Ahn, Hyun-Nie Aguilar-Vafaie, Maria E. Siuta, Jerzy Szmigielska, Barbara Cain, Thomas R. Crawford, Jarret T. Mastor, Khairul Anwar Rolland, Jean-Pierre Nansubuga, Florence Miramontez, Daniel R. Benet-Martinez, Veronica Rossier, Jerome Bratko, Denis Marusic, Iris Halberstadt, Jamin Yamaguchi, Mami Knezevic, Goran Puric, Danka Martin, Thomas A. Gheorghiu, Mirona Smith, Peter B. Barbaranelli, Claudio Wang, Lei Shakespeare-Finch, Jane Lima, Margarida P. Klinkosz, Waldemar Sekowski, Andrzej Alcalay, Lidia Simonetti, Franco Avdeyeva, Tatyana V. Pramila, V. S. Terracciano, Antonio TI The inaccuracy of national character stereotypes SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE National character; Stereotypes; Five-Factor Model; Personality traits; Cross-cultural ID NEO-PI-R; SELF-REPORTED CONSCIENTIOUSNESS; CROSS-CULTURAL COMPARISONS; PERSONALITY-TRAITS; 5-FACTOR MODEL; BIG 5; PROFILES; COUNTRIES; PERCEPTIONS; UNIVERSAL AB Consensual stereotypes of some groups are relatively accurate, whereas others are not. Previous work suggesting that national character stereotypes are inaccurate has been criticized on several grounds. In this article we (a) provide arguments for the validity of assessed national mean trait levels as criteria for evaluating stereotype accuracy and (b) report new data on national character in 26 cultures from descriptions (N= 3323) of the typical male or female adolescent, adult, or old person in each. The average ratings were internally consistent and converged with independent stereotypes of the typical culture member, but were weakly related to objective assessments of personality. We argue that this conclusion is consistent with the broader literature on the inaccuracy of national character stereotypes. (C) 2013 Elsevier Inc. All rights reserved. C1 [Chan, Wayne; Costa, Paul T., Jr.] Natl Inst Aging, Baltimore, MD USA. [Jussim, Lee] Rutgers State Univ, Dept Psychol, New Brunswick, NJ 08903 USA. [De Fruyt, Filip; De Bolle, Marleen] Univ Ghent, Dept Dev Personal & Social Psychol, B-9000 Ghent, Belgium. [Loeckenhoff, Corinna E.] Cornell Univ, Dept Human Dev, Ithaca, NY USA. [Hrebickova, Martina; Graf, Sylvie] Acad Sci Czech Republic, Inst Psychol, Brno, Czech Republic. [Realo, Anu; Allik, Jueri] Univ Tartu, Dept Psychol, EE-50090 Tartu, Estonia. [Allik, Jueri] Estonian Acad Sci, Tallinn, Estonia. [Nakazato, Katsuharu] Iwate Prefectural Univ, Fac Social Welf, Takizawa, Iwate, Japan. [Shimonaka, Yoshiko] Bunkyo Gakuin Univ, Dept Human Studies, Bunkyo, Japan. [Yik, Michelle] Hong Kong Univ Sci & Technol, Div Social Sci, Kowloon, Hong Kong, Peoples R China. [Fickova, Emilia] Slovak Acad Sci, Inst Expt Psychol, Bratislava, Slovakia. [Brunner-Sciarra, Marina; Reatigui, Norma] Univ Peruana Cayetano Heredia, Fac Psychol, Lima, Peru. [Leibovich de Figueora, Nora; Schmidt, Vanina] Univ Buenos Aires, Dept Psychol, Buenos Aires, DF, Argentina. [Ahn, Chang-Kyu] Pusan Natl Univ, Dept Educ, Pusan, South Korea. [Ahn, Hyun-Nie] Ewha Womans Univ, Dept Psychol, Seoul, South Korea. [Aguilar-Vafaie, Maria E.] Tarbiat Modares Univ, Dept Psychol, Tehran, Iran. [Siuta, Jerzy; Szmigielska, Barbara] Jagiellonian Univ, Inst Psychol, Krakow, Poland. [Cain, Thomas R.] Hampshire Coll, Sch Cognit Sci, Amherst, MA 01002 USA. [Crawford, Jarret T.] Coll New Jersey, Dept Psychol, Ewing, NJ USA. [Mastor, Khairul Anwar] Univ Kebangsaan Malaysia, Personal Res Grp, Bangi, NJ, Malaysia. [Rolland, Jean-Pierre] Univ Paris Ouest Nanterre Def, UFR STAPS, Nanterre, France. [Nansubuga, Florence] Makerere Univ, Inst Psychol, Kampala, Uganda. [Miramontez, Daniel R.] Off Inst Res & Planning, San Diego, CA USA. [Benet-Martinez, Veronica] Univ Pompeu Fabra, ICREA, Barcelona, Spain. [Benet-Martinez, Veronica] Univ Pompeu Fabra, Dept Polit & Social Sci, Barcelona, Spain. [Rossier, Jerome] Univ Lausanne, Inst Psychol, Lausanne, Switzerland. [Bratko, Denis] Univ Zagreb, Dept Psychol, Zagreb 41000, Croatia. [Marusic, Iris] Inst Social Res Zagreb, Zagreb, Croatia. [Halberstadt, Jamin; Yamaguchi, Mami] Univ Otago, Dept Psychol, Dunedin, New Zealand. [Knezevic, Goran; Puric, Danka] Univ Belgrade, Dept Psychol, Belgrade, Serbia. [Martin, Thomas A.] Susquehanna Univ, Dept Psychol, Selinsgrove, PA USA. [Gheorghiu, Mirona] Queens Univ, Sch Psychol, Belfast, Antrim, North Ireland. [Smith, Peter B.] Univ Sussex, Sch Psychol, Falmer, England. [Barbaranelli, Claudio] Univ Roma La Sapienza, Dept Psychol, Rome, Italy. [Wang, Lei] Peking Univ, Dept Psychol, Beijing 100871, Peoples R China. [Shakespeare-Finch, Jane] Queensland Univ Technol, Sch Psychol & Counseling, Brisbane, Qld 4001, Australia. [Lima, Margarida P.] Univ Coimbra, Fac Psychol & Educ Sci, Coimbra, Portugal. [Klinkosz, Waldemar; Sekowski, Andrzej] John Paul II Cathol Univ Lublin, Dept Psychol, Lublin, Poland. [Alcalay, Lidia; Simonetti, Franco] Pontificia Univ Catolica Chile, Escuela Psicol, Santiago, Chile. [Avdeyeva, Tatyana V.] Univ St Thomas, Grad Sch Profess Psychol, Minneapolis, MN USA. [Terracciano, Antonio] Florida State Univ, Coll Med, Dept Geriatr, Tallahassee, FL 32306 USA. RP Terracciano, A (reprint author), Florida State Univ, Coll Med, 1115W Call St,Room 4425-B, Tallahassee, FL 32306 USA. EM antonio.terracciano@med.fsu.edu RI Rossier, Jerome/A-3494-2009; Benet-Martinez, Veronica/B-5398-2011; Allik, Juri/D-5609-2009; Wang, Lei/D-2501-2016; Realo, Anu/M-9524-2016; Sekowski, Andrzej/O-7807-2016; Graf, Sylvie/D-9732-2014; Hrebickova, Martina/H-4410-2014; OI Rossier, Jerome/0000-0002-9924-3672; Benet-Martinez, Veronica/0000-0002-3352-9731; Allik, Juri/0000-0002-8358-4747; Wang, Lei/0000-0002-6156-9028; Shakespeare-Finch, Jane/0000-0003-4237-1320; Chan, Wayne/0000-0001-5061-1713; Graf, Sylvie/0000-0002-7810-5457; Hrebickova, Martina/0000-0003-4356-567X; Loeckenhoff, Corinna/0000-0003-1605-1323 NR 73 TC 10 Z9 10 U1 5 U2 47 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 EI 1095-7251 J9 J RES PERS JI J. Res. Pers. PD DEC PY 2013 VL 47 IS 6 BP 831 EP 842 DI 10.1016/j.jrp.2013.08.006 PG 12 WC Psychology, Social SC Psychology GA 267LI UT WOS:000328098800017 ER PT J AU Pine, DS AF Pine, Daniel S. TI A 60-Year Climb on the Mountain of Nosology SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID CLASSIFICATION; PREVALENCE; DISORDERS C1 NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Pine, DS (reprint author), NIMH, Intramural Res Program, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM Daniel.pine@Nih.gov FU Intramural NIH HHS NR 9 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD DEC PY 2013 VL 52 IS 12 BP 1251 EP 1254 DI 10.1016/j.jaac.2013.08.023 PG 4 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 266HG UT WOS:000328014100003 PM 24290456 ER PT J AU Dougherty, LR Smith, VC Bufferd, SJ Stringaris, A Leibenluft, E Carlson, GA Klein, DN AF Dougherty, Lea R. Smith, Victoria C. Bufferd, Sara J. Stringaris, Argyris Leibenluft, Ellen Carlson, Gabrielle A. Klein, Daniel N. TI Preschool Irritability: Longitudinal Associations With Psychiatric Disorders at Age 6 and Parental Psychopathology SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE irritability; longitudinal; mood dysregulation; preschool ID DIAGNOSTIC INTERVIEW; MOOD DYSREGULATION; MENTAL-DISORDERS; YOUTH; CHILDHOOD; CHILDREN; OPPOSITIONALITY; PREVALENCE; DIMENSIONS; TELEPHONE AB Objective: There is increasing scientific and clinical attention to chronic irritability in youth. However, little is known about the predictive validity and clinical significance of chronic irritability during early childhood. This prospective, longitudinal study examined associations of chronic irritability with psychiatric disorders and parental psychopathology in a large community sample of preschoolers. Method: Four hundred sixty-two preschool-age children were assessed at 3 and 6 years of age. Child psychopathology was assessed at baseline (3 years) and follow-up (6 years) using a diagnostic interview, the Preschool Age Psychiatric Assessment, with parents. Items from the Preschool Age Psychiatric Assessment were used to create a dimensional measurement of chronic irritability. Parental psychopathology was assessed with a diagnostic interview at baseline. Results: Chronic irritability was concurrently associated with a wide range of psychiatric disorders and functional impairment at 3 and 6 years of age. Irritability at 3 years predicted depression, oppositional defiant disorder, and functional impairment at 6 years after controlling for baseline disorders. Irritability also was associated with parental depression and anxiety. Conclusions: Findings underscore the central role of irritability in early-emerging mental health problems. They are consistent with longitudinal studies in older youth indicating that chronic irritability predicts later depression and anxiety and support the importance of early detection and interventions targeting preschool irritability. C1 [Dougherty, Lea R.; Smith, Victoria C.] Univ Maryland, College Pk, MD 20742 USA. [Bufferd, Sara J.] Calif State Univ, San Marcos, TX USA. [Stringaris, Argyris] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Leibenluft, Ellen] NIMH, Bipolar Spectrum Disorders Emot & Dev Branch, Bethesda, MD USA. [Carlson, Gabrielle A.; Klein, Daniel N.] Stony Brook Sch Med, Stony Brook, NY USA. [Klein, Daniel N.] SUNY Stony Brook, Stony Brook, NY USA. RP Dougherty, LR (reprint author), Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. EM ldougher@umd.edu FU National Institute of Mental Health [R01 MH069942]; General Clinical Research Center from Stony Brook University, National Center for Research Resources [M01 RR10710] FX This research was supported by National Institute of Mental Health grant R01 MH069942 (D.K.N.) and General Clinical Research Center grant M01 RR10710 from Stony Brook University, National Center for Research Resources. NR 33 TC 22 Z9 22 U1 1 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD DEC PY 2013 VL 52 IS 12 BP 1304 EP 1313 DI 10.1016/j.jaac.2013.09.007 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 266HG UT WOS:000328014100010 PM 24290463 ER PT J AU Strazzula, L Brown, KK Brieva, JC Camp, BJ Frankel, HC Kissin, E Mahlberg, MJ Mina, MA Pomeranz, MK Brownell, I Kroshinsky, D AF Strazzula, Lauren Brown, Katherine K. Brieva, Joaquin C. Camp, Brendan J. Frankel, Hillary C. Kissin, Eugene Mahlberg, Matthew J. Mina, Mary Alice Pomeranz, Miriam K. Brownell, Isaac Kroshinsky, Daniela TI Levamisole toxicity mimicking autoimmune disease SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE antineutrophil cytoplasmic antibody; cocaine; granulomatosis with polyangiitis (Wegener); levamisole; purpura; vasculitis; vasculopathy ID INDUCED VASCULITIS; RETIFORM PURPURA; COCAINE; NEUTROPENIA; EARS AB Background: Levamisole is present as a contaminant or additive in most cocaine sold in the United States. Cases of agranulocytosis attributed to levamisole-tainted cocaine have been widely described. A vasculopathic reaction to levamisole has also been reported; however, diagnostic features such as antineutrophil cytoplasmic antibody (ANCA) and additional autoimmune marker positivity are not well recognized. As such, many patients are given a misdiagnosis, prompting aggressive and often unnecessary treatment. Objective: We hope to educate practitioners about the clinical and laboratory features of levamisole-induced vasculopathy to ensure accurate diagnosis and management. Methods: This was a case series. Results: Six patients were admitted with purpuric lesions and vasculitic changes on biopsy specimen; 5 of them were given the diagnosis of and treated for autoimmune conditions before their true diagnosis was revealed. All patients had ANCA positivity, and 4 had additional abnormalities in autoimmune markers. All patients reported recent cocaine abuse, and were ultimately given the diagnosis of levamisole-induced vasculopathy. Limitations: This observational study is limited by sample size. Conclusions: Patients presenting with purpuric lesions with ANCA positivity should be assessed for cocaine exposure. It is important to recognize that levamisole may not only induce ANCA positivity but also other autoimmune marker abnormalities. Patients can often be treated with less aggressive therapeutic strategies than what is used for primary ANCA-associated vasculitides. C1 [Strazzula, Lauren; Frankel, Hillary C.; Mina, Mary Alice; Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Brown, Katherine K.; Brieva, Joaquin C.] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. [Camp, Brendan J.] New York Presbyterian Hosp, Dept Dermatol, New York, NY USA. [Camp, Brendan J.] Weill Cornell Med Ctr, New York, NY USA. [Frankel, Hillary C.; Mina, Mary Alice; Kroshinsky, Daniela] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Kissin, Eugene] Boston Univ, Dept Rheumatol, Boston, MA 02215 USA. [Mahlberg, Matthew J.; Pomeranz, Miriam K.] NYU, Med Ctr, Ronald O Perelman Dept Dermatol, New York, NY 10003 USA. [Brownell, Isaac] NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP Kroshinsky, D (reprint author), Dermatol Associates, 50 Staniford St,2nd Floor, Boston, MA 02114 USA. EM dkroshinsky@partners.org OI Pomeranz, Miriam Keltz/0000-0002-6959-9280 NR 15 TC 7 Z9 7 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2013 VL 69 IS 6 BP 954 EP 959 DI 10.1016/j.jaad.2013.07.037 PG 6 WC Dermatology SC Dermatology GA 262LN UT WOS:000327736900029 PM 24075227 ER PT J AU Aung, PP Ballester, LY Abdullaev, Z Pack, SD Cummins, DL Mahalingam, M AF Aung, Phyu P. Ballester, Leomar Y. Abdullaev, Zied Pack, Svetlana D. Cummins, Deborah L. Mahalingam, Meera TI ER/PR positive epidermotropic primary cutaneous eccrine carcinoma as a cutaneous manifestation of MEN 2B SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Aung, Phyu P.; Mahalingam, Meera] Boston Univ, Sch Med, Dept Dermatol, Dermatopathol Sect, Boston, MA 02118 USA. [Cummins, Deborah L.] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. [Ballester, Leomar Y.; Abdullaev, Zied; Pack, Svetlana D.] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Mahalingam, M (reprint author), Boston Univ, Sch Med, Dept Dermatol, Dermatopathol Sect, 609 Albany St,J-301, Boston, MA 02118 USA. EM mmahalin@bu.edu RI Pack, Svetlana/C-2020-2014 NR 5 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2013 VL 69 IS 6 BP E310 EP E312 DI 10.1016/j.jaad.2013.08.001 PG 4 WC Dermatology SC Dermatology GA 262LN UT WOS:000327736900014 PM 24238193 ER PT J AU Helms, CC Marvel, M Zhao, W Stahle, M Vest, R Kato, GJ Lee, JS Christ, G Gladwin, MT Hantgan, RR Kim-Shapiro, DB AF Helms, C. C. Marvel, M. Zhao, W. Stahle, M. Vest, R. Kato, G. J. Lee, J. S. Christ, G. Gladwin, M. T. Hantgan, R. R. Kim-Shapiro, D. B. TI Mechanisms of hemolysis-associated platelet activation SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE hemoglobin; hemolysis; nitric oxide; platelets; red blood cells ID SICKLE-CELL-DISEASE; RED-BLOOD-CELLS; NITRIC-OXIDE BIOAVAILABILITY; PULMONARY-HYPERTENSION; FREE HEMOGLOBIN; BLEEDING-TIME; AGGREGATION; ERYTHROCYTES; RATS; HYPERCOAGULABILITY AB BackgroundIntravascular hemolysis occurs after blood transfusion, in hemolytic anemias, and in other conditions, and is associated with hypercoagulable states. Hemolysis has been shown to potently activate platelets invitro and invivo, and several mechanisms have been suggested to account for this, including: (i) direct activation by hemoglobin (Hb); (ii) increase in reactive oxygen species (ROS); (iii) scavenging of nitric oxide (NO) by released Hb; and (iv) release of intraerythrocytic ADP. ObjectiveTo elucidate the mechanism of hemolysis-mediated platelet activation. MethodsWe used flow cytometry to detect PAC-1 binding to activated platelets for invitro experiments, and a Siemens' Advia120 hematology system to assess platelet aggregation by using platelet counts from invivo experiments in a rodent model. ResultsWe found that Hb did not directly activate platelets. However, ADP bound to Hb could cause platelet activation. Furthermore, platelet activation caused by shearing of red blood cells (RBCs) was reduced in the presence of apyrase, which metabolizes ADP to AMP. The use of ROS scavengers did not affect platelet activation. We also found that cell-free Hb enhanced platelet activation by abrogating the inhibitory effect of NO on platelet activation. Invivo infusions of ADP and purified (ADP-free) Hb, as well as hemolysate, resulted in platelet aggregation, as shown by decreased platelet counts. ConclusionTwo primary mechanisms account for RBC hemolysis-associated platelet activation: ADP release, which activates platelets; and cell-free Hb release, which enhances platelet activation by lowering NO bioavailability. C1 [Helms, C. C.] Univ Richmond, Dept Phys, Richmond, VA 23173 USA. [Marvel, M.; Vest, R.; Kim-Shapiro, D. B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Zhao, W.; Christ, G.] Wake Forest Inst Regenerat Med, Winston Salem, NC USA. [Stahle, M.; Hantgan, R. R.] Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27109 USA. [Kato, G. J.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Lee, J. S.; Gladwin, M. T.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Lee, J. S.; Gladwin, M. T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Kim-Shapiro, D. B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. RP Kim-Shapiro, DB (reprint author), Wake Forest Univ, Dept Phys, Olin Phys Lab, 1834 Wake Forest Rd, Winston Salem, NC 27109 USA. EM shapiro@wfu.edu RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU NIH [HL058091, HL098032, 1 ZIA HL006014]; Harbert Family Distinguished Chair funds FX This work was supported by NIH grants HL058091 and HL098032, and Harbert Family Distinguished Chair funds. G. J. Kato was supported by the NIH Intramural Program 1 ZIA HL006014. NR 46 TC 25 Z9 26 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD DEC PY 2013 VL 11 IS 12 BP 2148 EP 2154 DI 10.1111/jth.12422 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 266DQ UT WOS:000328003900009 PM 24119131 ER PT J AU Kopp, JB AF Kopp, Jeffrey B. TI JC viruria and kidney disease in APOL1 risk genotype individuals: is this a clue to a gene x environment interaction? SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID AFRICAN-AMERICANS; MERKEL CELL; VARIANTS ASSOCIATE; HUMAN POLYOMAVIRUS; NEPHROPATHY; BK; TRANSPLANTATION; IDENTIFICATION AB APOL1 nephropathy occurs in a minority of genetically at-risk individuals, suggesting that other factors, such as other genes or environmental factors, contribute. Divers and colleagues report that among individuals with two APOL1 risk alleles, those with JC viruria are less likely to manifest kidney disease compared with those lacking JC viruria. These data might suggest that JC virus infection confers protection against glomerular injury, perhaps by altering cell function or generating immunity against a related polyomavirus. C1 NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS NR 30 TC 6 Z9 6 U1 0 U2 0 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 DEC PY 2013 VL 84 IS 6 BP 1069 EP 1072 DI 10.1038/ki.2013.299 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 264ND UT WOS:000327884000003 PM 24280748 ER PT J AU Thapa, M Bommakanti, A Shamsuzzaman, M Gregory, B Samsel, L Zengel, JM Lindahl, L AF Thapa, Mamata Bommakanti, Ananth Shamsuzzaman, Md Gregory, Brian Samsel, Leigh Zengel, Janice M. Lindahl, Lasse TI Repressed synthesis of ribosomal proteins generates protein-specific cell cycle and morphological phenotypes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; SACCHAROMYCES-CEREVISIAE; ASSEMBLY FACTORS; YEAST RRP14P; BIOGENESIS; RNA; SIZE; 40S; MATURATION; ACTIVATION AB The biogenesis of ribosomes is coordinated with cell growth and proliferation. Distortion of the coordinated synthesis of ribosomal components affects not only ribosome formation, but also cell fate. However, the connection between ribosome biogenesis and cell fate is not well understood. To establish a model system for inquiries into these processes, we systematically analyzed cell cycle progression, cell morphology, and bud site selection after repression of 54 individual ribosomal protein (r-protein) genes in Saccharomyces cerevisiae. We found that repression of nine 60S r-protein genes results in arrest in the G2/M phase, whereas repression of nine other 60S and 22 40S r-protein genes causes arrest in the G1 phase. Furthermore, bud morphology changes after repression of some r-protein genes. For example, very elongated buds form after repression of seven 60S r-protein genes. These genes overlap with, but are not identical to, those causing the G2/M cell cycle phenotype. Finally, repression of most r-protein genes results in changed sites of bud formation. Strikingly, the r-proteins whose repression generates similar effects on cell cycle progression cluster in the ribosome physical structure, suggesting that different topological areas of the precursor and/or mature ribosome are mechanistically connected to separate aspects of the cell cycle. C1 [Thapa, Mamata; Bommakanti, Ananth; Shamsuzzaman, Md; Gregory, Brian; Zengel, Janice M.; Lindahl, Lasse] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21250 USA. [Samsel, Leigh] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Lindahl, L (reprint author), Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21250 USA. EM lindahl@umbc.edu FU National Science Foundation [MCB0349443, 0920578, DBI-0722569]; National Institute of General Medical Sciences [P41-GM103311] FX We thank Susan Fretz for help with strain construction and Philipp Milkereit and John Woolford for strains. We also thank John Woolford for helpful discussions. We gratefully acknowledge our departmental colleagues (Suzanne Rosenberg, Stephen Miller, Michelle Starz-Gaiano, Rachel Brewster, and Chere Petty) for use of and help with flow cytometer and microscopes. We thank the National Heart, Lung and Blood Institute at the National Institutes of Health for use of the Flow Cytometry Core Facility. This work was supported by National Science Foundation Grants MCB0349443 and 0920578 to J.M.Z. and L. L. and National Science Foundation Major Research Instrumentation Grant DBI-0722569 to D. B. and T. G. Finally, we acknowledge the use of the UCSF Chimera Package supported by National Institute of General Medical Sciences Grant P41-GM103311. NR 63 TC 7 Z9 7 U1 1 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC 1 PY 2013 VL 24 IS 23 BP 3620 EP 3633 DI 10.1091/mbc.E13-02-0097 PG 14 WC Cell Biology SC Cell Biology GA 267UZ UT WOS:000328125100004 PM 24109599 ER PT J AU Jain, N Miu, B Jiang, JK McKinstry, KK Prince, A Swain, SL Greiner, DL Thomas, CJ Sanderson, MJ Berg, LJ Kang, J AF Jain, Nitya Miu, Bing Jiang, Jian-kang McKinstry, Kai K. Prince, Amanda Swain, Susan L. Greiner, Dale L. Thomas, Craig J. Sanderson, Michael J. Berg, Leslie J. Kang, Joonsoo TI CD28 and ITK signals regulate autoreactive T cell trafficking SO NATURE MEDICINE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; COSTIMULATORY MOLECULES; B7/CD28 COSTIMULATION; ACTIN CYTOSKELETON; DEFICIENT MICE; ACTIVATION; CTLA-4; ANTIGEN; FAMILY; MOUSE AB Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) develop fatal autoimmunity characterized by lymphocytic infiltration into nonlymphoid tissues. Here, we demonstrate that the CD28 co-stimulatory pathway regulates the trafficking of self-reactive Ctla4(-/-) T cells to tissues. Concurrent ablation of the CD28-activated Tec family kinase Ilk does not block spontaneous T cell activation but instead causes self-reactive Ctla4(-/-) T cells to accumulate in secondary lymphoid organs. Despite excessive spontaneous T cell activation and proliferation in lymphoid organs, Itk(-/-); Ctla4(-/-) mice are otherwise healthy, mount antiviral immune responses and exhibit a long lifespan. We propose that ITK specifically licenses autoreactive T cells to enter tissues to mount destructive immune responses. Notably, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type 1 diabetes, highlighting their potential utility for the treatment of human autoimmune disorders. C1 [Jain, Nitya; Miu, Bing; McKinstry, Kai K.; Prince, Amanda; Swain, Susan L.; Berg, Leslie J.; Kang, Joonsoo] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. [Jiang, Jian-kang; Thomas, Craig J.] NIH, Chem Genom Ctr, Rockville, MD USA. [Greiner, Dale L.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Sanderson, Michael J.] Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, Worcester, MA 01605 USA. RP Kang, J (reprint author), Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. EM joonsoo.kang@umassmed.edu FU US National Institutes of Health (NIH) [AI46629, AI050864, AI046530, AI083505, RC1 DK086474]; Molecular Libraries Initiative; Intramural Research Program of the NIH National Human Genome Research Institute FX We thank E. Huseby, B. Seed and R. Friedline for discussion, S. Turley for advice with stromal cells, T. Hunig (University of Wurzburg) for the SACD28 antibody, M. Coles for assistance with microscopy, M. Krummel for advice on imaging, D. Serreze for studies with diabetogenic CD8+ T cells, E. Huseby (University of Massachusetts Medical School) for MHC class II-deficient Rag1-/- mice and R. Welsh for the LCMV infection protocol. Core resources supported by the University of Massachusetts Medical School Diabetes Endocrinology Research Center grant DK32520 were used. This work was supported by US National Institutes of Health (NIH) grants to D.L.G. (AI46629, AI050864), S.L.S. (AI046530), L.J.B. (AI083505) and J.K. (RC1 DK086474 and AI083505). US NIH Chemical Genomics Center was supported by the Molecular Libraries Initiative and the Intramural Research Program of the NIH National Human Genome Research Institute. NR 58 TC 19 Z9 19 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2013 VL 19 IS 12 BP 1632 EP 1637 DI 10.1038/nm.3393 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 268OW UT WOS:000328181400032 PM 24270545 ER PT J AU Park, SH Veerapu, NS Shin, EC Biancotto, A McCoy, JP Capone, S Folgori, A Rehermann, B AF Park, Su-Hyung Veerapu, Naga Suresh Shin, Eui-Cheol Biancotto, Angelique McCoy, J. Philip Capone, Stefania Folgori, Antonella Rehermann, Barbara TI Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection SO NATURE MEDICINE LA English DT Article ID INJECTION-DRUG USERS; IMMUNE-RESPONSES; REGULATORY CELLS; IN-VIVO; RECOVERED CHIMPANZEES; MEMORY; HCV; PERSISTENCE; SEROCONVERSION; RECHALLENGE AB Hepatitis C virus (HCV) is endemic in many countries due to its high propensity for establishing persistence(1). The presence of HCV-specific T cells in subjects repeatedly exposed to HCV who test negative for HCV RNA and antibodies and who do not have any history of HCV infection has been interpreted as T cell-mediated protection(2-5). Here, we show in nonhuman primates that repeated exposure to human plasma with trace amounts of HCV induced HCV-specific T cells without seroconversion and systemic viremia but did not protect upon subsequent HCV challenge. Rather, HCV-specific recall and de novo T cell responses, as well as intrahepatic T cell recruitment and interferon-gamma (IFN-gamma) production, were suppressed upon HCV challenge, concomitant with quantitative and qualitative changes in regulatory T cells (T-reg cells) that occurred after subinfectious HCV exposure and increased after HCV challenge. In vitro T-reg cell depletion restored HCV-specific T cell responses. Thus, T cells primed by trace amounts of HCV do not generate effective recall responses upon subsequent HCV infection. Subinfectious HCV exposure predisposes to T-reg cell expansion, which suppresses effector T cells during subsequent infection. Strategies to reverse this exposure-induced immune suppression should be examined to aid in the development of T cell-based vaccines against HCV and other endemic pathogens. C1 [Park, Su-Hyung; Veerapu, Naga Suresh; Shin, Eui-Cheol; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Biancotto, Angelique; McCoy, J. Philip] NHLBI, Flow Cytometry Core Facil, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Capone, Stefania; Folgori, Antonella] Okairos, Rome, Italy. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM rehermann@nih.gov RI Park, Su-Hyung/N-3514-2014; Shin, Eui-Cheol/C-1690-2011; OI Capone, Stefania/0000-0002-2272-120X FU intramural research program of the NIDDK FX We thank T.J. Rowell, J. Fontenot and the staff at New Iberia Research Center for the care of the chimpanzees and technical support and L. Holz (NIDDK) and W. Kastenmuller (NIAID) for discussion and reading of the manuscript. This work was supported by the intramural research program of the NIDDK. NR 40 TC 22 Z9 26 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2013 VL 19 IS 12 BP 1638 EP 1642 DI 10.1038/nm.3408 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 268OW UT WOS:000328181400033 PM 24270546 ER PT J AU Madan, RA Gulley, JL AF Madan, Ravi A. Gulley, James L. TI PROSTATE CANCER Intermediate efficacy end points to assess modern therapies SO NATURE REVIEWS UROLOGY LA English DT Editorial Material ID METASTASIS-FREE SURVIVAL; PHASE-3; DISEASE; TRIALS; MEN AB A retrospective, single institution study of 450 men with biochemical recurrence after radical prostatectomy included 140 men with androgen deprivation therapy deferred until metastatic disease onset. Metastasis-free survival was an independent predictor of overall survival. This research highlights the need to develop appropriate intermediate end points to expedite prostate cancer treatment. C1 [Madan, Ravi A.; Gulley, James L.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 10 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 1759-4812 EI 1759-4820 J9 NAT REV UROL JI Nat. Rev. Urol. PD DEC PY 2013 VL 10 IS 12 BP 686 EP 687 DI 10.1038/nrurol.2013.269 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 267VT UT WOS:000328127100003 PM 24276080 ER PT J AU Lapkouski, M Tian, L Miller, JT Le Grice, SFJ Yang, W AF Lapkouski, Mikalai Tian, Lan Miller, Jennifer T. Le Grice, Stuart F. J. Yang, Wei TI Structural requirements for RNA degradation by HIV-1 reverse transcriptase reply SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Letter ID RNA/DNA HYBRID; COMPLEX; DNA C1 [Lapkouski, Mikalai; Tian, Lan; Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Miller, Jennifer T.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Lapkouski, M (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov FU Intramural NIH HHS [Z01 DK036144-02] NR 6 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD DEC PY 2013 VL 20 IS 12 BP 1342 EP 1343 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 266FA UT WOS:000328007600002 PM 24304911 ER PT J AU Bartesaghi, A Merk, A Borgnia, MJ Milne, JLS Subramaniam, S AF Bartesaghi, Alberto Merk, Alan Borgnia, Mario J. Milne, Jacqueline L. S. Subramaniam, Sriram TI Prefusion structure of trimeric HIV-1 envelope glycoprotein determined by cryo-electron microscopy SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID VIRAL MEMBRANE-FUSION; INFLUENZA-VIRUS; MOLECULAR ARCHITECTURE; POTENT NEUTRALIZATION; HUMAN-ANTIBODY; GP120 CORE; CRYO-EM; HEMAGGLUTININ; TOMOGRAPHY; RESOLUTION AB The activation of trimeric HIV-1 envelope glycoprotein (Env) by its binding to the cell-surface receptor CD4 and co-receptors (CCR5 or CXCR4) represents the first of a series of events that lead to fusion between viral and target-cell membranes. Here, we present the cryo-EM structure, at subnanometer resolution (similar to 6 angstrom at 0.143 FSC), of the 'closed', prefusion state of trimeric HIV-1 Env complexed to the broadly neutralizing antibody VRC03. We show that three gp41 helices at the core of the trimer serve as an anchor around which the rest of Env is reorganized upon activation to the 'open' quaternary conformation. The architecture of trimeric HIV-1 Env in the prefusion state and in the activated intermediate state resembles the corresponding states of influenza hemagglutinin trimers, thus providing direct evidence for the similarity in entry mechanisms used by HIV-1, influenza and related enveloped viruses. C1 [Bartesaghi, Alberto; Merk, Alan; Borgnia, Mario J.; Milne, Jacqueline L. S.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Center for Cancer Research at the National Cancer Institute, US National Institutes of Health (NIH); NIH Intramural AIDS Targeted Antiviral Program FX This work was supported by funds to S.S. and J.L.S.M. from the Center for Cancer Research at the National Cancer Institute, US National Institutes of Health (NIH), and to S.S. from the NIH Intramural AIDS Targeted Antiviral Program. We thank J. Mascola (Vaccine Research Center, NIH) for providing VRC03 antibodies; K. Kang and W. Olson (Progenies) for providing soluble KNH1144 gp140 trimers; S. Fellini, S. Chacko and their colleagues for continued support with use of the Biowulf cluster for computing at NIH; D. Schauder and H. He for assistance with data collection; P. Rao and the NIH-FEI Living Lab for Structural Biology for assistance with collection of the tilt-pair images; and L. Earl for helpful discussions and comments. NR 39 TC 82 Z9 82 U1 6 U2 34 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD DEC PY 2013 VL 20 IS 12 BP 1352 EP 1357 DI 10.1038/nsmb.2711 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 266FA UT WOS:000328007600006 PM 24154805 ER PT J AU Low, LA AF Low, Lucie A. TI The impact of pain upon cognition: What have rodent studies told us? SO PAIN LA English DT Review ID DECISION-MAKING TASK; INFLAMMATORY PAIN; PREFRONTAL CORTEX; NEUROPATHIC PAIN; CHRONIC MORPHINE; RISK-ASSESSMENT; RAT MODEL; BEHAVIOR; DEFICITS; MEMORY C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Low, LA (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 35 Convent Dr,Room 1C-1012, Bethesda, MD 20892 USA. EM lucie.low@nih.gov OI Low, Lucie/0000-0001-6082-8625 FU Intramural Research Program of the NIH FX This research was supported (in part) by the Intramural Research Program of the NIH. Thanks are due to M. Catherine Bushnell, Mark Pitcher, David Seminowicz, Wiebke Gandhi, and Susanne Becker for critical reading and helpful suggestions. NR 36 TC 6 Z9 6 U1 5 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD DEC PY 2013 VL 154 IS 12 BP 2603 EP 2605 DI 10.1016/j.pain.2013.06.012 PG 3 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 260LK UT WOS:000327596200007 PM 23774574 ER PT J AU Person, RJ Tokar, EJ Xu, YY Orihuela, R Ngalame, NNO Waalkes, MP AF Person, Rachel J. Tokar, Erik J. Xu, Yuanyuan Orihuela, Ruben Ngalame, Ntube N. Olive Waalkes, Michael P. TI Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Cadmium; Human lung cells; Transformation; Adaptation; Lung cancer; Epithelial-to-mesenchymal transition ID INDUCED MALIGNANT-TRANSFORMATION; EPITHELIAL-MESENCHYMAL TRANSITION; INDUCED OXIDATIVE STRESS; ZINC TRANSPORTERS; EXPRESSION; METALLOTHIONEIN; PROGNOSIS; TESTIS; FAMILY; GENE AB Cadmium is a known human lung carcinogen. Here, we attempt to develop an in vitro model of cadmium-induced human lung carcinogenesis by chronically exposing the peripheral lung epithelia cell line, HPL-1D, to a low level of cadmium. Cells were chronically exposed to 5 mu M cadmium, a noncytotoxic level, and monitored for acquired cancer characteristics. By 20 weeks of continuous cadmium exposure, these chronic cadmium treated lung (CCT-LC) cells showed marked increases in secreted MMP-2 activity (3.5-fold), invasion (3.4-fold), and colony formation in soft agar (2-fold). CCT-LC cells were hyperproliferative, grew well in serum-free media, and overexpressed cyclin D1. The CCT-LC cells also showed decreased expression of the tumor suppressor genes p16 and SLC38A3 at the protein levels. Also consistent with an acquired cancer cell phenotype, CCT-LC cells showed increased expression of the oncoproteins K-RAS and N-RAS as well as the epithelial-to-mesenchymal transition marker protein Vimentin. Metallothionein (MT) expression is increased by cadmium, and is typically overexpressed in human lung cancers. The major MT isoforms, MT-1A and MT-2A were elevated in CCT-LC cells. Oxidant adaptive response genes HO-1 and HIF-1A were also activated in CCT-LC cells. Expression of the metal transport genes ZNT-1, ZNT-5, and ZIP-8 increased in CCT-LC cells culminating in reduced cadmium accumulation, suggesting adaptation to the metal. Overall, these data suggest that exposure of human lung epithelial cells to cadmium causes acquisition of cancer cell characteristics. Furthermore, transformation occurs despite the cell's ability to adapt to chronic cadmium exposure. Published by Elsevier Inc. C1 [Person, Rachel J.; Tokar, Erik J.; Xu, Yuanyuan; Orihuela, Ruben; Ngalame, Ntube N. Olive; Waalkes, Michael P.] NIEHS, Div Natl Toxicol Program, Natl Toxicol Program Lab, Inorgan Toxicol Grp, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), Div Natl Toxicol Program Lab, 111 TW Alexander Dr,MD E1-07, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov OI ORIHUELA, RUBEN/0000-0001-6718-6194 FU Intramural NIH HHS [ZIA ES102925-03, ZIA ES102925-02] NR 60 TC 22 Z9 25 U1 4 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 1 PY 2013 VL 273 IS 2 BP 281 EP 288 DI 10.1016/j.taap.2013.06.013 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 267LP UT WOS:000328099500005 PM 23811327 ER PT J AU Emond, C Sanders, JM Wikoff, D Birnbaum, LS AF Emond, Claude Sanders, J. Michael Wikoff, Daniele Birnbaum, Linda S. TI Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE PBPK; PBDE; BDE-47; m-MUP; P-gp; Mouse ID POLYBROMINATED DIPHENYL ETHERS; P-GLYCOPROTEIN; HOUSE MOUSE; METHYLSULFONYL METABOLITE; POLYCHLORINATED BIPHENYL; MOLECULAR HETEROGENEITY; TISSUE DISTRIBUTION; GENETIC-VARIATION; RISK-ASSESSMENT; PROTEINS AB Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. (C) 2013 Elsevier Inc. All rights reserved. C1 [Emond, Claude] BioSimulat Consulting Inc, Newark, DE USA. [Emond, Claude] Univ Montreal, Fac Med, Dept Environm, Montreal, PQ H3T 1A8, Canada. [Emond, Claude] Univ Montreal, Fac Med, Dept Occupat Hlth, Montreal, PQ H3T 1A8, Canada. [Sanders, J. Michael; Birnbaum, Linda S.] NCI, Res Triangle Pk, NC USA. [Wikoff, Daniele] ToxStrategies, Austin, TX USA. RP Emond, C (reprint author), Univ Montreal, Fac Med, Dept Environm & Occupat Hlth, 2375 Chemin Cote Ste Catherine,Bur 7085, Montreal, PQ H3T 1A8, Canada. EM claude.emond@umontreal.ca; sander10@mail.nih.gov; dwikoff@toxstrategies.com; bimbaumls@niehs.nih.gov FU Intramural Research Program of the NIH/National Cancer Institute [ZIA BC 011476] FX This work was supported by the Intramural Research Program of the NIH/National Cancer Institute [Project # ZIA BC 011476]. Any mention of trade names or commercial products in this manuscript does not constitute endorsement or recommendation for use. NR 49 TC 5 Z9 5 U1 2 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 1 PY 2013 VL 273 IS 2 BP 335 EP 344 DI 10.1016/j.taap.2013.09.007 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 267LP UT WOS:000328099500010 PM 24055880 ER PT J AU Titov, LP Siniuk, KV Wollenberg, KK Unemo, M Hedberg, ST Glazkova, SE Lebedzeu, FA Nosava, AS Yanovich, VO Xirasagar, S Hurt, D Huyen, Y AF Titov, Leonid P. Siniuk, Kanstantsin V. Wollenberg, Kurt K. Unemo, Magnus Hedberg, Sara Thulin Glazkova, Slavyana E. Lebedzeu, Fiodar A. Nosava, Alena S. Yanovich, Volcha O. Xirasagar, Sadhia Hurt, Darrell Huyen, Yentram TI EVOLUTIONARY EPIDEMIOLOGY OF NEISSERIA MENINGITIDIS STRAINS IN BELARUS COMPARED TO OTHER EUROPEAN COUNTRIES SO ACTA MICROBIOLOGICA ET IMMUNOLOGICA HUNGARICA LA English DT Article DE Neisseria meningitidis; multilocus sequence typing (MLST); sequence type (ST); clonal complex (CC); evolution; Belarus ID RECOMBINATION; POPULATION; IDENTIFICATION; CARRIAGE; VACCINE; CLONES AB Introduction. Meningococcal infections are major causes of death in children globally. In Belarus, the incidence of cases and fatality rate of meningococcal infections are low and comparable to the levels in other European countries. Aim. In the present study, the molecular and epidemiological traits of Neisseria meningitidis strains circulating in Belarus were characterized and compared to isolates from other European countries. Materials and Methods. Twenty N. meningitidis strains isolated from patients (n = 13) and healthy contacts (n = 7) during 2006-2012 in Belarus were selected for multilocus sequence typing (MLST), genosubtyping and FetA typing. The STs of the Belarusian strains were phylogenetically compared to the STs of 110 selected strains from 22 other European countries. Results. Overall, eleven different genosubtypes were observed, there were seven variants of variable region of the fetA gene detected. The majority of the STs (95%) found in Belarus were novel and all those were submitted to the Neisseria MLST database for assignment. Several newly discovered alleles of fumC (allele 451) and gdh (allele 560 and 621) appeared to be descendants of alleles which are widespread in Europe, and single aroE alleles (602 and 603) occurred as a result of separate evolution. Conclusions. N. meningitidis strains circulating in Belarus are heterogeneous and include sequence types, possibly, locally evolved in Belarus as well as representatives of widespread European hyperinvasive clonal complexes. C1 [Titov, Leonid P.; Siniuk, Kanstantsin V.; Glazkova, Slavyana E.; Lebedzeu, Fiodar A.; Nosava, Alena S.; Yanovich, Volcha O.] Republ Res & Pract Ctr Epidemiol & Microbiol, Minsk, Byelarus. [Wollenberg, Kurt K.; Xirasagar, Sadhia; Hurt, Darrell; Huyen, Yentram] NIAID, NIH, Bethesda, MD 20892 USA. [Unemo, Magnus; Hedberg, Sara Thulin] Orebro Univ Hosp, Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Orebro, Sweden. RP Titov, LP (reprint author), Republ Res & Pract Ctr Epidemiol & Microbiol, 23 Filimonova St, Minsk, Byelarus. EM leonidtitov@tut.by NR 22 TC 0 Z9 0 U1 1 U2 4 PU AKADEMIAI KIADO RT PI BUDAPEST PA PRIELLE K U 19, PO BOX 245,, H-1117 BUDAPEST, HUNGARY SN 1217-8950 EI 1588-2640 J9 ACTA MICROBIOL IMM H JI Acta Microbiol. Immunol. Hung. PD DEC PY 2013 VL 60 IS 4 BP 397 EP 410 DI 10.1556/AMicr.60.2013.4.2 PG 14 WC Immunology; Microbiology SC Immunology; Microbiology GA 261WV UT WOS:000327696200002 PM 24292084 ER PT J AU Litten, RZ Castle, IJP Falk, D Ryan, M Fertig, J Chen, CM Yi, HY AF Litten, Raye Z. Castle, I-Jen P. Falk, Daniel Ryan, Megan Fertig, Joanne Chen, Chiung M. Yi, Hsiao-ye TI The Placebo Effect in Clinical Trials for Alcohol Dependence: An Exploratory Analysis of 51 Naltrexone and Acamprosate Studies SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Dependence; Placebo Effect; Naltrexone; Acamprosate; Meta-Analysis ID RANDOMIZED CONTROLLED-TRIAL; MAJOR DEPRESSIVE DISORDER; COGNITIVE-BEHAVIORAL THERAPY; COPING SKILLS THERAPY; DOUBLE-BLIND; RELAPSE PREVENTION; META-REGRESSION; PSYCHIATRIC-DISORDERS; OUTPATIENT ALCOHOLICS; WEANED ALCOHOLICS AB BackgroundThe placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. MethodsFifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients (r(p)) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman's rank correlation coefficients (r(s)) were used to examine the strength of associations between study characteristics and placebo response. ResultsFor the end point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (r(p)=-0.55, p<0.01 and r(p)=-0.20, p=0.35, respectively) as well as in the acamprosate trials (r(p)=-0.45, p=0.09 and r(p)=-0.56, p=0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (r(s)=-0.42, p=0.05) across naltrexone trials and positively correlated with publication year (r(s)=0.57, p=0.03) across acamprosate trials. However, these 2 study characteristics were not significantly correlated with treatment effect size. ConclusionsThe placebo response varied considerably across trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects. C1 [Litten, Raye Z.; Falk, Daniel; Ryan, Megan; Fertig, Joanne] NIAAA, Div Treatment & Recovery Res, Bethesda, MD 20892 USA. [Castle, I-Jen P.; Chen, Chiung M.; Yi, Hsiao-ye] CSR Inc, Arlington, VA USA. RP Litten, RZ (reprint author), NIAAA, Div Treatment & Recovery Res, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM rlitten@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); Medications Development Program Analytic Contract; NIAAA [HHSN275201100002G]; National Institutes of Health, Department of Health and Human Services, Bethesda, MD FX This research was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health, Department of Health and Human Services, Bethesda, MD and by the Medications Development Program Analytic Contract funded by NIAAA Contract No. HHSN275201100002G to CSR, Incorporated, Arlington, VA. The authors thank Barbara Vann (CSR, Incorporated) for her excellent editorial comments, Robin A. LaVallee (CSR, Incorporated) for data entry, and Drs. Patrick K. Randall and Raymond F. Anton (Medical University of South Carolina, Charleston, SC), Drs. William D. Dundon and Helen M. Pettinati (University of Pennsylvania School of Medicine, Philadelphia, PA), and Dr. Wolfgang Wolwer (Heinrich Heine University, Dusseldorf, Germany) for providing their unpublished results. NR 98 TC 10 Z9 10 U1 7 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD DEC PY 2013 VL 37 IS 12 BP 2128 EP 2137 DI 10.1111/acer.12197 PG 10 WC Substance Abuse SC Substance Abuse GA 261VI UT WOS:000327692300016 PM 23889231 ER PT J AU Xiao, Q Arem, H Moore, SC Hollenbeck, AR Matthews, CE AF Xiao, Qian Arem, Hannah Moore, Steven C. Hollenbeck, Albert R. Matthews, Charles E. TI A Large Prospective Investigation of Sleep Duration, Weight Change, and Obesity in the NIH-AARP Diet and Health Study Cohort SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; obesity; sleep ID BODY-MASS INDEX; BROWN ADIPOSE-TISSUE; GHRELIN LEVELS; QUEBEC FAMILY; LEPTIN LEVELS; ASSOCIATION; GAIN; ADULTS; MELATONIN; POPULATION AB The relationship between sleep and obesity or weight gain in adults, particularly older populations, remains unclear. In a cohort of 83,377 US men and women aged 5172 years, we prospectively investigated the association between self-reported sleep duration and weight change over an average of 7.5 years of follow-up (19952004). Participants were free of cancer, heart disease, and stroke at baseline and throughout the follow-up. We observed an inverse association between sleep duration per night and weight gain in both men (P for trend 0.02) and women (P for trend 0.001). Compared with 78 hours of sleep, shorter sleep (5 hours or 56 hours) was associated with more weight gain (in kilograms; men: for 5 hours, 0.66, 95 confidence interval (CI): 0.19, 1.13, and for 56 hours, 0.12, 95 CI: 0.02, 0.26; women: for 5 hours, 0.43, 95 CI: 0.00, 0.86, and for 56 hours, 0.23, 95 CI: 0.08, 0.37). Among men and women who were not obese at baseline, participants who reported less than 5 hours of sleep per night had an approximately 40 higher risk of developing obesity than did those who reported 78 hours of sleep (for men, odds ratio 1.45, 95 CI: 1.06, 1.99; for women, odds ratio 1.37, 95 CI: 1.04, 1.79). The association between short sleep and excess weight gain was generally consistent across different categories of age, educational level, smoking status, baseline body mass index, and physical activity level. C1 [Xiao, Qian; Arem, Hannah; Moore, Steven C.; Matthews, Charles E.] NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Xiao, Q (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM qian.xiao@nih.gov RI matthews, Charles/E-8073-2015; Moore, Steven/D-8760-2016 OI matthews, Charles/0000-0001-8037-3103; Moore, Steven/0000-0002-8169-1661 FU National Institutes of Health, National Cancer Institute, Department of Health and Human Services FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Department of Health and Human Services. NR 43 TC 32 Z9 34 U1 0 U2 18 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 DEC 1 PY 2013 VL 178 IS 11 BP 1600 EP 1610 DI 10.1093/aje/kwt180 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 262ER UT WOS:000327717600002 PM 24049160 ER PT J AU Conde-Agudelo, A Romero, R AF Conde-Agudelo, Agustin Romero, Roberto TI Transdermal nitroglycerin for the treatment of preterm labor: a systematic review and metaanalysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE beta(2)-adrenergic receptor agonist; magnesium sulfate; neonatal morbidity; nifedipine; nitric-oxide donor; preterm birth; tocolytic agent ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CLINICAL-TRIAL; NITRIC-OXIDE DONORS; DOUBLE-BLIND; GLYCERYL TRINITRATE; MAGNESIUM-SULFATE; NEURODEVELOPMENTAL OUTCOMES; PARTURITION SYNDROME; ANTAGONIST ATOSIBAN; COMPOSITE OUTCOMES AB OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of transdermal nitroglycerin as a tocolytic agent in women with preterm labor. STUDY DESIGN: We conducted a systematic review and metaanalysis of randomized controlled trials. RESULTS: Thirteen studies were included (1302 women) comparing transdermal nitroglycerin vs placebo (2 studies; n = 186); beta(2)-adrenergic receptor agonists (9 studies; n = 1024); nifedipine (1 study; n = 50); and magnesium sulfate (1 study; n = 42). There were no significant differences between transdermal nitroglycerin and placebo for delivery within 48 hours of the initiation of treatment or at < 28, < 34, or < 37 weeks of gestation, adverse neonatal outcomes, and neurodevelopmental status at 24 months of life. Nevertheless, 1 study found a marginally significant reduction in the risk of a composite outcome of major neonatal morbidity and perinatal death (3/74 [4.1%] vs 11/79 [13.9%]; relative risk, 0.29; 95% confidence interval, 0.08-1.00). When compared with beta(2)-adrenergic receptor agonists, transdermal nitroglycerin was associated with a significant reduction in the risk of preterm birth at < 34 and < 37 weeks of gestation, admission to the neonatal intensive care unit, use of mechanical ventilation, and maternal side effects. There were no significant differences between transdermal nitroglycerin and nifedipine and magnesium sulfate in delivery within 48 hours of treatment and pregnancy prolongation, respectively. Overall, women who received transdermal nitroglycerin had a higher risk of headache. CONCLUSION: Although transdermal nitroglycerin appears to be more effective than b2-adrenergic receptor agonists, the current evidence does not support its routine use as a tocolytic agent for the treatment of preterm labor. Further double-blind placebo-controlled trials are needed. C1 [Conde-Agudelo, Agustin; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Bethesda, MD USA. [Conde-Agudelo, Agustin; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Natl Inst Human Serv, Bethesda, MD USA. [Conde-Agudelo, Agustin; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. [Conde-Agudelo, Agustin; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Natl Inst Human Serv, Detroit, MI USA. Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Conde-Agudelo, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Bethesda, MD USA. FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX Supported by the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 83 TC 0 Z9 1 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2013 VL 209 IS 6 AR 551.e1 DI 10.1016/j.ajog.2013.07.022 PG 18 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 259PN UT WOS:000327538900013 PM 23891631 ER PT J AU Huynh, N Blain, D Glaser, T Doss, EL Zein, WM Lang, DM Baker, EH Hill, S Brewer, CC Kopp, JB Bardakjian, TM Maumenee, IH Bateman, BJ Brooks, BP AF Huynh, Nancy Blain, Delphine Glaser, Tanya Doss, E. Lauren Zein, Wadih M. Lang, David M. Baker, Eva H. Hill, Suvimol Brewer, Carmen C. Kopp, Jeffrey B. Bardakjian, Tanya M. Maumenee, Irene H. Bateman, Bronwyn J. Brooks, Brian P. TI Systemic Diagnostic Testing in Patients With Apparently Isolated Uveal Coloboma SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CONGENITAL EYE MALFORMATIONS; UNILATERAL RENAL AGENESIS; CHARGE ASSOCIATION; CONSECUTIVE BIRTHS; CLINICAL-FEATURES; UNITED-KINGDOM; VISUAL-ACUITY; ANOMALIES; CHILDREN; MICROPHTHALMOS AB PURPOSE: To investigate the frequency and types of systemic findings in patients with apparently isolated uveal coloboma. DESIGN: Cross-sectional observational study. METHODS: SETTING: Single-center ophthalmic genetics clinic. STUDY POPULATION: Ninety-nine patients with uveal coloboma seen at the National Eye Institute. OBSERVATIONAL PROCEDURE: Results of audiology testing, echocardiogram, brain magnetic resonance imaging, renal ultrasound, and total spine radiographs. MAIN OUTCOME MEASURE: Prevalence of abnormal findings on systemic testing. RESULTS: Uveal coloboma affected only the anterior segment in 8 patients, only the posterior segment in 23 patients, and both anterior and posterior segments in 68 patients. Best-corrected visual acuity (BCVA) of eyes with coloboma was >= 20/40 in 45% of eyes; 23% of eyes had BCVA of <= 20/400. The majority of patients (74%) had good vision (>20/60) in at least 1 eye. Ten of the 19 patients (53%) who underwent echocardiography had abnormalities, with ventral septal defects being the most prevalent. Abnormal findings were observed in 5 of 72 patients (7%) who had a renal ultrasound and in 5 of 29 patients (17%) who underwent a brain MRI. Audiology testing revealed abnormalities in 13 of 75 patients (17%), and spine radiographs showed anomalies in 10 of 77 patients (13%). Most findings required no acute intervention. CONCLUSIONS: Although some patients with coloboma had evidence of extraocular abnormalities, the majority of findings on routine clinical examination did not require acute intervention, but some warranted follow-up. Results from the systemic evaluation of patients with coloboma should be interpreted with caution and in view of their clinical context. (Published by Elsevier Inc.) C1 [Huynh, Nancy; Blain, Delphine; Glaser, Tanya; Doss, E. Lauren; Zein, Wadih M.; Brooks, Brian P.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Lang, David M.] NEI, Pediat Consult Serv, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Baker, Eva H.; Hill, Suvimol] NEI, Dept Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Brewer, Carmen C.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, Bethesda, MD USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Bethesda, MD 20892 USA. [Bardakjian, Tanya M.] Einstein Med Ctr Philadelphia, Div Genet, Philadelphia, PA USA. [Maumenee, Irene H.] Univ Illinois, Coll Med, Dept Ophthalmol, Chicago, IL USA. [Bateman, Bronwyn J.] Univ Colorado, Childrens Hosp, Sch Med, Rocky Mt Lions Eye Inst, Aurora, CO USA. RP Brooks, BP (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10N226,MSC 1860, Bethesda, MD 20892 USA. EM brooksb@nei.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National Eye Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Deafness and Other Communication Disorders; Clinical Center of the National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, USA FX ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. This work was supported by the intramural research programs of the National Eye Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Deafness and Other Communication Disorders, and the Clinical Center of the National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, USA. Contributions of authors: design of study (N.H., D.B., D.L.L., E.H.B., S.H., C.C.B., J.B.K., B.P.B.); acquisition of data (B.P.B., N.H., D.B., TO,, E.L.D., W.Z., D.L.L., E.H.B:, S.H., C.C.B., J.B.K., T.M.B., I.H.M., B.J.B., B.P.B.); interpretation of data (N.H., D.B., T.G., B.P.B.); preparation of manuscript (N.H., B.P.B.); review and approval of manuscript (N.H., W.Z., D.L.L., E.H.B., S.H., C.C.B., J.B.K., T.M.B., I.H.M., B.J.B., B.P.B.). NR 22 TC 3 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2013 VL 156 IS 6 BP 1159 EP 1168 DI 10.1016/j.ajo.2013.06.037 PG 10 WC Ophthalmology SC Ophthalmology GA 261OQ UT WOS:000327674900013 PM 24012100 ER PT J AU Kohn, EC Romano, S Lee, JM AF Kohn, E. C. Romano, S. Lee, J. -M. TI Clinical implications of using molecular diagnostics for ovarian cancers SO ANNALS OF ONCOLOGY LA English DT Article DE morphological; biomarker; high-grade serous ovarian cancer; molecular; therapeutics ID GRADE SEROUS CARCINOMA; BREAST-CANCER; 2-TIER SYSTEM; PERITONEAL CARCINOMA; INHERITED OVARIAN; CELL CARCINOMA; BRAF MUTATION; OPEN-LABEL; EXPRESSION; HER2 AB In the era of morphologic diagnostics, any epithelial tumor on or involving the ovaries was presumed to come from and be strictly of ovarian origin, apart from the rare but clearly metastatic tumors. Thus, many women who might have had small fallopian tube primary cancers that rapidly extended on to or into the ovary were deemed to have ovarian cancer. Now, as we begin to better understand that there are different types of cancers of nonuterine Muellerian origin, we expand upon the morphologic to add the molecular characteristics. Morphomolecular characteristics are being applied to drive clinical advances including development and optimization of predictive and prognostic biomarkers, redefinition of historical controls, and consideration of novel clinical trial designs. Ovarian cancer, not a common cancer to start with, is now subdivided into types, making ever smaller clinical cohorts. The first studies evaluating tubo-ovarian Muellerian cancers of morphomolecular types have begun. Deleterious mutations in BRCA1 or 2 have been validated as the first new predictive and prognostic biomarker of the high-grade serous ovarian cancer type and polyADPribose polymerase inhibitors, the first targeted agents for this morphomolecular entity. Similar progress is developing in other tubo-ovarian cancer types. This new knowledge is driving the building of a structure-function-type relationship that is generating novel clinically applicable hypotheses for testing. C1 [Kohn, E. C.; Romano, S.; Lee, J. -M.] NCI, Mol Signaling Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Romano, S.] Walter Reed Natl Mil Med Ctr, Gynecol Oncol Ctr Excellence, John P Murtha Canc Ctr, Bethesda, MD USA. RP Kohn, EC (reprint author), 9609 Med Ctr Dr 5W426 MSC9737, Rockville, MD 20850 USA. EM kohne@mail.nih.gov FU Intramural Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA FX This work was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. NR 49 TC 6 Z9 6 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2013 VL 24 SU 10 BP 22 EP 26 DI 10.1093/annonc/mdt464 PG 5 WC Oncology SC Oncology GA 259EZ UT WOS:000327511500003 ER PT J AU Sassi, A Lazaroski, S Wu, G Haslam, SM Mellouli, F Patiroglu, T Jouhadi, Z Khadir, K Pfeifer, D Jakob, T Khemiri, M Ben-Mustapha, I Asplund, C Gustafsson, M Lundin, K Falk-Sorqvist, E Moens, L Unal, E Ozdemir, MA Gungor, HE Engelhardt, K Dziadzio, M Stauss, H Fleckenstein, B Fliegauf, M Meier, R Ben-Khemis, L Kraus, H Nadifi, S Eibel, H Nilsson, M Bejaoui, M Schaffer, A Smith, E Dell, A Barbouche, MR Grimbacher, B AF Sassi, Atfa Lazaroski, Sandra Wu, Gang Haslam, Stuart M. Mellouli, Fethi Patiroglu, Turkan Jouhadi, Zineb Khadir, Khadija Pfeifer, Dietmar Jakob, Thilo Khemiri, Monia Ben-Mustapha, Imen Asplund, Charlotta Gustafsson, Manuela Lundin, Karin Falk-Sorqvist, Elin Moens, Lotte Unal, Ekrem Ozdemir, Mehmet Akif Gungor, Hatice Eke Engelhardt, Karin Dziadzio, Magdalena Stauss, Hans Fleckenstein, Bernhard Fliegauf, Manfred Meier, Rebecca Ben-Khemis, Leila Kraus, Helene Nadifi, Sellama Eibel, Hermann Nilsson, Mats Bejaoui, Mohamed Schaeffer, Alejandro Smith, Edvard Dell, Anne Barbouche, Mohamed-Ridha Grimbacher, Bodo TI Hypomorphic, Homozygous Mutations In Phosphoglucomutase-3 Impair Immunity And Increase Serum IgE Levels SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Meeting Abstract CT UK-Primary-Immunodeficiency-Network (UK PIN) Meeting CY DEC 06-07, 2013 CL Liverpool, ENGLAND SP UK Primary Immunodeficiency Network C1 [Sassi, Atfa; Ben-Mustapha, Imen; Ben-Khemis, Leila; Barbouche, Mohamed-Ridha] Pasteur Inst Tunis, Lab Immunopathol Vaccinol & Mol Genet, Tunis, Tunisia. [Sassi, Atfa; Ben-Mustapha, Imen; Ben-Khemis, Leila; Barbouche, Mohamed-Ridha] Univ Tunis, Tunis, Tunisia. [Lazaroski, Sandra; Fliegauf, Manfred; Meier, Rebecca; Kraus, Helene; Eibel, Hermann; Grimbacher, Bodo] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Wu, Gang; Dell, Anne] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England. [Haslam, Stuart M.; Bejaoui, Mohamed] Bone Marrow Transplantat Ctr, Dept Pediat, Tunis, Tunisia. [Mellouli, Fethi; Unal, Ekrem; Ozdemir, Mehmet Akif] Erciyes Univ, Fac Med, Div Pediat Hematol & Oncol, Dept Pediat, Kayseri, Turkey. [Patiroglu, Turkan; Gungor, Hatice Eke] Erciyes Univ, Fac Med, Div Pediat Immunol, Dept Pediat, Kayseri, Turkey. [Jouhadi, Zineb; Khadir, Khadija] Hassan II Univ, Dept Pediat Infect Dis, Casablanca, Morocco. [Pfeifer, Dietmar] Univ Med Ctr Freiburg, Dept Hematol & Oncol, Freiburg, Germany. [Jakob, Thilo] Univ Med Ctr Freiburg, Dept Dermatol, Allergy Res Grp, Freiburg, Germany. [Khemiri, Monia] Childrens Hosp Tunis, Pediat Dept A, Tunis, Tunisia. [Asplund, Charlotta; Gustafsson, Manuela; Lundin, Karin; Smith, Edvard] Karolinska Inst, Dept Lab Med, Clin Res Ctr, S-10401 Stockholm, Sweden. [Falk-Sorqvist, Elin; Moens, Lotte; Nilsson, Mats] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Engelhardt, Karin; Dziadzio, Magdalena; Stauss, Hans] UCL, Dept Immunol, Royal Free Hosp, London WC1E 6BT, England. [Fleckenstein, Bernhard] Univ Erlangen Nurnberg, Inst Virol, D-91054 Erlangen, Germany. [Nadifi, Sellama] Hassan II Univ, Dept Genet, Casablanca, Morocco. [Schaeffer, Alejandro] NCBI, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD DEC PY 2013 VL 174 SU 1 SI SI BP 2 EP 2 PG 1 WC Immunology SC Immunology GA 256IO UT WOS:000327303400004 ER PT J AU Dhalla, F Murray, S Miller, J Sadler, R Soilleux, E Bhole, M Uzel, G Ferry, B Patel, YS Chapel, H AF Dhalla, Fatima Murray, Sarah Miller, Joanne Sadler, Ross Soilleux, Elizabeth Bhole, Malini Uzel, Gulbu Ferry, Berne Patel, Smita Y. Chapel, Helen TI X-MEN: The new mutants SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Meeting Abstract CT UK-Primary-Immunodeficiency-Network (UK PIN) Meeting CY DEC 06-07, 2013 CL Liverpool, ENGLAND SP UK Primary Immunodeficiency Network C1 [Dhalla, Fatima] John Radcliffe Hosp, Dept Immunol, Oxford Univ Hosp, Oxford OX3 9DU, England. [Miller, Joanne; Patel, Smita Y.; Chapel, Helen] Oxford Univ Hosp, Dept Immunol, Oxford, England. [Soilleux, Elizabeth] Oxford Univ Hosp, Dept Pathol, Oxford, England. [Uzel, Gulbu] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD DEC PY 2013 VL 174 SU 1 SI SI BP 6 EP 7 PG 2 WC Immunology SC Immunology GA 256IO UT WOS:000327303400012 ER PT J AU Mechanic, L Mendez, A Merrill, L Rogers, J Layton, M Todd, D Varanasi, A O'Brien, B Meyer, WA Zhang, M Schleicher, RL Moye, J AF Mechanic, Leah Mendez, Armando Merrill, Lori Rogers, John Layton, Marnie Todd, Deborah Varanasi, Arti O'Brien, Barbara Meyer, William A., III Zhang, Ming Schleicher, Rosemary L. Moye, Jack, Jr. TI Planned variation in preanalytical conditions to evaluate biospecimen stability in the National Children's Study (NCS) SO CLINICAL CHEMISTRY AND LABORATORY MEDICINE LA English DT Article DE adrenocorticotropic hormone (ACTH); biospecimen stability; carbohydrate-deficient transferrin (CDT); estradiol; free T-4; IGF-1; IL-6; insulin; preanalytical variation; vitamin C ID INSULIN-RESISTANCE; SAMPLE COLLECTION; ASCORBIC-ACID; WHOLE-BLOOD; PLASMA; SERUM; STORAGE; GLUCOSE; ANTICOAGULANTS; INTERLEUKIN-6 AB Background: Preanalytical conditions encountered during collection, processing, and storage of biospecimens may influence laboratory results. The National Children's Study (NCS) is a planned prospective cohort study of 100,000 families to examine the influence of a wide variety of exposures on child health. In developing biospecimen collection, processing, and storage procedures for the NCS, we identified several analytes of different biochemical categories for which it was unclear to what extent deviations from NCS procedures could influence measurement results. Methods: A pilot study was performed to examine effects of preanalytic sample handling conditions (delays in centrifugation, freezing delays, delays in separation from cells, additive delay, and tube type) on concentrations of eight different analytes. A total of 2825 measurements were made to assess 15 unique combinations of analyte and handling conditions in blood collected from 151 women of childbearing age (>= 20 individuals per handling condition). Results: The majority of analytes were stable under the conditions evaluated. However, levels of plasma -interleukin-6 and serum insulin were decreased in response to sample centrifugation delays of up to 5.5 h post-collection (p<0.0001). In addition, delays in freezing centrifuged plasma samples (comparing 24, 48 and 72 h to immediate freezing) resulted in increased levels of adrenocorticotropic hormone (p=0.0014). Conclusions: Determining stability of proposed analytes in response to preanalytical conditions and handling helps to ensure high-quality specimens for study now and in the future. The results inform development of procedures, plans for measurement of analytes, and interpretation of laboratory results. C1 [Moye, Jack, Jr.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, NIH, Bethesda, MD 20892 USA. [Mechanic, Leah] NCI, Host Susceptibil Factors Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci,NIH, Bethesda, MD 20892 USA. [Mendez, Armando] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Merrill, Lori; Rogers, John; Layton, Marnie; Todd, Deborah; O'Brien, Barbara] Westat Corp, Rockville, MD USA. [Varanasi, Arti] Adv Synergy LLC, Baltimore, MD USA. [Meyer, William A., III] Quest Diagnost, Baltimore, MD USA. [Zhang, Ming; Schleicher, Rosemary L.] Ctr Dis Control & Prevent CDC, Nutr Biomarkers Branch, Atlanta, GA USA. RP Moye, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, NIH, 6100 Execut Blvd,Room 5C01D,MSC 7510, Bethesda, MD 20892 USA. EM moyej@mail.nih.gov OI moye, john/0000-0001-9976-8586 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of the Director of the National Institutes of Health; NICHD [HHSN275200503395C, HHSN275201000107U, HHSN275200900010C, HHSN275201000121U] FX Research funding: This analysis was conducted as part of the National Children's Study, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and funded, through its appropriation, by the Office of the Director of the National Institutes of Health. Supported by NICHD Contracts HHSN275200503395C, HHSN275201000107U, HHSN275200900010C, and HHSN275201000121U. The manuscript was developed by a Writing Team identified by the National Children's Study Publications Committee for the purpose of timely sharing of NCS data. NR 35 TC 4 Z9 4 U1 1 U2 9 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1434-6621 EI 1437-4331 J9 CLIN CHEM LAB MED JI Clin. Chem. Lab. Med. PD DEC PY 2013 VL 51 IS 12 BP 2287 EP 2294 DI 10.1515/cclm-2013-0454 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 262MH UT WOS:000327739000024 PM 23924524 ER PT J AU Berngard, SC Berngard, JB Krebs, NF Garces, A Miller, LV Westcott, J Wright, LL Kindem, M Hambidge, KM AF Berngard, Samuel Clark Berngard, Jennifer Bishop Krebs, Nancy F. Garces, Ana Miller, Leland V. Westcott, Jamie Wright, Linda L. Kindem, Mark Hambidge, K. Michael TI Newborn length predicts early infant linear growth retardation and disproportionately high weight gain in a low-income population SO EARLY HUMAN DEVELOPMENT LA English DT Article DE Infant growth; Linear growth; Birth weight; Predictors of infant growth ID CHILD UNDERNUTRITION; BIRTH-WEIGHT; FETAL-GROWTH; GUATEMALAN INFANTS; MATERNAL STATURE; RURAL MALAWI; RISK-FACTORS; SUPPLEMENTATION; INTERVENTIONS; 1ST-TRIMESTER AB Background: Stunting is prevalent by the age of 6 months in the indigenous population of the Western Highlands of Guatemala. Aim: The objective of this study was to determine the time course and predictors of linear growth failure and weight-for-age in early infancy. Study design and subjects: One hundred and forty eight term newborns had measurements of length and weight in their homes, repeated at 3 and 6 months. Maternal measurements were also obtained. Results: Mean +/- SD length-for-age Z-score (LAZ) declined from newborn -1.0 +/- 1.01 to -2.20 +/- 1.05 and -2.26 +/- 1.01 at 3 and 6 months respectively. Stunting rates for newborn, 3 and 6 months were 47%, 53% and 56% respectively. A multiple regression model (R-2 = 0.64) demonstrated that the major predictor of LAZ at 3 months was newborn [AZ with the other predictors being newborn weight-for-age Z-score (WAZ), gender and maternal education * maternal age interaction. Because WAZ remained essentially constant and LAZ declined during the same period, weight-for-length Z-score (WLZ) increased from -0.44 to +1.28 from birth to 3 months. The more severe the linear growth failure, the greater WAZ was in proportion to the LAZ. Conclusion: The primary conclusion is that impaired fetal linear growth is the major predictor of early infant linear growth failure indicating that prevention needs to start with maternal interventions. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Berngard, Samuel Clark; Berngard, Jennifer Bishop; Krebs, Nancy F.; Miller, Leland V.; Westcott, Jamie; Hambidge, K. Michael] Univ Colorado Denver, Aurora, CO 80045 USA. [Garces, Ana] IMSALUD, Guatemala City, Guatemala. [Wright, Linda L.] NICHHD, NIH, Rockville, MD 20852 USA. [Kindem, Mark] RTI Int, Res Triangle Pk, NC 27709 USA. RP Hambidge, KM (reprint author), Univ Colorado Denver, 12700 East 19th Ave,Box C225, Aurora, CO 80045 USA. EM Michael.Hambidge@ucdenver.edu OI Berngard, Samuel Clark/0000-0002-4335-105X FU NIH Eunice Kennedy Shriver NICHD, NIH, Global Network for Women's and Children's Health Research [U01 HD 40657]; Rotary Scholarship; Adler Scholarship; Robinson-Durst Scholarship FX Supported by NIH Eunice Kennedy Shriver NICHD, NIH, Global Network for Women's and Children's Health Research U01 HD 40657; and Rotary, Adler, and Robinson-Durst Scholarships. NR 52 TC 13 Z9 13 U1 1 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-3782 EI 1872-6232 J9 EARLY HUM DEV JI Early Hum. Dev. PD DEC PY 2013 VL 89 IS 12 BP 967 EP 972 DI 10.1016/j.earlhumdev.2013.09.008 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 262RO UT WOS:000327755500009 PM 24083893 ER PT J AU Lowe, JR Duncan, AF Bann, CM Fuller, J Hintz, SR Das, A Higgins, RD Watterberg, KL AF Lowe, Jean R. Duncan, Andrea Freeman Bann, Carla M. Fuller, Jane Hintz, Susan R. Das, Abhik Higgins, Rosemary D. Watterberg, Kristi L. CA Eunice Kennedy Shriver Natl Inst TI Early working memory as a racially and ethnically neutral measure of outcome in extremely preterm children at 18-22 months SO EARLY HUMAN DEVELOPMENT LA English DT Article DE Working memory; Prematurity; Development ID LOW-BIRTH-WEIGHT; PRESCHOOL-CHILDREN; EXECUTIVE FUNCTION; BRAIN-INJURY; SCHOOL-AGE; INFANTS; BORN; DEFICITS AB Background: Difficulties with executive function have been found in preterm children, resulting in difficulties with learning and school performance. Aim: This study evaluated the relationship of early working memory as measured by object permanence items to the cognitive and language scores on the Bayley Scales-III in a cohort of children born extremely preterm. Study design: Logistic regression models were conducted to compare object permanence scores derived from the Bayley Scales-III by race/ethnicity and maternal education, controlling for medical covariates. Subjects: Extremely preterm toddlers (526), who were part of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's multi-center study, were evaluated at 18-22 months corrected age. Outcome measures: Object permanence scores derived from the Bayley Developmental Scales were compared by race/ethnicity and maternal education, controlling for medical covariates. Results: There were no significant differences in object permanence mastery and scores among the treatment groups after controlling for medical and social variables, including maternal education and race/ethnicity. Males and children with intraventricular hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia were less likely to demonstrate object permanence mastery and had lower object permanence scores. Children who attained object permanence mastery had significantly higher Bayley Scales-III cognitive and language scores after controlling for medical and socio-economic factors. Conclusions: Our measure of object permanence is free of influence from race, ethnic and socio-economic factors. Adding this simple task to current clinical practice could help detect early executive function difficulties in young children. Published by Elsevier Ireland Ltd. C1 [Lowe, Jean R.; Duncan, Andrea Freeman; Fuller, Jane; Watterberg, Kristi L.] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Bann, Carla M.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Hintz, Susan R.] Stanford Univ, Palo Alto, CA 94304 USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Lowe, JR (reprint author), 1 Univ New Mexico, Dept Pediat MSC10 5590, Albuquerque, NM 87131 USA. EM jrlowe@unm.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network Follow-up studies. NR 29 TC 3 Z9 3 U1 3 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-3782 EI 1872-6232 J9 EARLY HUM DEV JI Early Hum. Dev. PD DEC PY 2013 VL 89 IS 12 BP 1055 EP 1061 DI 10.1016/j.earlhumdev.2013.08.009 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 262RO UT WOS:000327755500024 PM 23993309 ER PT J AU Rubin, C Myers, T Stokes, W Dunham, B Harris, S Lautner, B Annelli, J AF Rubin, Carol Myers, Tanya Stokes, William Dunham, Bernadette Harris, Stic Lautner, Beth Annelli, Joseph TI Review of Institute of Medicine and National Research Council Recommendations for One Health Initiative SO EMERGING INFECTIOUS DISEASES LA English DT Article AB Human health is inextricably linked to the health of animals and the viability of ecosystems; this is a concept commonly known as One Health. Over the last 2 decades, the Institute of Medicine (IOM) and the National Research Council (NRC) have published consensus reports and workshop summaries addressing a variety of threats to animal, human, and ecosystem health. We reviewed a selection of these publications and identified recommendations from NRC and IOM/NRC consensus reports and from opinions expressed in workshop summaries that are relevant to implementation of the One Health paradigm shift. We grouped these recommendations and opinions into thematic categories to determine if sufficient attention has been given to various aspects of One Health. We conclude that although One Health themes have been included throughout numerous IOM and NRC publications, identified gaps remain that may warrant targeted studies related to the One Health approach. C1 [Rubin, Carol; Myers, Tanya] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. [Stokes, William] NIEHS, Res Triangle Pk, NC 27709 USA. [Dunham, Bernadette] US FDA, Rockville, MD 20857 USA. [Harris, Stic] Dept Homeland Secur, Washington, DC USA. [Lautner, Beth] USDA, Des Moines, IA USA. [Annelli, Joseph] USDA, Riverdale, MD USA. RP Rubin, C (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd NE,Mailstop A30, Atlanta, GA 30333 USA. EM crubin@cdc.gov NR 29 TC 6 Z9 6 U1 1 U2 10 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 DEC PY 2013 VL 19 IS 12 BP 1913 EP 1917 DI 10.3201/eid1912.121659 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 263RV UT WOS:000327826600001 PM 24274461 ER PT J AU Patayova, H Wimmerova, S Lancz, K Palkovicova, L Drobna, B Fabisikova, A Kovac, J Hertz-Picciotto, I Jusko, TA Trnovec, T AF Patayova, Henrieta Wimmerova, Sona Lancz, Kinga Palkovicova, L'ubica Drobna, Beata Fabisikova, Anna Kovac, Jan Hertz-Picciotto, Irva Jusko, Todd A. Trnovec, Tomas TI Anthropometric, socioeconomic, and maternal health determinants of placental transfer of organochlorine compounds SO ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH LA English DT Article; Proceedings Paper CT Contaminated land, ecological assessment, and remediation conference series (CLEAR) CY NOV 04-08, 2012 CL Hangzhou, PEOPLES R CHINA DE Placental transfer; Alcohol; PCB; Organochlorine pesticides ID PERSISTENT ORGANIC POLLUTANTS; POLYCHLORINATED-BIPHENYLS; PREGNANT-WOMEN; ADIPOSE-TISSUE; PRENATAL EXPOSURES; SOUTHERN SPAIN; BLOOD-LEVELS; HUMAN SERUM; CORD BLOOD; PCBS AB The aim of this study was to relate placental transfer, quantified by the cord to maternal serum concentration ratio (C/M), of five organochlorine pesticides (OCP) hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), gamma-hexachlorocyclohexane (gamma-HCH) , p,p'-DDT, p,p'-DDE and 15 polychlorinated biphenyl (PCB) congeners (28, 52, 101, 105, 114, 118, 123(+149), 138(+163), 153, 156(+171), 157, 167, 170, 180, and 189) to anthropometric, socioeconomic, and maternal health characteristics. We included into the study 1,134 births during the period 2002-2004 from two districts in eastern Slovakia with high organochlorine concentrations relative to other areas of the world. Only concentrations > LOD were taken into account. Variables as age, weight and height of mothers, parity, ethnicity, alcohol consumption, illness during pregnancy, smoking during pregnancy, hypertension, respiratory diseases, rheumatoid arthritis and diabetes mellitus, and birth weight were related to C/M. Results of regression analyses showed that C/M was predicted by several factors studied. Positive associations were observed for gestational alcohol consumption, fewer illnesses during pregnancy, maternal age, and maternal weight. Caucasians had a greater C/M compared to Romani for wet weight data of congeners 170 and 180 and in contrast C/M for HCB was greater in Romani. Our results show that drinking mothers compared to abstaining expose their fetuses not only to alcohol but to an increased level of several PCB congeners. A straightforward explanation of associations between C/M shifts and factors studied is very difficult, however, with regard to the high lipophilicity of OCPs and PCBs, changes in their kinetics probably reflect lipid kinetics. C1 [Patayova, Henrieta; Lancz, Kinga; Palkovicova, L'ubica; Trnovec, Tomas] Slovak Med Univ, Dept Environm Med, Bratislava 83303, Slovakia. [Drobna, Beata; Fabisikova, Anna] Slovak Med Univ, Dept Tox Organ Pollutants, Bratislava 83303, Slovakia. [Wimmerova, Sona] Slovak Med Univ, Inst Biophys Informat & Biostat, Bratislava 83303, Slovakia. [Kovac, Jan] Comenius Univ, Fac Med Bratislava, Dept Stomatol & Maxillofacial Surg, Bratislava 81372, Slovakia. [Hertz-Picciotto, Irva] Univ Calif Davis, Sch Med, Div Epidemiol, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Jusko, Todd A.] NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Trnovec, T (reprint author), Slovak Med Univ, Dept Environm Med, Limbova 12, Bratislava 83303, Slovakia. EM tomas.trnovec@szu.sk RI Tuomisto, Jouko/J-7450-2012 FU US National Institutes of Health, National Cancer Institute [R01-CA96525]; European Commission [227391] FX This project has been funded by the US National Institutes of Health, National Cancer Institute, grant R01-CA96525 and by the European Commission through the 7FP project OBELIX (No. 227391). NR 50 TC 9 Z9 9 U1 2 U2 21 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0944-1344 EI 1614-7499 J9 ENVIRON SCI POLLUT R JI Environ. Sci. Pollut. Res. PD DEC PY 2013 VL 20 IS 12 BP 8557 EP 8566 DI 10.1007/s11356-013-1786-7 PG 10 WC Environmental Sciences SC Environmental Sciences & Ecology GA 259AA UT WOS:000327498600026 PM 23677752 ER PT J AU Brooks-Kayal, AR Bath, KG Berg, AT Galanopoulou, AS Holmes, GL Jensen, FE Kanner, AM O'Brien, TJ Whittemore, VH Winawer, MR Patel, M Scharfman, HE AF Brooks-Kayal, Amy R. Bath, Kevin G. Berg, Anne T. Galanopoulou, Aristea S. Holmes, Gregory L. Jensen, Frances E. Kanner, Andres M. O'Brien, Terence J. Whittemore, Vicky H. Winawer, Melodie R. Patel, Manisha Scharfman, Helen E. TI Behavioral and neuroendocrine assays for studying epilepsy-associated depression Response SO EPILEPSIA LA English DT Letter C1 [Brooks-Kayal, Amy R.] Univ Colorado, Childrens Hosp Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Brooks-Kayal, Amy R.] Univ Colorado, Childrens Hosp Colorado, Sch Med, Dept Neurol, Aurora, CO USA. [Brooks-Kayal, Amy R.] Univ Colorado, Childrens Hosp Colorado, Sch Med, Dept Pharmaceut Sci, Aurora, CO USA. [Brooks-Kayal, Amy R.] Univ Colorado, Childrens Hosp Colorado, Sch Pharm, Dept Pediat, Aurora, CO USA. [Brooks-Kayal, Amy R.] Univ Colorado, Childrens Hosp Colorado, Sch Pharm, Dept Neurol, Aurora, CO USA. [Brooks-Kayal, Amy R.] Univ Colorado, Childrens Hosp Colorado, Sch Pharm, Dept Pharmaceut Sci, Aurora, CO USA. [Bath, Kevin G.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Berg, Anne T.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Galanopoulou, Aristea S.] Albert Einstein Coll Med, Lab Dev Epilepsy, Dominick P Purpura Dept Neurosci, Saul R Korey Dept Neurol, Bronx, NY 10467 USA. [Holmes, Gregory L.] Univ Vermont, Dept Neurol Sci, Burlington, VT USA. [Jensen, Frances E.] Univ Penn, Dept Neurol, Perlman Sch Med, Philadelphia, PA 19104 USA. [Kanner, Andres M.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [O'Brien, Terence J.] Univ Melbourne, Dept Med, Royal Melbourne Hosp, Melbourne Brain Ctr, Parkville, Vic 3052, Australia. [Whittemore, Vicky H.] NINDS, NIH, Bethesda, MD 20892 USA. [Winawer, Melodie R.] Columbia Univ, Dept Neurol, GH Sergievsky Ctr, New York, NY USA. [Patel, Manisha] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Aurora, CO USA. [Scharfman, Helen E.] NYU, Dept Psychiat, Nathan Kline Inst Psychiat Res, Langone Med Ctr, New York, NY 10016 USA. [Scharfman, Helen E.] NYU, Dept Physiol, Nathan Kline Inst Psychiat Res, Langone Med Ctr, New York, NY USA. [Scharfman, Helen E.] NYU, Dept Neurosci, Nathan Kline Inst Psychiat Res, Langone Med Ctr, New York, NY USA. RP Brooks-Kayal, AR (reprint author), Univ Colorado, Childrens Hosp Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. EM amy.brooks-kayal@childrens-colorado.org RI O'Brien, Terence/L-8102-2013 NR 1 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD DEC PY 2013 VL 54 IS 12 BP 2229 EP 2230 DI 10.1111/epi.12414 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 262PR UT WOS:000327750600027 PM 24304440 ER PT J AU Yamaguchi, T Wang, HL Morales, M AF Yamaguchi, Tsuyoshi Wang, Hui-Ling Morales, Marisela TI Glutamate neurons in the substantia nigra compacta and retrorubral field SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE A8; A9; dopamine; midbrain glutamatergic neurons; VGluT2; VTA ID VENTRAL TEGMENTAL AREA; DOPAMINERGIC-NEURONS; RAT-BRAIN; INTERFASCICULAR NUCLEUS; TERMINALS; ACCUMBENS; STRIATUM; MIDBRAIN; TSAI AB Dopaminergic neurons of the substantia nigra compacta (SNC), ventral tegmental area (VTA) and retrorubral field (RRF) play a role in reward, motivation, learning, memory, and movement. These neurons are intermingled with GABAergic neurons. Recent evidence shows that the VTA contains glutamatergic neurons expressing vesicular glutamate transporter type 2 (VGluT2); some of them co-express tyrosine hydroxylase (TH). Here, we used a combination of radioactive in situ hybridisation and immunohistochemistry to explore whether any of the vesicular glutamate transporters [vesicular glutamate transporter type 1 (VGluT1), VGluT2, or vesicular glutamate transporter type 3 (VGluT3)] were encoded by neurons in the SNC or RRF. We found expression of VGluT2 mRNA, but not of VGluT1 or VGluT3, in the SNC and RRF. These VGluT2 neurons rarely showed TH immunoreactivity. Within the SNC, the VGluT2 neurons were infrequently found at the rostral level, but were often seen at the medial and caudal levels intercalated in the mediolateral portion of the dorsal tier, at a ratio of one VGluT2 neuron per 4.4 TH neurons. At this level, VGluT2 neurons were also found in the adjacent substantia nigra reticulata and substantia nigra pars lateralis. Within the RRF, the VGluT2 neurons showed an increasing rostrocaudal gradient of distribution. The RRF proportion of VGluT2 neurons in relation to TH neurons was constant throughout the rostrocaudal levels, showing an average ratio of one VGluT2 neuron per 1.7 TH neurons. In summary, we provide evidence indicating that the SNC and RRF, which are traditionally considered to be dopaminergic areas, have neurons with the ability to participate in glutamate signaling. C1 [Yamaguchi, Tsuyoshi; Wang, Hui-Ling; Morales, Marisela] NIDA, Intramural Res Program, Neuronal Networks Sect, Baltimore, MD 21224 USA. RP Morales, M (reprint author), NIDA, Intramural Res Program, Neuronal Networks Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov OI YAMAGUCHI, TSUYOSHI/0000-0002-0058-9244 FU Intramural Research Program of the National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 26 TC 23 Z9 23 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X EI 1460-9568 J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 2013 VL 38 IS 11 BP 3602 EP 3610 DI 10.1111/ejn.12359 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 259IC UT WOS:000327519600008 PM 24102658 ER PT J AU Preuss, N van der Veen, JW Carlson, PJ Shen, J Hasler, G AF Preuss, Nora van der Veen, Jan Willem Carlson, Paul J. Shen, Jun Hasler, Gregor TI Low single dose gabapentin does not affect prefrontal and occipital gamma-aminobutyric acid concentrations SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Gamma-aminobutyric acid; Gabapentin; Magnetic resonance spectroscopy; Epilepsy; Anxiety; Mood disorders ID MAGNETIC-RESONANCE SPECTROSCOPY; PANIC DISORDER; BRAIN GABA; ANXIETY DISORDERS; MAJOR DEPRESSION; GLUTAMATE; EPILEPSY; RELEASE; MOOD; DRUG AB The gamma-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0 mg, 150 mg and 300 mg GBP. Subjects were scanned on a 3T scanner using a transmit-receive head coil that provided a relatively homogenous radiofrequency field to obtain spectroscopy measurement in the medial prefrontal (MPFC) and occipital cortex (OCC). There was no dose-dependent effect of GBP on GABA levels in the OCC or MPFC. There was also no effect on Glx, choline or N-acetyl-aspartate concentrations. The previously reported finding of increased GABA levels after GBP treatment is not evident for healthy subjects at the dose of 150 and 300 mg. As a result, if subjects are scanned on a 3T scanner, low dose GPB is not useful as an experimental challenge agent on the GABA system. (C) 2013 Elsevier B.V. and ECNP. All rights reserved. C1 [Preuss, Nora] Univ Bern, Dept Psychol, CH-3000 Bern, Switzerland. [van der Veen, Jan Willem; Shen, Jun] NIMH, Magnet Resonance Spect Core, NIH, Bethesda, MD 20892 USA. [Carlson, Paul J.] Univ Utah, Sch Med, Salt Lake City Vet Affairs Med Ctr, Salt Lake City, UT USA. [Carlson, Paul J.] Univ Utah, Sch Med, Dept Psychiat, Salt Lake City, UT 84112 USA. [Shen, Jun] NIMH, Sect Magnet Resonance Spect, NIH, Bethesda, MD 20892 USA. [Hasler, Gregor] Univ Bern, Psychiat Univ Hosp, CH-3000 Bern 60, Switzerland. RP Hasler, G (reprint author), Univ Bern, Psychiat Univ Hosp, Bolligenstr 111, CH-3000 Bern 60, Switzerland. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 NR 48 TC 1 Z9 1 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD DEC PY 2013 VL 23 IS 12 BP 1708 EP 1713 DI 10.1016/j.euroneuro.2013.08.006 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 265AK UT WOS:000327921900005 PM 24071367 ER PT J AU Xiao, M Prabakaran, P Chen, WZ Kessing, B Dimitrov, DS AF Xiao, Madelyne Prabakaran, Ponraj Chen, Weizao Kessing, Bailey Dimitrov, Dimiter S. TI Deep sequencing and Circos analyses of antibody libraries reveal antigen-driven selection of Ig V-H genes during HIV-1 infection SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE 454 sequencing; Antibodyome; Antibody repertoire; HIV-1; Human monoclonal antibody; VDJ analysis ID NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSE; REPERTOIRE; EVOLUTION; NAIVE AB The vast diversity of antibody repertoires is largely attributed to heavy chain (V-H) recombination of variable (V), diversity (D) and joining (J) gene segments. We used 454 sequencing information of the variable domains of the antibody heavy chain repertoires from neonates, normal adults and an HIV-1-infected individual, to analyze, with Circos software, the VDJ pairing patterns at birth, adulthood and a time-dependent response to HIV-1 infection. Our comparative analyses of the Ig VDJ repertoires from these libraries indicated that, from birth to adulthood, VDJ recombination patterns remain the same with some slight changes, whereas some VH families are selected and preferentially expressed after long-term infection with HIV-1. We also demonstrated that the immune system responds to HIV-1 chronic infection by selectively expanding certain HV families in an attempt to combat infection. Our findings may have implications for understanding immune responses in pathology as well as for development of new therapeutics and vaccines. Published by Elsevier Inc. C1 [Xiao, Madelyne] Urbana High Sch, Ijamsville, MD 21754 USA. [Prabakaran, Ponraj; Chen, Weizao; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Prabakaran, Ponraj] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Xiao, Madelyne; Kessing, Bailey] Leidos Biomed Res Inc, BSP CCR Genet Core, Frederick Natl Lab, Frederick, MD 21702 USA. [Xiao, Madelyne] NCI, Werner H Kirsten Student Intern Program, NIH, Frederick, MD 21702 USA. RP Prabakaran, P (reprint author), NCI Frederick, 1050 Boyles St,Bldg 469,Rm 140, Frederick, MD 21702 USA. EM prabakaran.ponraj@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH, National Cancer Institute [NO1-CO-12400, HHSN261200800001E] FX We thank Drs. B. Haynes, H. Liao, C. Broder, and T. Fouts for reagents. We thank the Laboratory of Molecular Technology and Advanced Biomedical Computing Center of SAIC-Frederick Inc. for sequencing service. We thank Ms. Maria G. Singarayan for constructing the PostgreSQL database and developing JAVA applications. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Federal Funds from the NIH, National Cancer Institute, under Contract No. NO1-CO-12400 and HHSN261200800001E. 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. NR 24 TC 7 Z9 8 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 EI 1096-0945 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD DEC PY 2013 VL 95 IS 3 BP 357 EP 363 DI 10.1016/j.yexmp.2013.10.004 PG 7 WC Pathology SC Pathology GA 266EZ UT WOS:000328007500016 PM 24158018 ER PT J AU Bogich, TL Anthony, SJ Nichols, JD AF Bogich, Tiffany L. Anthony, Simon J. Nichols, James D. TI Surveillance theory applied to virus detection: a case for targeted discovery SO FUTURE VIROLOGY LA English DT Review DE adaptive management; detection; modeling; structured decision-making; surveillance; virus discovery ID BORNA-DISEASE AGENT; INFECTIOUS-DISEASES; VACCINATION STRATEGIES; PATHOGEN DISCOVERY; OPTIMAL MANAGEMENT; HOST-SPECIFICITY; TRANSMISSION; CORONAVIRUS; UNCERTAINTY; EMERGENCE AB Virus detection and mathematical modeling have gone through rapid developments in the past decade. Both offer new insights into the epidemiology of infectious disease and characterization of future risk; however, modeling has not yet been applied to designing the best surveillance strategies for viral and pathogen discovery. We review recent developments and propose methods to integrate viral and pathogen discovery and mathematical modeling through optimal surveillance theory, arguing for a more targeted approach to novel virus detection guided by the principles of adaptive management and structured decision-making. C1 [Bogich, Tiffany L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bogich, Tiffany L.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Anthony, Simon J.] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY USA. [Anthony, Simon J.] EcoHealth Alliance, New York, NY USA. [Nichols, James D.] US Geol Survey, Patuxent Wildlife Res Ctr, Laurel, MD USA. RP Bogich, TL (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM tbogich@princeton.edu OI Bogich, Tiffany/0000-0002-8143-5289 NR 42 TC 1 Z9 1 U1 1 U2 13 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0794 EI 1746-0808 J9 FUTURE VIROL JI Future Virol. PD DEC PY 2013 VL 8 IS 12 BP 1201 EP 1206 DI 10.2217/fvl.13.105 PG 6 WC Virology SC Virology GA 258PE UT WOS:000327470400010 ER PT J AU Chandler, RJ Tarasenko, TN Cusmano-Ozog, K Sun, Q Sutton, VR Venditti, CP McGuire, PJ AF Chandler, R. J. Tarasenko, T. N. Cusmano-Ozog, K. Sun, Q. Sutton, V. R. Venditti, C. P. McGuire, P. J. TI Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1 SO GENE THERAPY LA English DT Article DE urea cycle disorders; citrullinemia; AAV8; hyperammonemia ID UREA CYCLE DISORDERS; ESSENTIAL AMINO-ACID; ARGININOSUCCINATE SYNTHETASE; OTC DEFICIENCY; AAV8 VECTOR; TRANSPLANTATION; ARGININE; METABOLISM; THERAPY; ENZYME AB Citrullinemia type 1 (CTLN1) is an autosomal recessive disorder of metabolism caused by a deficiency of argininosuccinate synthetase. Despite optimal management, CTLN1 patients still suffer from lethal metabolic instability and experience life-threatening episodes of acute hyperammonemia. A murine model of CTLN1 (fold/fold) that displays lethality within the first 21 days of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy. An AAV serotype 8 (AAV8) vector was engineered to express the human ASS1 cDNA under the control of a liver-specific promoter (thyroxine-binding globulin, TBG), AAV8-TBG-hASS1, and delivered to 7-10 days old mice via intraperitoneal injection. Greater than 95% of the mice were rescued from lethality and survival was extended beyond 100 days after receiving a single dose of vector. AAV8-TBG-hASS7 treatment resulted in liver-specific expression of hASS1, increased ASS1 enzyme activity, reduction in plasma ammonia and citrulline concentrations and significant phenotypic improvement of the fold/fold growth and skin phenotypes. These experiments highlight a gene transfer approach using AAV8 vector for liver-targeted gene therapy that could serve as a treatment for CTLN1. C1 [Chandler, R. J.; Venditti, C. P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Tarasenko, T. N.; McGuire, P. J.] NHGRI, Phys Scientist Dev Program, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Cusmano-Ozog, K.] Childrens Natl Med Ctr, Dept Genet & Metab, Washington, DC 20010 USA. [Sun, Q.; Sutton, V. R.] Baylor Coll Med, Biochem Genet Lab, Houston, TX 77030 USA. RP McGuire, PJ (reprint author), NHGRI, NIH, 49 Convent Dr,Room 4A62, Bethesda, MD 20892 USA. EM peter.mcguire@nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX For this work, RJC, TNT, CPV, and PJM were supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Thanks to the National Human Genome Research Institute mouse core for mouse care and technical assistance. NR 23 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD DEC PY 2013 VL 20 IS 12 BP 1188 EP 1191 DI 10.1038/gt.2013.53 PG 4 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 265CB UT WOS:000327926200012 PM 24131980 ER PT J AU Rimbault, M Beale, HC Schoenebeck, JJ Hoopes, BC Allen, JJ Kilroy-Glynn, P Wayne, RK Sutter, NB Ostrander, EA AF Rimbault, Maud Beale, Holly C. Schoenebeck, Jeffrey J. Hoopes, Barbara C. Allen, Jeremy J. Kilroy-Glynn, Paul Wayne, Robert K. Sutter, Nathan B. Ostrander, Elaine A. TI Derived variants at six genes explain nearly half of size reduction in dog breeds SO GENOME RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; GROWTH-HORMONE; POSTNATAL-GROWTH; DOMESTIC DOG; HUMAN HEIGHT; TGF-BETA; BIOLOGICAL PATHWAYS; BODY HEIGHT; HMGI-C; ADULT AB Selective breeding of dogs by humans has generated extraordinary diversity in body size. A number of multibreed analyses have been undertaken to identify the genetic basis of this diversity. We analyzed four loci discovered in a previous genome-wide association study that used 60,968 SNPs to identify size-associated genomic intervals, which were too large to assign causative roles to genes. First, we performed fine-mapping to define critical intervals that included the candidate genes GHR, HMGA2, SMAD2, and STC2, identifying five highly associated markers at the four loci. We hypothesize that three of the variants are likely to be causative. We then genotyped each marker, together with previously reported size-associated variants in the IGF1 and IGF1R genes, on a panel of 500 domestic dogs from 93 breeds, and identified the ancestral allele by genotyping the same markers on 30 wild canids. We observed that the derived alleles at all markers correlated with reduced body size, and smaller dogs are more likely to carry derived alleles at multiple markers. However, breeds are not generally fixed at all markers; multiple combinations of genotypes are found within most breeds. Finally, we show that 46%-52.5% of the variance in body size of dog breeds can be explained by seven markers in proximity to exceptional candidate genes. Among breeds with standard weights <41 kg (90 lb), the genotypes accounted for 64.3% of variance in weight. This work advances our understanding of mammalian growth by describing genetic contributions to canine size determination in non-giant dog breeds. C1 [Rimbault, Maud; Beale, Holly C.; Schoenebeck, Jeffrey J.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Hoopes, Barbara C.] Colgate Univ, Dept Biol, Hamilton, NY 13346 USA. [Allen, Jeremy J.; Sutter, Nathan B.] Cornell Univ, Dept Clin Sci, Coll Vet Med, Ithaca, NY 14853 USA. [Kilroy-Glynn, Paul] Dublin City Univ, Sch Biotechnol, Dublin 9, Ireland. [Wayne, Robert K.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU American Kennel Club-Canine Health Foundation; Intramural Program of the National Human Genome Research Institute of the National Institutes of Health; Cornell University; NIGMS PRAT postdoctoral fellowship; Research Council of Colgate University; NSF-DEB [1021397, 0733033]; NIH [5R21HG006051-02] FX We thank the American Kennel Club-Canine Health Foundation, the Intramural Program of the National Human Genome Research Institute of the National Institutes of Health (E.A.O., M. R., H. C. B., and J.J.S.), and Cornell University (N.B.S. and J.J.A.) for supporting this work. J.J.S. was funded by an NIGMS PRAT postdoctoral fellowship. Sabbatical support for B. C. H. was provided by a grant from the Research Council of Colgate University. R. K. W. is supported by grants NSF-DEB 1021397 and 0733033, and N.B.S. by NIH grant 5R21HG006051-02. We thank Drs. John Novembre, Heidi Parker, and Jonine Figueroa for their helpful insights and feedback. We thank the NIH Intramural Sequencing Center staff for valuable technical and computational assistance. We thank Dr. Shelley Hoogstraten-Miller and Irene Ginty for assistance in blood draws. Finally, we are grateful to the many dog owners and breeders who generously provided DNA samples for this study. NR 64 TC 23 Z9 23 U1 10 U2 51 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD DEC PY 2013 VL 23 IS 12 BP 1985 EP 1995 DI 10.1101/gr.157339.113 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 265JJ UT WOS:000327946900003 PM 24026177 ER PT J AU Lai, AY Mav, D Shah, R Grimm, SA Phadke, D Hatzi, K Melnick, A Geigerman, C Sobol, SE Jaye, DL Wade, PA AF Lai, Anne Y. Mav, Deepak Shah, Ruchir Grimm, Sara A. Phadke, Dhiral Hatzi, Katerina Melnick, Ari Geigerman, Cissy Sobol, Steve E. Jaye, David L. Wade, Paul A. TI DNA methylation profiling in human B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-cell activation SO GENOME RESEARCH LA English DT Article ID STEM-CELLS; METHYLTRANSFERASE GENE; HUMAN GENOME; TRANSCRIPTIONAL REPRESSION; IMMUNODEFICIENCY SYNDROME; T-CELLS; MEMORY; DIFFERENTIATION; PLURIPOTENT; EXPRESSION AB Memory is a hallmark of adaptive immunity, wherein lymphocytes mount a superior response to a previously encountered antigen. It has been speculated that epigenetic alterations in memory lymphocytes contribute to their functional distinction from their naive counterparts. However, the nature and extent of epigenetic alterations in memory compartments remain poorly characterized. Here we profile the DNA methylome and the transcriptome of B-lymphocyte subsets representing stages of the humoral immune response before and after antigen exposure in vivo from multiple humans. A significant percentage of activation-induced losses of DNA methylation mapped to transcription factor binding sites. An additional class of demethylated loci mapped to Alu elements across the genome and accompanied repression of DNA methyltransferase 3A. The activation-dependent DNA methylation changes were largely retained in the progeny of activated B cells, generating a similar epigenetic signature in downstream memory B cells and plasma cells with distinct transcriptional programs. These findings provide insights into the methylation dynamics of the genome during cellular differentiation in an immune response. C1 [Lai, Anne Y.; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Mav, Deepak; Shah, Ruchir; Phadke, Dhiral] SRA Int Inc, Durham, NC 27709 USA. [Grimm, Sara A.] NIEHS, Res Triangle Pk, NC 27709 USA. [Hatzi, Katerina; Melnick, Ari] Weill Cornell Med Coll, New York, NY 10065 USA. [Geigerman, Cissy; Jaye, David L.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Sobol, Steve E.] Emory Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Atlanta, GA 30322 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH [Z01ES101965]; National Institutes of Health [DK60647]; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services [HHSN291200555547C]; GSA [GS-00F-003L] FX We thank the members of the Wade laboratory, Drs. T. Archer, K. Adelman, R. Jothi, J. Taylor, and M. Resnick for critical comments and suggestions for this manuscript. We thank the NIEHS Microarray, Flow Cytometry, and DNA Sequencing core facilities, as well as the NIH Intramural Sequencing Center, for their assistance. We also thank Diane Lawson for technical assistance with immunohistochemistry, Hrisavgi Kondilis-Mangum for assistance with graphics, and Dr. M. Kondo for assistance with cell sorting. This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (project number Z01ES101965 to P. A. W.), and by grants from the National Institutes of Health (DK60647 to D. L. J.). D. M., D. P., and R. S. were supported in whole or in part with federal funds from the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, under delivery order number HHSN291200555547C and GSA contract number GS-00F-003L. NR 62 TC 20 Z9 20 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD DEC PY 2013 VL 23 IS 12 BP 2030 EP 2041 DI 10.1101/gr.155473.113 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 265JJ UT WOS:000327946900007 PM 24013550 ER PT J AU Oh, J Freeman, AF Park, M Sokolic, R Candotti, F Holland, SM Segre, JA Kong, HDH AF Oh, Julia Freeman, Alexandra F. Park, Morgan Sokolic, Robert Candotti, Fabio Holland, Steven M. Segre, Julia A. Kong, Heidi H. CA NISC Comparative Sequencing Progra TI The altered landscape of the human skin microbiome in patients with primary immunodeficiencies SO GENOME RESEARCH LA English DT Article ID HYPER-IGE SYNDROME; STAPHYLOCOCCUS-AUREUS; ATOPIC-DERMATITIS; DIAGNOSTIC-CRITERIA; BINDING PROTEIN; SCORAD INDEX; MUTATIONS; BACTERIAL; DISEASE; EPIDERMIDIS AB While landmark studies have shown that microbiota activate and educate host immunity, how immune systems shape microbiomes and contribute to disease is incompletely characterized. Primary immunodeficiency (PID) patients suffer recurrent microbial infections, providing a unique opportunity to address this issue. To investigate the potential influence of host immunity on the skin microbiome, we examined skin microbiomes in patients with rare monogenic PIDs: hyper-IgE (STAT3-deficient), Wiskott-Aldrich, and dedicator of cytokinesis 8 syndromes. While specific immunologic defects differ, a shared hallmark is atopic dermatitis (AD)-like eczema. We compared bacterial and fungal skin microbiomes (41 PID, 13 AD, 49 healthy controls) at four clinically relevant sites representing the major skin microenvironments. PID skin displayed increased ecological permissiveness with altered population structures, decreased site specificity and temporal stability, and colonization with microbial species not observed in controls, including Clostridium species and Serratia marcescens. Elevated fungal diversity and increased representation of opportunistic fungi (Candida, Aspergillus) supported increased PID skin permissiveness, suggesting that skin may serve as a reservoir for the recurrent fungal infections observed in these patients. The overarching theme of increased ecological permissiveness in PID skin was counterbalanced by the maintenance of a phylum barrier in which colonization remained restricted to typical human-associated phyla. Clinical parameters, including markers of disease severity, were positively correlated with prevalence of Staphylococcus, Corynebacterium, and other less abundant taxa. This study examines differences in microbial colonization and community stability in PID skin and informs our understanding of host-microbiome interactions, suggesting a bidirectional dialogue between skin commensals and the host organism. C1 [Oh, Julia; Sokolic, Robert; Candotti, Fabio; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Park, Morgan; NISC Comparative Sequencing Progra] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM jsegre@mail.nih.gov; konghe@mail.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU NIH NHGRI; NCI; National Institutes of Health [1UH2AR057504-01, 4UH3AR057504-02]; [1K99AR059222] FX We thank members of the Segre laboratory, Helen C. Su, and Mark C. Udey for their helpful discussions and, in particular, Sean Conlan, Clayton Deming, Jennifer Meyer, Effie Nomicos, Deborah Schoenfeld, and Elizabeth Garabedian for their underlying efforts. This work was supported by NIH NHGRI and NCI Intramural Research Programs and in part by 1K99AR059222 (H. H. K.). Sequencing was funded by grants from the National Institutes of Health (1UH2AR057504-01 and 4UH3AR057504-02). NR 51 TC 48 Z9 49 U1 4 U2 48 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD DEC PY 2013 VL 23 IS 12 BP 2103 EP 2114 DI 10.1101/gr.159467.113 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 265JJ UT WOS:000327946900013 PM 24170601 ER PT J AU Kohli, A Sims, Z Marti, M Nelson, AK Osinusi, A Bon, D Herrmann, E Kotb, C Silk, R Teferi, G Symonds, WT Pang, PS McHutchison, JG Subramanian, M Polis, MA Masur, H Kottilil, S AF Kohli, Anita Sims, Zayani Marti, Miriam Nelson, Amy K. Osinusi, Anu Bon, Dimitra Herrmann, Eva Kotb, Colleen Silk, Rachel Teferi, Gebeyehu Symonds, William T. Pang, Phil S. McHutchison, John G. Subramanian, Mani Polis, Michael A. Masur, Henry Kottilil, Shyam TI Combination Oral, Ribavirin Free, Antiviral Therapy to Optimize Treatment Outcomes for Hepatitis C GT-1 Treatment Naive Patients: Interim Results from the NIAID SYNERGY Trial SO HEPATOLOGY LA English DT Meeting Abstract C1 [Kohli, Anita; Kotb, Colleen; Silk, Rachel] SAIC Frederick Inc, Clin Res Directorate Clin Monitoring Res Program, Frederick, MD USA. [Kohli, Anita; Sims, Zayani; Osinusi, Anu; Masur, Henry] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Marti, Miriam; Nelson, Amy K.; Polis, Michael A.; Kottilil, Shyam] NIAID, NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. [Osinusi, Anu] Univ Maryland, Dept Infect Dis, Baltimore, MD 21201 USA. [Bon, Dimitra; Herrmann, Eva] Goethe Univ Frankfurt, Inst Biostst & Math Modeling, D-60054 Frankfurt, Germany. [Teferi, Gebeyehu] Unity Hlth Care Inc, Washington, DC USA. [Symonds, William T.; Pang, Phil S.; McHutchison, John G.; Subramanian, Mani] Gilead Sci, Foster City, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2013 VL 58 IS 6 MA LB8 BP 1382A EP 1382A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 257LH UT WOS:000327385000009 ER PT J AU Koh, C Zhao, XC Samala, N Sakiani, S Liang, TJ Talwalkar, JA AF Koh, Christopher Zhao, Xiongce Samala, Niharika Sakiani, Sasan Liang, T. Jake Talwalkar, Jayant A. TI AASLD Clinical Practice Guidelines: A Critical Review of Scientific Evidence and Evolving Recommendations SO HEPATOLOGY LA English DT Article ID INTRAHEPATIC PORTOSYSTEMIC SHUNT; PRIMARY BILIARY-CIRRHOSIS; ACUTE LIVER-FAILURE; AMERICAN ASSOCIATION; AUTOIMMUNE HEPATITIS; PORTAL-HYPERTENSION; POSITION PAPER; WILSON-DISEASE; ADULT PATIENTS; UPDATE 2009 AB The American Association for the Study of Liver Diseases (AASLD) practice guidelines provide recommendations in diagnosing and managing patients with liver disease from available scientific evidence in combination with expert consensus opinions. The aim was to systematically review the evolution of recommendations from AASLD guidelines and identify gaps limiting the evidence-based foundations of these guidelines. Initial and current AASLD guidelines published from January 1998 to August 2012 were reviewed. The AGREE II instrument was used to evaluate rigor and transparency of guideline development. The number of recommendations, distribution of grades (strength or certainty), classes (benefit versus risk), and types of recommendations were evaluated. Whenever possible, multiple versions were evaluated for evolving scientific evidence. A total of 991 recommendations from 28 guidelines on 17 topics were evaluated. From initial to current guidelines, the total number of recommendations increased by 36% (512 to 699). The largest increases were from chronic hepatitis B virus (HBV) (+71), liver transplantation (+53), and autoimmune hepatitis (AIH) (+27). Most current recommendations are grade II (44%) and less than 20% are grade I. The AGREE II evaluation showed global improvement in guideline quality. Both HBV and chronic hepatitis C guidelines had greatest increases in grade I recommendations (+383% and +67%, respectively). The greatest increases in treatment recommendations were from HBV (grade I, +1,150%), liver transplantation (grade II, +112%), and AIH (grade III, +105%). Conclusion: Despite significant increases in the numbers of recommendations within AASLD practice guidelines over time, only a minority are supported by grade I evidence, highlighting the need for developing well-designed investigations to provide evidence for areas of uncertainty and improving the quality of future guidelines in hepatobiliary diseases. (Hepatology 2013; 58:2142-2152) C1 [Koh, Christopher; Samala, Niharika; Sakiani, Sasan; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. [Talwalkar, Jayant A.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. RP Koh, C (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Rm 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM Christopher.koh@nih.gov FU NIDDK, NIH FX Supported by the Intramural Research Programs of the NIDDK, NIH. NR 40 TC 17 Z9 22 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2013 VL 58 IS 6 BP 2142 EP 2152 DI 10.1002/hep.26578 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 257LH UT WOS:000327385000061 PM 23775835 ER PT J AU Ogawa, S Watanabe, M Sakurai, Y Inutake, Y Watanabe, S Tai, XG Abe, R AF Ogawa, Shuhei Watanabe, Masashi Sakurai, Yuichi Inutake, Yu Watanabe, Shiho Tai, Xuguang Abe, Ryo TI CD28 signaling in primary CD4(+) T cells: identification of both tyrosine phosphorylation-dependent and phosphorylation-independent pathways SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE CD28; co-stimulation; phosphorylation; T-cell activation ID PROTEIN-KINASE-C; NF-KAPPA-B; COSTIMULATORY MOLECULE CD28; PHOSPHATIDYLINOSITOL 3-KINASE; CD28-MEDIATED COSTIMULATION; IMMUNOLOGICAL SYNAPSE; CYTOPLASMIC DOMAIN; RECEPTOR CD28; ANTIGEN RECEPTOR; CUTTING EDGE AB In addition to TCR signaling, the activation and proliferation of naive T cells require CD28-mediated co-stimulation. Once engaged, CD28 is phosphorylated and can then activate signaling pathways by recruiting molecules to its YMNM motif and two PxxP motifs. In this study, we analyzed the relationship between tyrosine phosphorylation and the co-stimulatory function of CD28 in murine primary CD4(+) T cells. Tyrosine phosphorylation is decreased in CD28 where the N-terminal PxxP motif is mutated (nPA). In cells expressing nPA, activation of Akt and functional co-stimulation were decreased. In contrast, where the C-terminal PxxP motif is mutated, tyrosine phosphorylation and activation of the ERK, Akt and NF-kappa B were intact, but proliferation and IL-2 production were decreased. Using the Y-189 to F mutant, we also demonstrated that in naive CD4(+) T cells, tyrosine at position 189 in the YMNM motif is critical for both tyrosine phosphorylation and the functional co-stimulatory effects of CD28. This mutation did not affect unfractionated T-cell populations. Overall, our data suggest that CD28 signaling uses tyrosine phosphorylation-dependent and phosphorylation-independent pathways. C1 [Ogawa, Shuhei; Watanabe, Shiho; Abe, Ryo] Tokyo Univ Sci, Res Inst Biomed Sci, Noda, Chiba 2780022, Japan. [Ogawa, Shuhei; Abe, Ryo] Tokyo Univ Sci, Ctr Technol Canc, Noda, Chiba 2780022, Japan. [Watanabe, Masashi; Tai, Xuguang] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Sakurai, Yuichi; Inutake, Yu; Abe, Ryo] Tokyo Univ Sci, Fac Pharmaceut Sci, Noda, Chiba 2780022, Japan. RP Abe, R (reprint author), Tokyo Univ Sci, Res Inst Biomed Sci, 2669 Yamazaki, Noda, Chiba 2780022, Japan. EM rabe@rs.noda.tus.ac.jp FU Japan Society for the Promotion of Science [21590541] FX Japan Society for the Promotion of Science (C; 21590541). NR 58 TC 6 Z9 6 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 EI 1460-2377 J9 INT IMMUNOL JI Int. Immunol. PD DEC PY 2013 VL 25 IS 12 BP 671 EP 681 DI 10.1093/intimm/dxt028 PG 11 WC Immunology SC Immunology GA 263FM UT WOS:000327792300002 PM 24048955 ER PT J AU Siegel, AM Stone, KD Cruse, G Lawrence, MG Olivera, A Jung, MY Barber, JS Freeman, AF Holland, SM O'Brien, M Jones, N Wisch, LB Kong, HH Desai, A Farber, O Gilfillan, AM Rivera, J Milner, JD AF Siegel, Andrea M. Stone, Kelly D. Cruse, Glenn Lawrence, Monica G. Olivera, Ana Jung, Mi-yeon Barber, John S. Freeman, Alexandra F. Holland, Steven M. O'Brien, Michelle Jones, Nina Wisch, Laura B. Kong, Heidi H. Desai, Avanti Farber, Orly Gilfillan, Alasdair M. Rivera, Juan Milner, Joshua D. TI Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Autosomal dominant hyper-IgE syndrome; Job syndrome; signal transducer and activator of transcription 3; mast cell; degranulation ID HYPER-IGE SYNDROME; FOLLICULAR-HELPER-CELLS; TRANSCRIPTION FACTOR; FOOD ALLERGY; B-CELLS; RECEPTOR; GENERATION; BASOPHILS; CHILDREN; BCL6 AB Background: Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. Objective: Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. Methods: We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. Results: Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FceRI-mediated proximal and distal signaling, as well as reduced degranulation. Conclusion: This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others. C1 [Siegel, Andrea M.; Stone, Kelly D.; Cruse, Glenn; Lawrence, Monica G.; Jung, Mi-yeon; Barber, John S.; O'Brien, Michelle; Jones, Nina; Wisch, Laura B.; Desai, Avanti; Farber, Orly; Gilfillan, Alasdair M.; Milner, Joshua D.] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. [Olivera, Ana; Rivera, Juan] NIAMSD, Immunogenet Mol Lab, Bethesda, MD 20892 USA. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Kong, Heidi H.] NIH, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Milner, JD (reprint author), NIAID, Lab Allerg Dis, Bldg 10,Room 12S236A,10 Ctr Dr, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases within the National Institutes of Health FX Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases and National Institute of Arthritis and Musculoskeletal and Skin Diseases within the National Institutes of Health. NR 32 TC 30 Z9 30 U1 1 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2013 VL 132 IS 6 BP 1388 EP + DI 10.1016/j.jaci.2013.08.045 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA 259PG UT WOS:000327538200018 PM 24184145 ER PT J AU Mueller, GA Pedersen, LC Lih, FB Glesner, J Moon, AF Chapman, MD Tomer, KB London, RE Pomes, A AF Mueller, Geoffrey A. Pedersen, Lars C. Lih, Fred B. Glesner, Jill Moon, Andrea F. Chapman, Martin D. Tomer, Kenneth B. London, Robert E. Pomes, Anna TI The novel structure of the cockroach allergen Bla g 1 has implications for allergenicity and exposure assessment SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergen; asthma; Bla g 1; cockroach; structure; ligand-binding proteins; exposure assessment ID INNER-CITY CHILDREN; GREEN FLUORESCENT PROTEIN; MAJOR HUMAN ALLERGEN; AMERICAN COCKROACH; BLATTELLA-GERMANICA; INDOOR ALLERGENS; MONOCLONAL-ANTIBODY; CRYSTAL-STRUCTURE; GENE-EXPRESSION; ASTHMA AB Background: Sensitization to cockroach allergens is a major risk factor for asthma. The cockroach allergen Bla g 1 has multiple repeats of approximately 100 amino acids, but the fold of the protein and its biological function are unknown. Objective: We sought to determine the structure of Bla g 1, investigate the implications for allergic disease, and standardize cockroach exposure assays. Methods: nBla g 1 and recombinant constructs were compared by using ELISA with specific murine IgG and human IgE. The structure of Bla g 1 was determined by x-ray crystallography. Mass spectrometry and nuclear magnetic resonance spectroscopy were used to examine the ligand-binding properties of the allergen. Results: The structure of an rBla g 1 construct with comparable IgE and IgG reactivity to the natural allergen was solved by x-ray crystallography. The Bla g 1 repeat forms a novel fold with 6 helices. Two repeats encapsulate a large and nearly spherical hydrophobic cavity, defining the basic structural unit. Lipids in the cavity varied depending on the allergen origin. Palmitic, oleic, and stearic acids were associated with nBla g 1 from cockroach frass. One unit of Bla g 1 was equivalent to 104 ng of allergen. Conclusions: Bla g 1 has a novel fold with a capacity to bind various lipids, which suggests a digestive function associated with nonspecific transport of lipid molecules in cockroaches. Defining the basic structural unit of Bla g 1 facilitates the standardization of assays in absolute units for the assessment of environmental allergen exposure. C1 [Mueller, Geoffrey A.; Pedersen, Lars C.; Lih, Fred B.; Moon, Andrea F.; Tomer, Kenneth B.; London, Robert E.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Glesner, Jill; Chapman, Martin D.; Pomes, Anna] Indoor Biotechnol, Charlottesville, VA USA. RP Mueller, GA (reprint author), NIEHS, 111 TW Alexander Dr,MD MR 01, Res Triangle Pk, NC 27709 USA. EM Mueller3@niehs.nih.gov OI Pomes, Anna/0000-0002-8729-1829 FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES102885-01, Z01-ES50161, ZIA-ES102645]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI077653]; US department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX Supported in part by Research Project no. Z01-ES102885-01 to R.E.L., Z01-ES50161 to K.B.T., and ZIA-ES102645 to L.C.P. in the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. R01AI077653 (to A.P. and M.D.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Use of the Advanced Photon Source, Argonne National Laboratory, was supported by the US department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38. NR 60 TC 15 Z9 15 U1 1 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2013 VL 132 IS 6 BP 1420 EP + DI 10.1016/j.jaci.2013.06.014 PG 16 WC Allergy; Immunology SC Allergy; Immunology GA 259PG UT WOS:000327538200021 PM 23915714 ER PT J AU Lawrence, MG Barber, JS Sokolic, RA Garabedian, EK Desai, AN O'Brien, M Jones, N Bali, P Hershfield, MS Stone, KD Candotti, F Milner, JD AF Lawrence, Monica G. Barber, John S. Sokolic, Robert A. Garabedian, Elizabeth K. Desai, Avanti N. O'Brien, Michelle Jones, Nina Bali, Pawan Hershfield, Michael S. Stone, Kelly D. Candotti, Fabio Milner, Joshua D. TI Elevated IgE and atopy in patients treated for early-onset ADA-SCID SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID ALLERGIC DISEASE; DEFICIENCY; CELLS C1 [Lawrence, Monica G.; Barber, John S.; Desai, Avanti N.; O'Brien, Michelle; Stone, Kelly D.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Sokolic, Robert A.; Garabedian, Elizabeth K.; Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Jones, Nina] SAIC Frederick Inc, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. [Bali, Pawan; Hershfield, Michael S.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Bali, Pawan; Hershfield, Michael S.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Lawrence, MG (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [ZIA AI001099-04]; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 9 TC 5 Z9 5 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2013 VL 132 IS 6 BP 1444 EP 1446 DI 10.1016/j.jaci.2013.05.040 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 259PG UT WOS:000327538200029 PM 23895897 ER PT J AU Rosemblat, G Shin, D Kilicoglu, H Sneiderman, C Rindflesch, TC AF Rosemblat, Graciela Shin, Dongwook Kilicoglu, Halil Sneiderman, Charles Rindflesch, Thomas C. TI A methodology for extending domain coverage in SemRep SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Natural language processing application; Domain-independent ontology development methodology; Semantic predications; UMLS knowledge sources ID BIOMEDICAL TEXT; KNOWLEDGE; ONTOLOGY; SYSTEM AB We describe a domain-independent methodology to extend SemRep coverage beyond the biomedical domain. SemRep, a natural language processing application originally designed for biomedical texts, uses the knowledge sources provided by the Unified Medical Language System (UMLS (c)). Ontological and terminological extensions to the system are needed in order to support other areas of knowledge. We extended SemRep's application by developing a semantic representation of a previously unsupported domain. This was achieved by adapting well-known ontology engineering phases and integrating them with the UMLS knowledge sources on which SemRep crucially-depends. While the process to extend SemRep coverage has been successfully applied in earlier projects, this paper presents in detail the step-wise approach we followed and the mechanisms implemented. A case study in the field of medical informatics illustrates how the ontology engineering phases have been adapted for optimal integration with the UMLS. We provide qualitative and quantitative results, which indicate the validity and usefulness of our methodology. Published by Elsevier Inc. C1 [Rosemblat, Graciela; Shin, Dongwook; Kilicoglu, Halil; Sneiderman, Charles; Rindflesch, Thomas C.] NIH, Natl Lib Med, Lister Hill Ctr, Cognit Sci Branch, Bethesda, MD 20894 USA. RP Rosemblat, G (reprint author), Natl Lib Med, Lister Hill Ctr, Bldg 38A,7S713B,8600 Rockville Pike, Bethesda, MD 20894 USA. EM grosemblat@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 41 TC 2 Z9 2 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD DEC PY 2013 VL 46 IS 6 BP 1099 EP 1107 DI 10.1016/j.jbi.2013.08.005 PG 9 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 266GU UT WOS:000328012900014 PM 23973273 ER PT J AU Chawla, N Arora, NK AF Chawla, Neetu Arora, Neeraj K. TI Why do some patients prefer to leave decisions up to the doctor: lack of self-efficacy or a matter of trust? SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Cancer; Patient preferences; Patient decision support; Patient-provider communication ID CANCER SURVIVORS; PHYSICIAN SCALE; CENTERED CARE; PARTICIPATION; INFORMATION; PERSPECTIVE; OUTCOMES; ROLES AB Decision-making preferences among cancer survivors during their follow-up care remains understudied and limited research examines factors that underlie these preferences. The purpose of this study was to assess cancer patients' decision-making preferences during follow-up care, the role of trust and self-efficacy, and the effect of preferences on health outcomes. Six hundred twenty-three bladder, leukemia, and colorectal cancer survivors were recruited to the Assessment of Patient Experiences of Cancer Care study between April 2003 and November 2004. Respondents were asked about their follow-up care experiences, including decision-making preferences, trust in physicians, self-efficacy, health-related quality of life (HRQOL), and health appraisal. Unadjusted mean scores of trust and self-efficacy measures by decision preference group were examined. Multinomial logistic and linear regressions were conducted to examine predictors of decision-making preferences and the impact of decision-making preferences on HRQOL and health appraisal. While the majority of patients preferred shared decision-making (61.0 %), 16.1 % preferred to control their decisions and 22.1 % preferred physician control over decisions. Compared to the other groups, patients preferring physician control had greater trust in their physician (p < 0.001), similar self-efficacy for engaging in the decision-making process, and lower self-efficacy for taking responsibility over decisions (p < 0.001). There were no notable differences between decision-making groups on outcome measures. Patients who prefer physicians to control decisions are as confident about participating in the decision-making process and experience similar health outcomes as those preferring greater decisional control. Physicians need to tailor their communication behavior to encourage participation and trust among all patients. Findings from this study provide unique insights into the decision-making preferences of cancer patients during receipt of follow-up care, which remains an understudied phase of cancer care delivery. Results underscore the need for approaches to decision-making and patient engagement to become more nuanced and to encourage patients to participate in decision-making in ways they are most comfortable. Furthermore, physicians and health care professionals should foster environments that promote trust and clear communication regardless of patient decision-making styles. C1 [Chawla, Neetu; Arora, Neeraj K.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. RP Chawla, N (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E450, Rockville, MD 20850 USA. EM neetu.chawla@nih.gov; aroran@mail.nih.gov FU National Cancer Institute [N01-PC-35136] FX This paper reflects the personal opinions of Dr. Chawla and Dr. Arora and does not convey any official position of the National Cancer Institute. Funding for data collection was provided by the National Cancer Institute as a contract to the Cancer Prevention Institute of California (formerly known as the Northern California Cancer Center), contract no. N01-PC-35136. Findings from this study were presented at Academy Health Annual Research Meeting, June 24-26, 2012, Orlando, FL, USA. The authors would like to acknowledge the Dr. Ingrid Oakley-Girvan for her data collection efforts for this study. NR 35 TC 11 Z9 11 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD DEC PY 2013 VL 7 IS 4 BP 592 EP 601 DI 10.1007/s11764-013-0298-2 PG 10 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 259CK UT WOS:000327504800009 PM 23892559 ER PT J AU Te Riele, ASJM James, CA Philips, B Rastegar, N Bhonsale, A Groeneweg, JA Murray, B Tichnell, C Judge, DP Van der Heijden, JF Cramer, MJM Velthuis, BK Bluemke, DA Zimmerman, SL Kamel, IR Hauer, RNW Calkins, H Tandri, H AF Te Riele, Anneline S. J. M. James, Cynthia A. Philips, Binu Rastegar, Neda Bhonsale, Aditya Groeneweg, Judith A. Murray, Brittney Tichnell, Crystal Judge, Daniel P. Van der Heijden, Jeroen F. Cramer, Maarten J. M. Velthuis, Birgitta K. Bluemke, David A. Zimmerman, Stefan L. Kamel, Ihab R. Hauer, Richard N. W. Calkins, Hugh Tandri, Harikrishna TI Mutation-Positive Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: The Triangle of Dysplasia Displaced SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE arrhythmogenic right ventricular dysplasia; cardiomyopathy; magnetic resonance imaging; electroanatomic mapping; ventricular tachcardia; phenotype; genetics; implantable cardioverter defibrillator ID TASK-FORCE CRITERIA; MAGNETIC-RESONANCE; HUMAN HEART; CARDIOMYOPATHY; TACHYCARDIA; ABLATION; SUBSTRATE; FAMILIES; DISEASE AB ARVD/C: The Triangle of Dysplasia Displaced IntroductionThe traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes. Methods and ResultsWe analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (<0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation. ConclusionMutation-positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C. C1 [Te Riele, Anneline S. J. M.; Groeneweg, Judith A.; Van der Heijden, Jeroen F.; Cramer, Maarten J. M.; Hauer, Richard N. W.] Univ Med Ctr Utrecht, Dept Cardiol, Utrecht, Netherlands. [Te Riele, Anneline S. J. M.; James, Cynthia A.; Philips, Binu; Bhonsale, Aditya; Murray, Brittney; Tichnell, Crystal; Judge, Daniel P.; Calkins, Hugh; Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Rastegar, Neda; Bluemke, David A.; Zimmerman, Stefan L.; Kamel, Ihab R.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Groeneweg, Judith A.; Hauer, Richard N. W.] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Velthuis, Birgitta K.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Tandri, H (reprint author), Johns Hopkins Univ Hosp, Div Cardiol, Dept Med, 600 N Wolfe St,Carnegie 565D, Baltimore, MD 21287 USA. EM htandri1@jhmi.edu OI te Riele, Anneline/0000-0003-1115-6193; Bluemke, David/0000-0002-8323-8086 FU Dutch Heart Foundation; Alexandre Suerman Stipend; Interuniversity Cardiology Institute of the Netherlands; National Heart, Lung, and Blood Institute [K23HL093350]; St. Jude Medical Foundation; Medtronic Inc.; Bogle Foundation; Healing Hearts Foundation; Campanella family; Wilmerding Endowments; Dr. Francis P. Chiaramonte Private Foundation; Medtronic; St. Jude Medical FX The authors wish to acknowledge funding from the Dutch Heart Foundation (to ASJMtR), the Alexandre Suerman Stipend (to ASJMtR), the Interuniversity Cardiology Institute of the Netherlands (to JAG), the National Heart, Lung, and Blood Institute (K23HL093350 to HT), the St. Jude Medical Foundation, and Medtronic Inc. The Johns Hopkins ARVD/C Program (ARVD. com) is supported by the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, and Wilmerding Endowments, and the Dr. Francis P. Chiaramonte Private Foundation.; Dr. Calkins received research support from Medtronic and St. Jude Medical. Other authors: No disclosures. NR 25 TC 29 Z9 29 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD DEC PY 2013 VL 24 IS 12 BP 1311 EP 1320 DI 10.1111/jce.12222 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 260OB UT WOS:000327603100014 PM 23889974 ER PT J AU Yaniv, Y Lakatta, EG AF Yaniv, Yael Lakatta, Edward G. TI Pacemaker Gene Mutations, Bradycardia, Arrhythmias and the Coupled Clock Theory SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Letter ID AUTOMATICITY; CA(V)1.3 C1 [Yaniv, Yael; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Biomed Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Yaniv, Y (reprint author), NIA, Cardiovasc Sci Lab, Biomed Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. EM yanivy@nia.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU Intramural NIH HHS [Z99 AG999999] NR 7 TC 5 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD DEC PY 2013 VL 24 IS 12 BP E28 EP E29 DI 10.1111/jce.12236 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 260OB UT WOS:000327603100012 PM 24015891 ER PT J AU Canepa, M Milaneschi, Y Ameri, P AlGhatrif, M Leoncini, G Spallarossa, P Pontremoli, R Brunelli, C Strait, JB Lakatta, EG Ferrucci, L AF Canepa, Marco Milaneschi, Yuri Ameri, Pietro AlGhatrif, Majd Leoncini, Giovanna Spallarossa, Paolo Pontremoli, Roberto Brunelli, Claudio Strait, James B. Lakatta, Edward G. Ferrucci, Luigi TI Relationship Between Inter-Arm Difference in Systolic Blood Pressure and Arterial Stiffness in Community-Dwelling Older Adults SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Article ID CARDIOVASCULAR EVENTS; VASCULAR-DISEASE; HYPERTENSION; PREVALENCE; STENOSIS; METAANALYSIS; ASSOCIATION; VARIABILITY; CANDIDATES AB A significant inter-arm difference in systolic blood pressure (IADSBP) has recently been associated with worse cardiovascular outcomes. The authors hypothesized that part of this association is mediated by arterial stiffness, and examined the relationship between significant IADSBP and carotid-femoral pulse wave velocity (CF-PWV) in a sample from the Baltimore Longitudinal Study of Aging. Of 1045 participants, 50 (4.8%) had an IADSBP 10mm Hg at baseline, and 629 had completed data from 2 visits (for a total of 1704 visits during 8years). CF-PWV was significantly higher in patients with an IADSBP 10mm Hg (7.3 +/- 1.9 vs 8.2 +/- 2, P=.002). Compared with others, patients with IADSBP 10mm Hg also had higher body mass index, waist circumference, and triglycerides; higher prevalence of diabetes; and lower high-density lipoprotein (HDL) cholesterol (P<.001 for all). A significant association with IADSBP 10mm Hg was observed for CF-PWV in both cross-sectional (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.06-1.87; P=.01) and longitudinal (OR, 1.15; 95% CI, 1.03-1.29; P=.01) multivariate analyses. Female sex, Caucasian race, high body mass index (plus diabetes and low HDL cholesterol only cross-sectionally) were other independent correlates of IADSBP 10mm Hg. Significant IADSBP is associated with increased arterial stiffness in community-dwelling older adults. C1 [Canepa, Marco; Milaneschi, Yuri; Strait, James B.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21225 USA. [Canepa, Marco; AlGhatrif, Majd; Strait, James B.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Human Cardiovasc Studies Unit, NIH, Baltimore, MD 21225 USA. [Canepa, Marco; Ameri, Pietro; Leoncini, Giovanna; Spallarossa, Paolo; Pontremoli, Roberto; Brunelli, Claudio] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Milaneschi, Yuri] VU Univ Med Ctr GGZ InGeest, Dept Psychiat, Amsterdam, Netherlands. [AlGhatrif, Majd] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP Canepa, M (reprint author), NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Harbor Hosp Ctr Room NM524,3001 South Hanover St, Baltimore, MD 21225 USA. EM marco.canepa@nih.gov FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 31 TC 14 Z9 14 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD DEC PY 2013 VL 15 IS 12 BP 880 EP 887 DI 10.1111/jch.12178 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 260YX UT WOS:000327631700006 PM 24299691 ER PT J AU Margolis, KL Davis, BR Baimbridge, C Ciocon, JO Cuyjet, AB Dart, RA Einhorn, PT Ford, CE Gordon, D Hartney, TJ Haywood, LJ Holtzman, J Mathis, DE Oparil, S Probstfield, JL Simpson, LM Stokes, JD Wiegmann, TB Williamson, JD AF Margolis, Karen L. Davis, Barry R. Baimbridge, Charles Ciocon, Jerry O. Cuyjet, Aloysius B. Dart, Richard A. Einhorn, Paula T. Ford, Charles E. Gordon, David Hartney, Thomas J. Haywood, L. Julian Holtzman, Jordan Mathis, David E. Oparil, Suzanne Probstfield, Jeffrey L. Simpson, Lara M. Stokes, John D. Wiegmann, Thomas B. Williamson, Jeff D. CA ALLHAT Collaborative Res Grp TI Author Response to Lipid-Lowering in African Americans in ALLHAT-Optimism Bias? SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Letter C1 [Margolis, Karen L.] Hlth Partners Inst Educ & Res, Minneapolis, MN USA. [Davis, Barry R.; Baimbridge, Charles; Ford, Charles E.; Simpson, Lara M.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Ciocon, Jerry O.] Cleveland Clin Florida, Weston, FL USA. [Cuyjet, Aloysius B.] Nassau Univ Med Ctr, E Meadow, NY USA. [Dart, Richard A.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Einhorn, Paula T.; Gordon, David] NHLBI, Bethesda, MD 20892 USA. [Hartney, Thomas J.] Vet Affairs Med Ctr Augusta, Augusta, GA USA. [Haywood, L. Julian] LAC & USC Med Ctr, Keck Sch Med, Los Angeles, CA USA. [Holtzman, Jordan] Vet Affairs Med Ctr, Minneapolis, MN USA. [Mathis, David E.] Mercer Univ, Macon, GA 31207 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Birmingham, AL USA. [Probstfield, Jeffrey L.] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Stokes, John D.] Christie Clin, Champaign, IL USA. [Wiegmann, Thomas B.] Vet Affairs Med Ctr Kansas City, Kansas City, MO USA. [Williamson, Jeff D.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Margolis, KL (reprint author), Hlth Partners Inst Educ & Res, Minneapolis, MN 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 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD DEC PY 2013 VL 15 IS 12 BP 941 EP 941 DI 10.1111/jch.12220 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 260YX UT WOS:000327631700018 PM 24299695 ER PT J AU Gardell, AM Yang, J Sacchi, R Fangue, NA Hammock, BD Kultz, D AF Gardell, Alison M. Yang, Jun Sacchi, Romina Fangue, Nann A. Hammock, Bruce D. Kueltz, Dietmar TI Tilapia (Oreochromis mossambicus) brain cells respond to hyperosmotic challenge by inducing myo-inositol biosynthesis SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE osmoregulation; compatible osmolyte; myo-inositol; brain; tilapia ID INDUCED PROLACTIN-RELEASE; CENTRAL-NERVOUS-SYSTEM; EEL ANGUILLA-ANGUILLA; RAT-BRAIN; ORGANIC OSMOLYTES; MESSENGER-RNA; INOSITOL COTRANSPORTER; ENVIRONMENTAL SALINITY; SEAWATER ACCLIMATION; CHRONIC HYPOGLYCEMIA AB This study aimed to determine the regulation of the de novo myo-inositol biosynthetic (MIB) pathway in Mozambique tilapia (Oreochromis mossambicus) brain following acute (25 ppt) and chronic (30, 60 and 90 ppt) salinity acclimations. The MIB pathway plays an important role in accumulating the compatible osmolyte, myo-inositol, in cells in response to hyperosmotic challenge and consists of two enzymes, myo-inositol phosphate synthase and inositol monophosphatase. In tilapia brain, MIB enzyme transcriptional regulation was found to robustly increase in a time (acute acclimation) or dose (chronic acclimation) dependent manner. Blood plasma osmolality and Na+ and Cl- concentrations were also measured and significantly increased in response to both acute and chronic salinity challenges. Interestingly, highly significant positive correlations were found between MIB enzyme mRNA and blood plasma osmolality in both acute and chronic salinity acclimations. Additionally, a mass spectrometry assay was established and used to quantify total myo-inositol concentration in tilapia brain, which closely mirrored the hyperosmotic MIB pathway induction. Thus, myo-inositol is a major compatible osmolyte that is accumulated in brain cells when exposed to acute and chronic hyperosmotic challenge. These data show that the MIB pathway is highly induced in response to environmental salinity challenge in tilapia brain and that this induction is likely prompted by increases in blood plasma osmolality. Because the MIB pathway uses glucose-6-phosphate as a substrate and large amounts of myo-inositol are being synthesized, our data also illustrate that the MIB pathway likely contributes to the high energetic demand posed by salinity challenge. C1 [Gardell, Alison M.; Sacchi, Romina; Kueltz, Dietmar] Univ Calif Davis, Dept Anim Sci, Davis, CA 95616 USA. [Gardell, Alison M.; Yang, Jun; Hammock, Bruce D.; Kueltz, Dietmar] Univ Calif Davis, Superfund Res Program, NIEHS, Davis, CA 95616 USA. [Yang, Jun; Hammock, Bruce D.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Yang, Jun; Hammock, Bruce D.] Univ Calif Davis, UCDMC Comprehens Canc Ctr, Davis, CA 95616 USA. [Fangue, Nann A.] Univ Calif Davis, Davis, CA 95616 USA. RP Gardell, AM (reprint author), Univ Calif Davis, Dept Anim Sci, 1 Shields Ave, Davis, CA 95616 USA. EM amgardell@ucdavis.edu FU NSF [IOS-1049780]; NIEHS Superfund Research Grant [P42 ES004699]; NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant [U24 DK097154]; West Coast Central Comprehensive Metabolomics Resource Core Grant [WC3MRC]; NIEHS/UC Davis Superfund for a Pre-doctoral Training Fellowship; NIEHS/UC Davis Superfund Enrichment Activity Award; UC Davis Jastro-Shields Research Fellowship FX Funding for this study was primarily provided by NSF Grant IOS-1049780 (to D.K.) and NIEHS Superfund Research Grant P42 ES004699 (to B.D.H. and D.K.). This research was partially supported by NIH and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant U24 DK097154 (to B.D.H.) and through the West Coast Central Comprehensive Metabolomics Resource Core Grant WC3MRC (to B.D.H.). Additional support was provided by NIEHS/UC Davis Superfund for a Pre-doctoral Training Fellowship, a NIEHS/UC Davis Superfund Enrichment Activity Award and a UC Davis Jastro-Shields Research Fellowship (all to A.M.G.). This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Science Foundation (NSF) or the National Institutes of Health (NIH). Deposited in PMC for release after 12 months. NR 92 TC 9 Z9 9 U1 1 U2 13 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 EI 1477-9145 J9 J EXP BIOL JI J. Exp. Biol. PD DEC PY 2013 VL 216 IS 24 BP 4615 EP 4625 DI 10.1242/jeb.088906 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 266YB UT WOS:000328059000019 PM 24072790 ER PT J AU Murphy, MM Spungen, JH Barraj, LM Bailey, RL Dwyer-, JT AF Murphy, Mary M. Spungen, Judith H. Barraj, Leila M. Bailey, Regan L. Dwyer-, Johanna T. TI Revising the Daily Values May Affect Food Fortification and in Turn Nutrient Intake Adequacy SO JOURNAL OF NUTRITION LA English DT Article ID DIETARY; LEVEL AB The Nutrition Facts panel on food labels in the United States currently displays Daily Values (DVs) that are based on outdated RDAs. The FDA has indicated that it plans to update the DVs based on the newer Dietary Reference Intakes (DRIs), but there is controversy regarding the best method for calculating new DVs from the DRIs. To better understand the implications of DV revisions, assuming that manufacturers choose to maintain current label claims for micronutrients from voluntarily fortified foods, we modeled intake of 8 micronutrients using NHANES 2007-2008 data and 2 potential methods for calculating DVs: the population-weighted Estimated Average Requirement (EAR) and the population-coverage RDA. In each scenario, levels of fortified nutrients were adjusted to maintain the current %DV. Usual nutrient intakes and percentages with usual intakes less than the EAR were estimated for the U.S. population and subpopulations aged >= 4 y (n = 7976). For most nutrients, estimates of the percentage of the U.S. population with intakes below the EAR were similar regardless of whether the DV corresponded to the population-weighted EAR or the population-coverage RDA. Potential decreases were observed in adequacy of nutrients of concern for women of childbearing age, namely iron and folate (up to 9% and 3%, respectively), adequacy of calcium among children (up to 6%), and adequacy of vitamin A intakes in the total population (5%) assuming use of the population-weighted EAR compared with the population-coverage RDA for setting the DV. Results of this modeling exercise will help to inform decisions in revising the DVs. C1 [Murphy, Mary M.; Spungen, Judith H.; Barraj, Leila M.] Exponent Inc, Washington, DC USA. [Bailey, Regan L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Dwyer-, Johanna T.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Dwyer-, Johanna T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Dwyer-, Johanna T.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Murphy, MM (reprint author), Exponent Inc, Washington, DC USA. EM mmurphy@exponent.com OI Dwyer, Johanna/0000-0002-0783-1769 FU Fortification Committee of the International Life Sciences Institute, North America, Washington, DC FX Supported by the Fortification Committee of the International Life Sciences Institute, North America, Washington, DC. This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited NR 28 TC 3 Z9 4 U1 0 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD DEC PY 2013 VL 143 IS 12 BP 1999 EP 2006 DI 10.3945/jn.113.181099 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 260CB UT WOS:000327571500018 PM 24132571 ER PT J AU Ames, NJ Peng, C Powers, JH Leidy, NK Miller-Davis, C Rosenberg, A VanRaden, M Wallen, GR AF Ames, Nancy J. Peng, Claudia Powers, John H. Leidy, Nancy Kline Miller-Davis, Claiborne Rosenberg, Alice VanRaden, Mark Wallen, Gwenyth R. TI Beyond Intuition: Patient Fever Symptom Experience SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Fever; symptoms; qualitative research; content validity ID MORTALITY AB Context. Fever is an important sign of inflammation recognized by health care practitioners and family caregivers. However, few empirical data obtained directly from patients exist to support many of the long-standing assumptions about the symptoms of fever. Many of the literature-cited symptoms, including chills, diaphoresis, and malaise, have limited scientific bases, yet they often represent a major justification for antipyretic administration. Objectives. To describe the patient experience of fever symptoms for the preliminary development of a fever assessment questionnaire. Methods. Qualitative interviews were conducted with 28 inpatients, the majority (86%) with cancer diagnoses, who had a recorded temperature of >= 38 degrees C within approximately 12 hours before the interview. A semi-structured interview guide was used to elicit patient fever experiences. Thematic analyses were conducted by three independent research team members, and the data were verified through two rounds of consensus building. Results. Eleven themes emerged. The participants reported experiences of feeling cold, weakness, warmth, sweating, nonspecific bodily sensations, gastrointestinal symptoms, headaches, emotional changes, achiness, respiratory symptoms, and vivid dreams/hallucinations. Conclusion. Our data not only confirm long-standing symptoms of fever but also suggest new symptoms and a level of variability and complexity not captured by the existing fever literature. Greater knowledge of patients' fever experiences will guide more accurate assessment of symptoms associated with fever and the impact of antipyretic treatments on patient symptoms in this common condition. Results from this study are contributing to the content validity of a future instrument that will evaluate patient outcomes related to fever interventions. Published by Elsevier Inc. on behalf of U.S. Cancer Pain Relief Committee. C1 [Ames, Nancy J.; Peng, Claudia; Miller-Davis, Claiborne; Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [VanRaden, Mark] NIAID, Bethesda, MD 20892 USA. [Powers, John H.; Rosenberg, Alice] NCI, Clin Res Directorate CMRP, SAIC Frederick Inc, Frederick, MD 21701 USA. [Leidy, Nancy Kline] United BioSource Corp, Bethesda, MD USA. RP Ames, NJ (reprint author), NIH, Ctr Clin, Bldg 10,Rm 3-5627,10 Ctr Dr, Bethesda, MD 20892 USA. EM names@cc.nih.gov FU National Institutes of Health Intramural Research Program; National Institute of Allergy and Infectious Diseases; National Cancer Institute, NIH [HHSN2612008 00001E] FX Financial support for this project was provided by the National Institutes of Health Intramural Research Program. This research also was supported in part by the National Institute of Allergy and Infectious Diseases.; SAIC funding statements: This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN2612008 00001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor imply endorsement by the U. S. government. The authors declare no conflicts of interest. NR 20 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2013 VL 46 IS 6 BP 807 EP 816 DI 10.1016/j.jpainsymman.2013.02.012 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 262WM UT WOS:000327768600004 PM 23742739 ER PT J AU Aziz, NM Grady, PA Curtis, JR AF Aziz, Noreen M. Grady, Patricia A. Curtis, J. Randall TI Training and Career Development in Palliative Care and End-of-Life Research: Opportunities for Development in the US SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Palliative care; end of life; research training ID EVIDENCE-BASED RECOMMENDATIONS; INTENSIVE-CARE; MEDICAL-EDUCATION; RANDOMIZED-TRIAL; UNITED-STATES; CANCER CARE; PROGRAMS; QUALITY; COMMUNICATION; ADVANCE AB There has been a dramatic increase in attention to the field of palliative care and end-of-life (PCEOL) research over the past 20 years. This increase is particularly notable in the development of palliative care clinical and educational programs. However, there remain important shortcomings in the evidence base to ensure access to and delivery of effective palliative care for patients with life-limiting illness and their families. Development of this evidence base will require that we train the next generation of researchers to focus on issues in PCEOL. The purpose of this article was to explore the current status of the recruitment, training, and retention of future investigators in PCEOL research in the U. S. and propose recommendations to move us forward. Some key contextual issues for developing and supporting this research workforce are articulated, along with timely and important research areas that will need to be addressed during research training and career development. We provide targeted key recommendations to facilitate the nurturing and support of the future research workforce that is needed to ensure the development and implementation of the science necessary for providing high-quality, evidence-based palliative care to all who need and desire it. (C) 2013 U. S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Aziz, Noreen M.; Grady, Patricia A.] NINR, NIH, Bethesda, MD 20892 USA. [Curtis, J. Randall] Univ Washington, Harborview Med Ctr, Div Pulm & Crit Care, Seattle, WA 98104 USA. [Curtis, J. Randall] Univ Washington, Harborview Med Ctr, Dept Med, Palliat Care Ctr Excellence, Seattle, WA 98104 USA. RP Curtis, JR (reprint author), Univ Washington, Harborview Med Ctr, UW Palliat Care Ctr Excellence, Div Pulm & Crit Care Med, Box 359762,325 9th Ave, Seattle, WA 98104 USA. EM jrc@u.washington.edu FU NINR FX This work was supported by NINR. The opinions expressed in this commentary are exclusively those of the authors and do not necessarily reflect the opinions of the funding agency. The authors declare no conflicts of interest. NR 43 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2013 VL 46 IS 6 BP 938 EP 946 DI 10.1016/j.jpainsymman.2013.02.008 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 262WM UT WOS:000327768600015 PM 23631858 ER PT J AU Ferreira, JN Figueiredo, R AF Ferreira, Joao N. Figueiredo, Rui TI Prevention and management of persistent idiopathic facial pain after dental implant placement SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID INFERIOR ALVEOLAR NERVE; OROFACIAL PAIN; POSTOPERATIVE PAIN; ANXIETY; INJURY; SURGERY; NEUROPATHY; HYPNOSIS; TAXONOMY; PROPOSAL C1 [Ferreira, Joao N.] Natl Inst Dent & Craniofacial Res, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Figueiredo, Rui] Univ Barcelona, Sch Dent, Barcelona, Spain. [Figueiredo, Rui] Inst Invest Biomed Bellvitge, Sch Dent, Barcelona, Spain. RP Ferreira, JN (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Ctr Clin, 30 Convent Dr,Bldg 30,Room 429, Bethesda, MD 20892 USA. EM andraderequicj@mail.nih.gov RI Figueiredo, Rui/C-2428-2008; Ferreira, Joao/M-1517-2016 OI Figueiredo, Rui/0000-0002-2122-6530; Ferreira, Joao/0000-0002-4230-4593 FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md FX This study was supported in part by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md. NR 27 TC 1 Z9 1 U1 1 U2 7 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD DEC PY 2013 VL 144 IS 12 BP 1358 EP 1361 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 262JV UT WOS:000327731900009 PM 24282265 ER PT J AU Jackson, SN Woods, AS AF Jackson, Shelley N. Woods, Amina S. TI Imaging of Noncovalent Complexes by MALDI-MS SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article DE Noncovalent complexes; MALDI; Imaging; Electrostatic and hydrophobic interactions; Matrix properties ID ASSISTED-LASER-DESORPTION/IONIZATION; IONIZATION MASS-SPECTROMETRY; PROTEIN COMPLEXES; STRANDED-DNA; PHOSPHATE; RECEPTOR; PEPTIDES; ARGININE; SINGLE AB Noncovalent interactions govern how molecules communicate. Mass spectrometry is an important and versatile tool for the analysis of noncovalent complexes (NCX). Electrospray mass spectrometry (ESI-MS) is the most widely used MS technique for the study of NCXs because of its softer ionization and easy compatibility with the solution phase of NCX mixtures. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has also been used to study NCXs. However, successful analysis depends upon several experimental factors, such as matrix selection, solution pH, and instrumental parameters. In this study, we employ MALDI imaging mass spectrometry to investigate the location and formation of NCXs, involving both peptides and proteins, in a MALDI sample spot. C1 [Jackson, Shelley N.; Woods, Amina S.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov NR 40 TC 3 Z9 3 U1 0 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1044-0305 EI 1879-1123 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD DEC PY 2013 VL 24 IS 12 BP 1950 EP 1956 DI 10.1007/s13361-013-0745-3 PG 7 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 258LF UT WOS:000327460100016 PM 24092630 ER PT J AU Nomani, F Kamal, AK AF Nomani, Fauzia Kamal, Ayeesha Kamran TI Granulocyte-Colony Stimulating factor for mobilizing bone marrow stem cells in the Sub acute Stroke.How safe is the use of Granulocyte-colony stimulating factor in sub-acute stroke? Isthis stem cell trial of recovery enhancement beneficial? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 1 TC 0 Z9 0 U1 0 U2 4 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD DEC PY 2013 VL 63 IS 12 BP 1558 EP 1559 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 263TL UT WOS:000327830800027 PM 24397109 ER PT J AU Saw, J Curtis, DJ Hussey, DJ Dobrovic, A Aplan, PD Slape, CI AF Saw, Jesslyn Curtis, David J. Hussey, Damian J. Dobrovic, Alexander Aplan, Peter D. Slape, Christopher I. TI The fusion partner specifies the oncogenic potential of NUP98 fusion proteins SO LEUKEMIA RESEARCH LA English DT Article DE NUP98; Homeobox; HOX; Leukemia; Translocation ID MYELODYSPLASTIC SYNDROME; MYELOID-LEUKEMIA; GENE; LEUKEMOGENESIS; EXPRESSION; TRANSFORMATION; TRANSCRIPTION; NUCLEOPORIN; NUP98-HOXA9; HOXA9 AB NUP98 is among the most promiscuously translocated genes in hematological diseases. Among the 28 known fusion partners, there are two categories: homeobox genes and non-homeobox genes. The homeobox fusion partners are well-studied in animal models, resulting in HoxA cluster overexpression and hematological disease. The non-homeobox fusion partners are less well studied. We created transgenic animal models for three NUP98 fusion genes (one homeobox, two non-homeobox), and show that in this system, the NUP98-homeobox fusion promotes self-renewal and aberrant gene expression to a significantly greater extent. We conclude that homeobox partners create more potent NUP98 fusion oncogenes than do non-homeobox partners. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Saw, Jesslyn; Curtis, David J.; Slape, Christopher I.] Monash Univ, Australian Ctr Blood Dis, Cent Clin Sch, Div Blood Canc, Melbourne, Vic 3800, Australia. [Hussey, Damian J.] Flinders Univ S Australia, Flinders Med Ctr, Dept Surg, Bedford Pk, SA 5042, Australia. [Dobrovic, Alexander] Ludwig Inst Canc Res, Heidelberg, Vic, Australia. [Dobrovic, Alexander] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Slape, CI (reprint author), Monash Univ, Dept Biochem & Mol Biol, Bldg 77, Melbourne, Vic 3800, Australia. EM christopher.slape@monash.edu RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016; OI Slape, Christopher/0000-0002-8407-3092; Dobrovic, Alexander/0000-0003-3414-112X FU National Health and Medical Research Council of Australia; Cancer Council of Victoria; National Institutes of Health, National Cancer Institute FX We thank Lionel Feigenbaum of the NCI Transgenic core facility for the generation of the mice, animal facility staff for animal care, and Geza Paukovics, Michael Thomson and Jeanne Le Massurier for flow cytometric sorting. This research was supported by the National Health and Medical Research Council of Australia, the Cancer Council of Victoria and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 25 TC 5 Z9 5 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD DEC PY 2013 VL 37 IS 12 BP 1668 EP 1673 DI 10.1016/j.leukres.2013.09.013 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 259PV UT WOS:000327539700014 PM 24090997 ER PT J AU Qi, CF Zhang, RH Sun, JF Li, ZY Shin, DM Wang, HS Kovalchuk, AL Sakai, T Xiong, HB Kon, N Gu, W Morse, HC AF Qi, Chen-Feng Zhang, Ruihua Sun, Jiafang Li, Zhaoyang Shin, Dong-Mi Wang, Hongsheng Kovalchuk, Alexander L. Sakai, Tomomi Xiong, Huabao Kon, Ning Gu, Wei Morse, Herbert C., III TI Homeostatic defects in B cells deficient in the E3 ubiquitin ligase ARF-BPI are restored by enhanced expression of MYC SO LEUKEMIA RESEARCH LA English DT Article DE ARF BP1; MYC; p53; B cell development ID C-MYC; TUMOR-SUPPRESSOR; P53; PROLIFERATION; MICE; DIFFERENTIATION; NEUROGENESIS; ACTIVATION; NEOPLASMS; ARF-BP1 AB The E3 ligase ARF-BP1 governs the balance of life and death decisions by directing the degradation of p53 and enhancing the transcriptional activity of MYC. We find B cells selectively deficient in ARF-BP1 have many defects in developing and mature B cells associated with increased expression of p53 and reduced expression of Myc. Overexpression of Myc results in suppression of p53 and complete reversal of defects induced by ARF-BP1 deficiency. These findings indicate that the dynamic balance between MYC and p53 required for normal B cell maturation and function is finely tuned and critically dependent on the activities of ARF-BP1. Published by Elsevier Ltd. C1 [Qi, Chen-Feng; Sun, Jiafang; Shin, Dong-Mi; Wang, Hongsheng; Kovalchuk, Alexander L.; Sakai, Tomomi; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Zhang, Ruihua; Xiong, Huabao; Kon, Ning] Mt Sinai Sch Med, Dept Med, Inst Immunol, New York, NY USA. [Li, Zhaoyang] Univ Maryland Greenebaum Canc Ctr, Oncol Program, Baltimore, MD USA. [Shin, Dong-Mi] Seoul Natl Univ, Dept Food & Nutr, Seoul, South Korea. [Gu, Wei] Columbia Univ Coll Phys & Surg, Inst Canc Genet, New York, NY 10032 USA. [Gu, Wei] Columbia Univ Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY 10032 USA. RP Qi, CF (reprint author), NIAID, Immunogenet Lab, NIH, 5640 Fishers Lane,Room 1528, Rockville, MD 20852 USA. EM cqi@niaid.nih.gov; hmorse@niaid.nih.gov RI ZHANG, RUIHUA/G-8685-2014 FU NIH, National Institute of Allergy and Infectious Diseases; NIH [RO1CA169246] FX This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases and NIH grant RO1CA169246 to WG. We are indebted to Dr. Alfonso Macias for his contributions to animal management and Dr. Zohreh Naghashfar for her contributions to microarray studies. NR 20 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD DEC PY 2013 VL 37 IS 12 BP 1680 EP 1689 DI 10.1016/j.leukres.2013.09.009 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 259PV UT WOS:000327539700016 PM 24199708 ER PT J AU Lesniak, WG Mishra, MK Jyoti, A Balakrishnan, B Zhang, F Nance, E Romero, R Kannan, S Kannan, RM AF Lesniak, Wojciech G. Mishra, Manoj K. Jyoti, Arnar Balakrishnan, Bindu Zhang, Fan Nance, Elizabeth Romero, Roberto Kannan, Sujatha Kannan, Rangaramanujam M. TI Biodistribution of Fluorescently Labeled PAMAM Dendrimers in Neonatal Rabbits: Effect of Neuroinflammation SO MOLECULAR PHARMACEUTICS LA English DT Article DE PAMAM dendrimer; biodistribution; brain uptake quantification; cellular imaging; pharmacokinetics; neuroinflammation; cerebral palsy ID IN-VIVO BIODISTRIBUTION; POLYAMIDOAMINE DENDRIMERS; COMPOSITE NANODEVICES; MAGNETIC-RESONANCE; POLY(AMIDOAMINE) DENDRIMERS; TOXICITY EVALUATION; CONTRAST AGENTS; SERUM-ALBUMIN; CANCER; NANOPARTICLES AB Dendrimers are being explored in many preclinical studies as drug, gene, and imaging agent delivery systems. Understanding their detailed organ, tissue, cellular uptake, and retention can provide valuable insights into their effectiveness as delivery vehides and the associated toxicity. This work explores a fluorescence-quantification based assay that enables simultaneous quantitative biodistribution and imaging of dendrimers with a single agent. We have labeled an ethylenediamine-core generation-4 hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer using the fluorescent photostable, near-IR cyanine dye (Cy5) and performed quantitative and qualitative biodistribution of the dendrimer-Cy5 conjugates (D-Cy5) in healthy neonatal rabbits and neonatal rabbits with cerebral palsy (CP). The biodistribution of D-Cy5 and free Cy5 dye was evaluated in newborn rabbits, based on the developed quantification methods using fluorescence spectroscopy, high-performance liquid chromatography (HPLC), and size exclusion chromatography (SEC) and supported by microscopic imaging. The uptake was assessed in the brain, heart, liver, lungs, kidneys, blood serum, and urine. Results obtained based on these three independent methods are in good agreement and indicate the fast renal clearance of D-Cy5 and free Cy5 with relatively higher organs accumulation of the D-Cy5 conjugate. Following systemic administration, the D-Cy5 mainly accumulated in kidneys and bladder at 24 h. The quantitative biodistribution is in good agreement with previous studies based on radiolabeling. These methods for dendrimers quantification are easier and more practical, provide excellent sensitivity (reaching 0.1 ng per gram of tissue), and allow for quantification of dendrimers in different organs over longer time periods without concerns for radioactive decay, while also enabling tissue and cellular imaging in the same animal. In kits with fetal-neuroinflarnmation induced CP, there was a significantly higher uptake of D-Cy5 in the brain, while biodistribution in other organs was similar to that of healthy kits. C1 [Lesniak, Wojciech G.; Mishra, Manoj K.; Zhang, Fan; Kannan, Rangaramanujam M.] Johns Hopkins Sch Med, Dept Ophthalmol, Ctr Nanomed, Baltimore, MD 21287 USA. [Jyoti, Arnar; Balakrishnan, Bindu; Nance, Elizabeth; Kannan, Sujatha] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. RP Kannan, RM (reprint author), Johns Hopkins Sch Med, Dept Ophthalmol, Ctr Nanomed, Baltimore, MD 21287 USA. EM krangar1@jhmi.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH; NICHD [R01HD069562-02] 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), NIH, and by NICHD R01HD069562-02 (S.K). NR 41 TC 23 Z9 23 U1 1 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD DEC PY 2013 VL 10 IS 12 BP 4560 EP 4571 DI 10.1021/mp400371r PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 263TS UT WOS:000327831500017 PM 24116950 ER PT J AU Kachko, A Loesgen, S Shahzad-ul-Hussan, S Tan, W Zubkova, I Takeda, K Wells, F Rubin, S Bewley, CA Major, ME AF Kachko, Alla Loesgen, Sandra Shahzad-ul-Hussan, Syed Tan, Wendy Zubkova, Iryna Takeda, Kazuyo Wells, Frances Rubin, Steven Bewley, Carole A. Major, Marian E. TI Inhibition of Hepatitis C Virus by the Cyanobacterial Protein Microcystis viridis Lectin: Mechanistic Differences between the High-Mannose Specific Lectins MVL, CV-N, and GNA SO MOLECULAR PHARMACEUTICS LA English DT Article DE hepatitis C; antiviral lectin; HCV entry inhibitor; cyanovirin-N (CV-N); HCVcc; biolayer interferometry ID HUMAN-IMMUNODEFICIENCY-VIRUS; CARBOHYDRATE-BINDING AGENTS; REVEALS EXTENDED MICROHETEROGENEITY; HIGH-AFFINITY BINDING; ANTI-HIV ACTIVITY; CYANOVIRIN-N; ENVELOPE GLYCOPROTEINS; GALANTHUS-NIVALIS; IMMUNE-RESPONSES; STRUCTURAL BASIS AB Plant or microbial lectins are known to exhibit potent antiviral activities against viruses with glycosylated surface proteins, yet the mechanism(s) by which these carbohydrate-binding proteins exert their antiviral activities is not fully understood. Hepatitis C virus (HCV) is known to possess glycosylated envelope proteins (gpE1E2) and to be potently inhibited by lectins. Here, we tested in detail the antiviral properties of the newly discovered Microcystis viridis lectin (MVL) along with cyanovirin-N (CV-N) and Galanthus nivalis agglutinin (GNA) against cell culture HCV, as well as their binding properties toward viral particles, target cells, and recombinant HCV glycoproteins. Using infectivity assays, CV-N, MVL, and GNA inhibited HCV with IC50 values of 0.6 nM, 30.4 nM, and 11.1 nM, respectively. Biolayer interferometry analysis demonstrated a higher affinity of GNA to immobilized recombinant HCV glycoproteins compared to CV-N and MVL. Complementary studies, including fluorescence-activated cell sorting (FACS) analysis, confocal microscopy, and pre- and post-virus binding assays, showed a complex mechanism of inhibition for CV-N and MVL that includes both viral and cell association, while GNA functions by binding directly to the viral particle. Combinations of GNA with CV-N or MVL in HCV infection studies revealed synergistic inhibitory effects, which can be explained by different glycan recognition profiles of the mainly high-mannoside specific lectins, and supports the hypothesis that these lectins inhibit through different and complex modes of action. Our findings provide important insights into the mechanisms by which lectins inhibit HCV infection. Overall, the data suggest MVL and CV-N have the potential for toxicity due to interactions with cellular proteins while GNA may be a better therapeutic agent due to specificity for the HCV gpE1E2. C1 [Kachko, Alla; Tan, Wendy; Zubkova, Iryna; Wells, Frances; Major, Marian E.] US FDA, Ctr Biol Evaluat & Res, Lab Hepatitis Viruses, Div Viral Prod, Bethesda, MD 20892 USA. [Takeda, Kazuyo] US FDA, Ctr Biol Evaluat & Res, Microscopy & Imaging Core Facil, Bethesda, MD 20892 USA. [Rubin, Steven] US FDA, Ctr Biol Evaluat & Res, Lab Method Dev, Div Viral Prod, Bethesda, MD 20892 USA. [Loesgen, Sandra; Shahzad-ul-Hussan, Syed; Bewley, Carole A.] NIAID, Bioorgan Chem Lab, Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Shahzad-ul-Hussan, Syed] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Major, ME (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Hepatitis Viruses, Div Viral Prod, Bethesda, MD 20892 USA. EM Marian.Major@fda.hhs.gov FU Food and Drug Administration Intramural Research Program; Intramural Research Program, National Institutes of Health (NIDDK); Intramural AIDS Targeted Antiviral Program, Office of the Director (CAB) FX The authors thank Drs. Alain Debrabant and Rana Nagatkatti, Center for Biologics Evaluation and Research, FDA, for the usage of their Octet red 96 system. This work was supported by Food and Drug Administration Intramural Research Program, the Intramural Research Program, National Institutes of Health (NIDDK), and the Intramural AIDS Targeted Antiviral Program, Office of the Director (CAB). NR 57 TC 6 Z9 6 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD DEC PY 2013 VL 10 IS 12 BP 4590 EP 4602 DI 10.1021/mp400399b PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 263TS UT WOS:000327831500019 PM 24152340 ER PT J AU Rosenberg, HF Foster, PS AF Rosenberg, Helene F. Foster, Paul S. TI Eosinophil cytolysis and release of cell-free granules SO NATURE REVIEWS IMMUNOLOGY LA English DT Letter ID PIECEMEAL DEGRANULATION; SECRETION; MECHANISM C1 [Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, NIH, Bethesda, MD 20892 USA. [Foster, Paul S.] Univ Newcastle, Fac Hlth, Prior Res Ctr Asthma & Resp Dis, Hunter Med Res Inst, Newcastle, NSW 2300, Australia. [Foster, Paul S.] Univ Newcastle, Fac Hlth, Sch Biomed Sci & Pharm, Newcastle, NSW 2300, Australia. RP Rosenberg, HF (reprint author), NIAID, Inflammat Immunobiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov; paul.foster@newcastle.edu.au NR 12 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 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD DEC PY 2013 VL 13 IS 12 DI 10.1038/nri3341-c2 PG 1 WC Immunology SC Immunology GA 262EU UT WOS:000327717900016 ER PT J AU Canepa, M Strait, JB Milaneschi, Y AlGhatrif, M Ramachandran, R Makrogiannis, S Moni, M David, M Brunelli, C Lakatta, EG Ferrucci, L AF Canepa, M. Strait, J. B. Milaneschi, Y. AlGhatrif, M. Ramachandran, R. Makrogiannis, S. Moni, M. David, M. Brunelli, C. Lakatta, E. G. Ferrucci, L. TI The relationship between visceral adiposity and left ventricular diastolic function: Results from the Baltimore Longitudinal Study of Aging SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE Adiposity; Diastolic function; Triglycerides; Sex hormone-binding globulin; Adipokines ID ALL-CAUSE MORTALITY; HEART-DISEASE; OBESITY; ASSOCIATION; ADIPONECTIN; STIFFNESS; ARTERIAL; LEPTIN; FAT AB Background and aims: It is unclear whether subcutaneous and visceral fat are differentially correlated to the decline in left ventricular (LV) diastolic function with aging. This study sought to examine the hypothesis that age-related changes in the regional fat distribution account for changes in LV diastolic function and to explore potential mediators of this association. Methods and results: In this cross-sectional study, we evaluated 843 participants of the Baltimore Longitudinal Study of Aging with echocardiogram, dual-energy X-ray absorptiometry (DEXA), abdominal computed tomography (CT) and blood tests performed at the same visit. LV diastolic function was assessed by parameters of LV relaxation (E/A ratio, Em and Em/Am ratio) and LV filling pressures (E/Em ratio). Total body fat was computed by DEXA, while visceral and subcutaneous fat were determined from abdominal CT. In multivariate models adjusted for demographics, cardiovascular risk factors, antihypertensive medications, physical activity and LV mass, both visceral and subcutaneous fat were associated with LV diastolic dysfunction. When both measures of adiposity were simultaneously included in the same model, only visceral fat was significantly associated with LV diastolic dysfunction. Triglycerides and sex-hormone binding globulin, but not adiponectin and leptin, were found to be significant mediators of the relationship between visceral fat and LV diastolic function, explaining 28-47% of the association. Bootstrapping analyses confirmed the significance of these findings. Conclusions: Increased visceral adiposity is associated with LV diastolic dysfunction, possibly through a metabolic pathway involving blood lipids and ectopic fat accumulation rather than adipokines. Published by Elsevier B.V. C1 [Canepa, M.; Strait, J. B.; Milaneschi, Y.; Ramachandran, R.; Makrogiannis, S.; David, M.; Ferrucci, L.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21225 USA. [Canepa, M.; Strait, J. B.; AlGhatrif, M.; Moni, M.; Lakatta, E. G.] NIA, Lab Cardiovasc Sci, Human Cardiovasc Studies Unit, NIH, Baltimore, MD 21225 USA. [Canepa, M.; Brunelli, C.] Univ Genoa, Res Ctr Cardiovasc Biol, Genoa, Italy. [Milaneschi, Y.] VU Univ Med Center GGZ inGeest, Dept Psychiat, Amsterdam, Netherlands. [AlGhatrif, M.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP Canepa, M (reprint author), NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH,Harbor Hosp Ctr, 3001 S Hanover St, Baltimore, MD 21225 USA. EM marco.canepa@nih.gov FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 31 TC 14 Z9 14 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0939-4753 EI 1590-3729 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD DEC PY 2013 VL 23 IS 12 BP 1263 EP 1270 DI 10.1016/j.numecd.2013.04.003 PG 8 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA 267EG UT WOS:000328078900016 PM 23809149 ER PT J AU Epstein, MS Ephros, HD Epstein, JB AF Epstein, Matthew S. Ephros, Hillel D. Epstein, Joel B. TI Review of current literature and implications of RANKL inhibitors for oral health care providers SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Review ID BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; MULTIPLE-MYELOMA; BREAST-CANCER; OSTEOCLAST DIFFERENTIATION; PROSTATE-CANCER; JAW ONJ; DENOSUMAB; OSTEONECROSIS; THERAPY AB Bisphosphonates (BPs) were the first class of drugs commonly used to prevent skeletal-related events (SRE) in patients with osteoporosis, multiple myeloma (MM), or solid tumors with metastases to bone. A new alternative class of agents, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, are now available for use in these indications and have the potential to replace intravenous BPs. This paper presents a review of the current literature on denosumab and its association with osteonecrosis of the jaw (ONJ). Denosumab is a RANKL inhibitor that has recently been approved for the prevention of SRE for the same indications as BPs except for MM. Although the overall frequency of denosumab-related ONJ may be similar or higher than estimates of the occurrence rate of bisphosphonate-related ONJ, evidence continues to support appropriate planning and preventive care can reduce the likelihood of adverse effects, including osteonecrosis. C1 [Epstein, Matthew S.; Ephros, Hillel D.] St Josephs Reg Med Ctr, Paterson, NJ USA. [Ephros, Hillel D.] Seton Hall Univ, Sch Hlth & Med Sci, S Orange, NJ 07079 USA. [Epstein, Joel B.] NCI, Div Otolaryngol & Head & Neck Surg, City Hope, Duarte, CA USA. [Epstein, Joel B.] Cedars Sinai Hlth Syst, Los Angeles, CA USA. RP Epstein, MS (reprint author), St Josephs Reg Med Ctr, 523 Washington St,Apt 2, Hoboken, NJ 07030 USA. EM epsteinmatthew@gmail.com NR 39 TC 9 Z9 9 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 EI 1528-395X J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD DEC PY 2013 VL 116 IS 6 BP E437 EP E442 DI 10.1016/j.oooo.2012.01.046 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 258BN UT WOS:000327433200004 PM 22901640 ER PT J AU Webster, LR Provan, PJ Graham, DJ Byth, K Walker, RL Davis, S Salisbury, EL Morey, AL Ward, RL Hawkins, NJ Clarke, CL Meltzer, PS Balleine, RL AF Webster, Lucy R. Provan, Pamela J. Graham, Dinny J. Byth, Karen Walker, Robert L. Davis, Sean Salisbury, Elizabeth L. Morey, Adrienne L. Ward, Robyn L. Hawkins, Nicholas J. Clarke, Christine L. Meltzer, Paul S. Balleine, Rosemary L. TI Prohibitin expression is associated with high grade breast cancer but is not a driver of amplification at 17q21.33 SO PATHOLOGY LA English DT Article DE Breast cancer; genomic amplification; grade; prohibitin ID COMPARATIVE GENOMIC HYBRIDIZATION; IN-SITU HYBRIDIZATION; REGION POLYMORPHISM; CELL-LINES; ER STATUS; ARRAY; RISK; MYC; SENSITIVITY; PROTEINS AB Aims:In a study of ductal carcinoma in situ of the breast, we identified five genes at chromosome 17q21.33 that were over-expressed in high grade cases, and showed a correlation between expression and gene copy number. The aim of this study was to investigate potential drivers of genomic amplification at 17q21.33.Methods:Analysis of high resolution comparative genomic hybridisation and published data specified a minimum region of amplification at 17q21.33. Prohibitin (PHB) expression was examined by immunohistochemistry in 285 invasive breast cancers. Gene copy number was examined by fluorescence in situ hybridisation.Results:The minimum region of amplification at 17q21.33 included ten genes with PHB selected as a candidate driver. Increased PHB expression was associated with higher grade breast cancer and poorer survival. Amplification of PHB was detected in 13 of 235 cases (5.5%) but was not associated with PHB expression. PHB amplification was most common in the ERBB2+ breast cancer subtype, although high expression was most prevalent in basal-like and luminal B cancers.Conclusions:Amplification at 17q21.33 is a recurrent feature of breast cancer that forms part of a firestorm' pattern of genomic aberration. PHB is not a driver of amplification, however PHB may contribute to high grade breast cancer. C1 [Webster, Lucy R.; Provan, Pamela J.; Graham, Dinny J.; Byth, Karen; Clarke, Christine L.; Balleine, Rosemary L.] Univ Sydney, Sydney Med Sch Westmead, Westmead, NSW 2145, Australia. [Webster, Lucy R.; Provan, Pamela J.; Graham, Dinny J.; Clarke, Christine L.; Balleine, Rosemary L.] Westmead Inst Canc Res, Westmead, NSW, Australia. [Webster, Lucy R.; Provan, Pamela J.; Graham, Dinny J.; Byth, Karen; Clarke, Christine L.; Balleine, Rosemary L.] Westmead Millennium Inst, Westmead, NSW, Australia. [Salisbury, Elizabeth L.] Westmead Hosp, Inst Clin Pathol & Med Res, Westmead, NSW 2145, Australia. [Webster, Lucy R.; Provan, Pamela J.; Clarke, Christine L.; Balleine, Rosemary L.] Western Sydney & Nepean Blue Mt Local Hlth Dist, Sydney West Canc Network, Westmead, NSW, Australia. [Morey, Adrienne L.] St Vincents Hosp, Darlinghurst, NSW 2010, Australia. [Ward, Robyn L.] Univ New S Wales, Prince Wales Clin Sch, Randwick, NSW, Australia. [Hawkins, Nicholas J.] Univ New S Wales, Sch Med Sci, Randwick, NSW, Australia. [Webster, Lucy R.] Charles Sturt Univ, Sch Biomed Sci, Wagga Wagga, NSW, Australia. [Walker, Robert L.; Davis, Sean; Meltzer, Paul S.] NCI, Genet Branch, Bethesda, MD 20892 USA. RP Balleine, RL (reprint author), Westmead Hosp, Inst Clin Pathol & Med Res, Westmead, NSW 2145, Australia. EM rosemary.balleine@sydney.edu.au RI Ward, Robyn/I-2313-2013; Hawkins, Nicholas/A-8461-2008; OI Ward, Robyn/0000-0002-6877-8906; Hawkins, Nicholas/0000-0002-2204-3189; Davis, Sean/0000-0002-8991-6458 FU Cure Cancer Australia Foundation; National Health and Medical Research Council of Australia (NHMRC) [306700]; Cancer Institute New South Wales (CINSW); University of Sydney FX This work was supported by funding by the Cure Cancer Australia Foundation, the National Health and Medical Research Council of Australia (NHMRC; grant number 306700), the Cancer Institute New South Wales (CINSW) and the University of Sydney Cancer Research Fund. RLB was a CINSW Fellow. The authors state that there are no conflicts of interest to disclose. NR 37 TC 1 Z9 1 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0031-3025 EI 1465-3931 J9 PATHOLOGY JI Pathology PD DEC PY 2013 VL 45 IS 7 BP 629 EP 636 DI 10.1097/PAT.0000000000000004 PG 8 WC Pathology SC Pathology GA 261CF UT WOS:000327640800001 PM 24247619 ER PT J AU Colon-Lopez, V Banerjee, G Gertz, AM Ortiz, AP Calo, W Finney-Rutten, LJ Colon-Ramos, U Hesse, BW Tortolero, G AF Colon-Lopez, Vivian Banerjee, Geetanjoli Gertz, Alida Maria Ortiz, Ana Patricia Calo, William Finney-Rutten, Lila J. Colon-Ramos, Uriyoan Hesse, Bradford W. Tortolero, Guillermo TI Behavioral Correlates of Fruit and Vegetable Intake in Puerto Rico: Results from the Health Information National Trends Survey SO PUERTO RICO HEALTH SCIENCES JOURNAL LA English DT Article DE Puerto Rico; Fruit and Vegetable Intake Recommendations; Nutrition; HINTS ID NON-HISPANIC WHITES; UNITED-STATES; CANCER; CONSUMPTION; DISPARITIES; PREVALENCE; BLACKS; RICANS AB Objective: A diet high in fruit and vegetables (FV) is associated with a decreased risk for chronic diseases, such as cancer. Limited information exists regarding the factors associated with FV intake in persons living in Puerto Rico. The objective of this study was to examine sociodemographic, behavioral, and health-belief factors associated with dietary habits in Puerto Rico. Methods: Secondary data analysis of adults aged 18 years and older from the Puerto Rico Health Information National Trends Survey (HINTS-PR) conducted in 2009. Multivariate logistic regression models were used to identify factors associated with meeting the established recommendations for FV consumption. Results: Only 14.5% of the adults in Puerto Rico met the recommendations for daily FV intake, and the vast majority (90.9%) were unaware of current recommendations. Bivariate analyses demonstrated that being obese, having lower than a high school education, and not knowing the recommendations were significantly associated with not meeting these recommendations. In the multivariate logistic regression analysis, being obese (OR = 3.77; 95% CI = 1.41-10.08) and not being aware of the current dietary recommendations (OR = 9.26; 95% CI = 3.77-22.73) continued to be significantly associated with not meeting the FV intake recommendations. Conclusion: The Puerto Rican population is far from meeting FV consumption recommendations, with prevalence estimates of consumption that are below the US median. Low FV intake might put the population in Puerto Rico at increased risk of developing cancer as well as a number of other chronic diseases that are secondary both to improper nutrition and to obesity. C1 [Colon-Lopez, Vivian] Univ Puerto Rico, Grad Sch Publ Hlth, Dept Hlth Serv Adm, San Juan, PR 00936 USA. [Colon-Lopez, Vivian; Banerjee, Geetanjoli; Ortiz, Ana Patricia; Tortolero, Guillermo] Univ Puerto Rico, Ctr Comprehens Canc, Canc Control & Populat Sci Program, San Juan, PR 00936 USA. [Banerjee, Geetanjoli] Yale Univ, Sch Publ Hlth, Dept Epidemiol, New Haven, CT USA. [Gertz, Alida Maria] Johns Hopkins Univ Hosp, Dept Internal Med, Baltimore, MD 21287 USA. [Ortiz, Ana Patricia] Univ Puerto Rico, Grad Sch Publ Hlth, Dept Biostat & Epidemiol, San Juan, PR 00936 USA. [Calo, William] Univ Texas Houston, Sch Publ Hlth, Div Management Policy & Community Hlth, Houston, TX USA. [Finney-Rutten, Lila J.] Frederick Natl Canc Inst, SAIC Inc, Frederick, MD USA. [Colon-Ramos, Uriyoan] George Washington Univ, Dept Global Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Hesse, Bradford W.] NCI, Bethesda, MD 20892 USA. RP Colon-Lopez, V (reprint author), Univ Puerto Rico, Sch Publ Hlth, Med Sci Campus,POB 36937, San Juan, PR 00936 USA. EM vivian.colon@upr.edu OI Hesse, Bradford/0000-0003-1142-1161 FU Centers for Disease Control and Prevention, Hispanic-Serving Health Professions School [U50/325128-02]; National Institutes of Health, National Cancer Institute [HHSN261200800001E]; Hispanic-Serving Health Professions Schools; NCI FX The project described herein was supported by the Centers for Disease Control and Prevention, Hispanic-Serving Health Professions School (U50/325128-02), and a grant from the National Institutes of Health, National Cancer Institute (HHSN261200800001E). In addition, this study could not have been accomplished without the help of the University of Puerto Rico, Medical Sciences Campus, Comprehensive Cancer Center staff, especially Lorena Gonzalez Sepulveda, epidemiology student; Lizbeth Del Toro Mejias; and, finally, Adriana Font and Alexandra Acosta, undergraduate research assistants from the University of Puerto Rico, Rio Piedras Campus. We would like to thank the Hispanic-Serving Health Professions Schools and the NCI, as well, for their financial support. NR 24 TC 9 Z9 9 U1 0 U2 8 PU UNIV PUERTO RICO MEDICAL SCIENCES CAMPUS PI SAN JUAN PA OFFICE DEAN ACADEMIC AFFAIRS BOX 365067, SAN JUAN, PR 00936-5067 USA SN 0738-0658 J9 P R HEALTH SCI J JI P. R. Health Sci. J. PD DEC PY 2013 VL 32 IS 4 BP 194 EP 199 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 259PM UT WOS:000327538800006 PM 24397217 ER PT J AU Pollack, AZ Louis, GMB Chen, Z Peterson, CM Sundaram, R Croughan, MS Sun, LP Hediger, ML Stanford, JB Varner, MW Palmer, CD Steuerwald, AJ Parsons, PJ AF Pollack, Anna Z. Louis, Germaine M. Buck Chen, Zhen Peterson, C. Matthew Sundaram, Rajeshwari Croughan, Mary S. Sun, Liping Hediger, Mary L. Stanford, Joseph B. Varner, Michael W. Palmer, Christopher D. Steuerwald, Amy J. Parsons, Patrick J. TI Trace elements and endometriosis: The ENDO Study SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Arsenic; Cadmium; Chromium; Endometriosis; Lead; Metals; Mercury; Trace elements ID PLASMA-MASS SPECTROMETRY; OXIDATIVE STRESS; URINE CADMIUM; WOMEN; EXPOSURE; MERCURY; LEAD; BLOOD; ASSOCIATION; CLASSIFICATION AB There has been limited study of trace elements and endometriosis. Using a matched cohort design, 473 women aged 18-44 years were recruited into an operative cohort, along with 131 similarly aged women recruited into a population cohort. Endometriosis was defined as surgically visualized disease in the operative cohort, and magnetic resonance imaging diagnosed disease in the population cohort. Twenty trace elements in urine and three in blood were quantified using inductively coupled plasma mass spectrometry. Logistic regression estimated the adjusted odds (a0R) of endometriosis diagnosis for each element by cohort. No association was observed between any element and endometriosis in the population cohort. In the operative cohort, blood cadmium was associated with a reduced odds of diagnosis (aOR = 0.55; 95% CI: 0.31, 0.98), while urinary chromium and copper reflected an increased odds (aOR = 1.97; 95% CI: 1.21,3.19; aOR = 2.66; 95% CI: 1.26, 5.64, respectively). The varied associations underscore the need for continued research. Published by Elsevier Inc. C1 [Pollack, Anna Z.; Louis, Germaine M. Buck; Chen, Zhen; Sundaram, Rajeshwari; Sun, Liping; Hediger, Mary L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Peterson, C. Matthew] Univ Utah, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Salt Lake City, UT 84108 USA. [Croughan, Mary S.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94110 USA. [Croughan, Mary S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94110 USA. [Stanford, Joseph B.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84108 USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Div Maternal Fetal Med, Salt Lake City, UT 84132 USA. [Palmer, Christopher D.; Steuerwald, Amy J.; Parsons, Patrick J.] New York State Dept Hlth, Lab Inorgan & Nucl Chem, Wadsworth Ctr, Albany, NY 12201 USA. [Palmer, Christopher D.; Steuerwald, Amy J.; Parsons, Patrick J.] SUNY Albany, Dept Environm Hlth Sci, Albany, NY 12201 USA. RP Pollack, AZ (reprint author), NICHD, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM pollacka@mail.nih.gov RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; Pollack, Anna/0000-0002-4313-3298; Parsons, Patrick/0000-0001-9133-875X; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health [NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02] FX Funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (Contracts NO1-DK-6-3428; NO1-DK-6-3427; 10001406-02; 10001406-02). Ethicon Endo-Surgery, LLC donated HARMONIC (R) ACE 36P shears and scalpel blades through a signed Materials Transfer Agreement with the University of Utah and NICHD. The authors acknowledge the efforts of Dr. Anne M. Kennedy for reading the MRI images. NR 54 TC 11 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD DEC PY 2013 VL 42 BP 41 EP 48 DI 10.1016/j.reprotox.2013.05.009 PG 8 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 260BD UT WOS:000327569100005 PM 23892002 ER PT J AU Sadowski, SM He, M Gesuwan, K Gulati, N Celi, F Merino, MJ Nilubol, N Kebebew, E AF Sadowski, Samira M. He, Mei Gesuwan, Krisana Gulati, Neelam Celi, Francesco Merino, Maria J. Nilubol, Naris Kebebew, Electron TI Prospective screening in familial nonmedullary thyroid cancer SO SURGERY LA English DT Article ID CARCINOMA; MANAGEMENT AB Background. Approximately 8% of nonmedullary thyroid cancers are familial. The optimal age for screening in familial nonmedullary thyroid cancer (FNMTC) is unknown. Methods. Kindreds with FNMTC (2 or more first-degree relatives affected) were screened prospectively with thyroid ultrasonography. Results. Fifteen kindreds showed an overall prevalence of thyroid nodule(s) >= 5 mm of 44% at screening; 19% in the second generation, and 90% in the generation anterior to the index case. The youngest age of detection was 10 years for thyroid nodules and 18 years for thyroid cancer. Microcalcification of thyroid nodules at screening was associated with a greater risk of cancer (P < .05). Family members diagnosed with thyroid cancer by ultrasonographic screening were diagnosed at a younger age and had a lower rate of extra thyroidal invasion (P < .05). Conclusion. In FNMTC, first-degree relatives 10 years or older, including the generation anterior to the index case, should have thyroid screening by ultrasonography, which may result in earlier diagnosis. C1 [Sadowski, Samira M.; He, Mei; Gesuwan, Krisana; Gulati, Neelam; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Celi, Francesco] NCI, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Translat Surg Pathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Sadowski, SM (reprint author), NCI, Endocrine Oncol Branch, NIH, Clin Res Ctr, Bldg 10-CRC,Room 3W-5840, Bethesda, MD 20892 USA. EM samira.sadowskiveuthey@nih.gov FU Center for Cancer Research, National Cancer Institute and National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health FX This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute and National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health. NR 16 TC 8 Z9 9 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2013 VL 154 IS 6 BP 1194 EP 1198 DI 10.1016/j.surg.2013.06.019 PG 5 WC Surgery SC Surgery GA 260BY UT WOS:000327571200014 PM 23978593 ER PT J AU Patel, D Boufraqech, M Jain, M Zhang, L He, M Gesuwan, K Gulati, N Nilubol, N Fojo, T Kebebew, E AF Patel, Dhaval Boufraqech, Myriem Jain, Meenu Zhang, Lisa He, Mei Gesuwan, Krisana Gulati, Neelam Nilubol, Nails Fojo, Tito Kebebew, Electron TI M1R-34a and miR-483-5p are candidate serum biomarkers for adrenocortical tumors SO SURGERY LA English DT Article ID MICRORNA; CANCER AB Background. Nonfunctioning adrenal incidentalomas are common and many patients undergo adrenalectomy to exclude adrenocortical. carcinoma (ACC). Recent studies have shown dysregulated microRNA (miRNA) expression in ACC. The objective of this study was to determine the feasibility and diagnostic accuracy of measuring serum miRNAs in patients with benign and malignant adrenocortical neoplasms. Method. Five miRNAs were selected from miRNA profiling studies in ACC (miR-let-7d, -34a, -195, -214, and 483-5p). Total miRNA was extracted from serum samples in patients with malignant and benign adrenal neoplasms. miRNAs levels w. ere measured by quantitative reverse transcript polymerase chain reaction and normalized to miR-16. To determine if miRNAs were secreted from ACC cells, we measured miRNA levels in culture. Results. Serum samples from 22 patients with cortical adenomas and 17 patients with ACC were analyzed, and all 5 miRNAs were detected. We found greater levels of miR-34a (P =.001) and miR-4835p (P =.011) in patients with ACC. The area under the receiver operating characteristic curve was 0.81 for miR-34a and 0.74 for miR-438-5p. MiR-34a and miR-483-5p levels in ACC cells were greater in the supernatant at 48 hours compared with intracellular levels. Conclusion. We show that dysregulated miRNAs in ACC are detectable in human serum samples. MiR34a and miR-483-5p are candidate serum biomarkers for distinguishing between benign and malignant adrenocortical tumors. C1 [Patel, Dhaval; Boufraqech, Myriem; Jain, Meenu; Zhang, Lisa; He, Mei; Gesuwan, Krisana; Gulati, Neelam; Nilubol, Nails; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Patel, D (reprint author), NCI, Endocrine Oncol Branch, NIH, Clin Res Ctr, Bldg 10-CRC,Room 3-5840, Bethesda, MD 20892 USA. EM pateldt@mail.nih.gov RI Boufraqech, Myriem/E-4823-2016 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 18 TC 24 Z9 27 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2013 VL 154 IS 6 BP 1224 EP 1228 DI 10.1016/j.surg.2013.06.022 PG 5 WC Surgery SC Surgery GA 260BY UT WOS:000327571200022 PM 24238045 ER PT J AU Kaplan, SA Lee, JY O'Neill, EA Meehan, AG Kusek, JW AF Kaplan, Steven A. Lee, Jeannette Y. O'Neill, Edward A. Meehan, Alan G. Kusek, John W. TI Prevalence of low testosterone and its relationship to body mass index in older men with lower urinary tract symptoms associated with benign prostatic hyperplasia SO AGING MALE LA English DT Article DE Benign prostatic hyperplasia; lower urinary tract symptoms; Medical Therapy of Prostatic Symptoms trial; testosterone deficiency ID NUTRITION EXAMINATION SURVEY; HORMONE-BINDING GLOBULIN; LATE-ONSET HYPOGONADISM; 3RD NATIONAL-HEALTH; MIDDLE-AGED MEN; METABOLIC SYNDROME; ANDROGEN DEFICIENCY; ERECTILE DYSFUNCTION; REPLACEMENT THERAPY; ELDERLY-MEN AB Purpose: We examined the prevalence of low testosterone (LT) and its relationship with body mass index (BMI) in men with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), who were enrolled in a clinical trial of drug therapy, the Medical Therapy of Prostatic Symptoms (MTOPS) Study. Materials and methods: MTOPS enrolled 3047 men, and of these, 1896 had total testosterone (TT) measured at baseline. LT was defined as a single measurement of TT of <5300 ng/dL. Results: The overall prevalence of LT was 25.7%. Prevalence increased with increasing BMI; 14.7% among men who were normal weight (BMI <525 kg/m(2)) and 24.2% and 39.3% among overweight (BMI 25 to <530 kg/m(2)), and obese (baseline BMI >= 30 kg/m(2)) men, respectively. Conclusions: LT was observed in about one in four MTOPS study participants with baseline TT measurements. The prevalence of LT increased markedly with increasing BMI. Our findings suggest a high prevalence of LT in obese men with LUTS/BPH. Physicians should be alert to the possibility of symptoms of hypogonadism in this population. C1 [Kaplan, Steven A.] Weill Cornell Med Coll, New York, NY USA. [Lee, Jeannette Y.] Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. [O'Neill, Edward A.; Meehan, Alan G.] Merck & Co Inc, Whitehouse Stn, NJ USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. RP Kaplan, SA (reprint author), Cornell Univ, Weill Cornell Med Coll, Inst Bladder & Prostate Hlth, 525 East 68th St F9 West,Box 261, New York, NY 10065 USA. EM kaplans@med.cornell.edu FU National Institute of Diabetes, Digestive and Kidney Diseases [U01 DK49977, U01 DK46416, U01 DK41418, U01 DK46429, U01 DK46431, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49880, U01 DK 49912, U01 DK49921, U01 DK49951, U01 DK49954, U01 DK49960, U01 DK49961, U01 DK49963, U01 DK49964, U01 DK49971, U01 DK49980]; National Center for Minority Health and Health Disparities; NIH; Merck; Pfizer FX S.A.K. has received compensation from Merck & Co., Inc. A.G.M. and E.A.O. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA, and may hold stock/stock options in the company. J.W.K. and J.Y.L. have no disclosures to report. MTOPS was supported by the following cooperative agreements from the National Institute of Diabetes, Digestive and Kidney Diseases: U01 DK49977, U01 DK46416, U01 DK41418, U01 DK46429, U01 DK46431, U01 DK46437, U01 DK46468, U01 DK46472, U01 DK49880, U01 DK 49912, U01 DK49921, U01 DK49951, U01 DK49954, U01 DK49960, U01 DK49961, U01 DK49963, U01 DK49964, U01 DK49971, U01 DK49980, as well as by the National Center for Minority Health and Health Disparities, NIH. Financial support and drug products for MTOPS were also provided by Merck and Pfizer. NR 35 TC 7 Z9 8 U1 1 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1368-5538 EI 1473-0790 J9 AGING MALE JI Aging Male PD DEC PY 2013 VL 16 IS 4 BP 169 EP 172 DI 10.3109/13685538.2013.844786 PG 4 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 259CU UT WOS:000327505800005 PM 24134648 ER PT J AU Wendler, D AF Wendler, David TI What Should Be Disclosed to Research Participants? SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE informed consent; research; disclosure; risks ID CLINICAL-TRIALS; HEALTH-CARE; SUPPORT; FRAMEWORK; CANCER; OHRP; VIEW AB Debate surrounding the SUPPORT study highlights the absence of consensus regarding what information should be disclosed to potential research participants. Some commentators endorse the view that clinical research should be subject to high disclosure standards, even when it is testing standard-of-care interventions. Others argue that trials assessing standard-of-care interventions need to disclose only the information that is disclosed in the clinical care setting. To resolve this debate, it is important to identify the ethical concerns raised by clinical research and determine what consent process is needed to address them. C1 NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Ctr Clin, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU National Institutes of Health (NIH) FX This work was funded by National Institutes of Health (NIH) intramural research funds. However, the views expressed are the author's own. They do not represent the position or policy of the NIH, the PHS, or the DHHS. The author has no competing interests with respect to this article. NR 21 TC 11 Z9 11 U1 0 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD DEC 1 PY 2013 VL 13 IS 12 BP 3 EP 8 DI 10.1080/15265161.2013.851578 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 254HI UT WOS:000327155300002 PM 24256522 ER PT J AU Resnik, DB AF Resnik, David B. TI What Are Reasonably Foreseeable Risks? SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID SUPPORT; CONSENT C1 [Resnik, David B.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Mail Drop CU 03,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 9 TC 2 Z9 2 U1 0 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD DEC 1 PY 2013 VL 13 IS 12 BP 29 EP 30 DI 10.1080/15265161.2013.849304 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 254HI UT WOS:000327155300010 PM 24256530 ER PT J AU Hidalgo, G Ng, DK Moxey-Mims, M Minnick, ML Blydt-Hansen, T Warady, BA Furth, SL AF Hidalgo, Guillermo Ng, Derek K. Moxey-Mims, Marva Minnick, Maria Lourdes Blydt-Hansen, Tom Warady, Bradley A. Furth, Susan L. TI Association of Income Level With Kidney Disease Severity and Progression Among Children and Adolescents With CKD: A Report From the Chronic Kidney Disease in Children (CKiD) Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Socioeconomic status; children; adolescents; chronic kidney disease; progression; growth ID GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; SOCIOECONOMIC DISPARITIES; RACIAL-DIFFERENCES; UNITED-STATES; HEALTH; DIALYSIS; RACE; US AB Background: Among adults, lower socioeconomic status (SES) is a risk factor for chronic kidney disease (CKD), progression to end-stage renal disease, and poor health outcomes; but its impact on young people with CKD is not established. Study Design: Prospective cohort study. Settings & Participants: 572 children and adolescents aged 1-16 years with mild to moderate CKD residing in the United States and Canada who were enrolled in the Chronic Kidney Disease in Children (CKiD) Study. Predictor: Self-reported annual household income category as a proxy measure for SES: >=$75,000 (high income), $30,000 to <$75,000 (middle income) and, <$30,000 (low income). Outcomes & Measurements: Clinical characteristics and CKD severity at baseline (glomerular filtration rate [GFR] and comorbid conditions related to disease severity and management) and longitudinally (GFR decline and changes in blood pressure z scores and height z scores per year). Results: At baseline, low and middle household incomes, compared to high income, were associated with minority race (39% and 20% vs 7%), lower maternal education (28% and 5% vs 1%), abnormal birth history (34% and 32% vs 21%), and having at least one clinical comorbid condition (66% and 64% vs 55%). Baseline median GFRs were similar across income categories (43-45 mL/min/1.73 m(2)). After adjusting for baseline differences, average GFR declines per year for the low-, middle-, and high-income categories were -2.3%, -2.7%, and -1.9%, respectively, and were not statistically significantly different among groups. Blood pressure control tended to improve in all groups (z score, -0.10 to -0.04) but higher income was associated with a faster improvement. Each group showed similar deficits in height at baseline. Height deficits diminished over time for participants from high-income families, but not among those from low-income families (z scores for height per year, 0.05 and -0.004, respectively; P = 0.03 for comparison of high and low income). Limitations: Income is an imperfect measure for SES; CKiD participants are not representative of children and adolescents with CKD who are uninsured or not receiving care; statistical power to detect associations by income level is limited. Conclusions: GFR decline was similar across income groups but better improvement in BP was observed among those with high income. Children and adolescents with CKD from lower income households are at higher risk of impaired growth. (C) 2013 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Hidalgo, Guillermo] E Carolina Univ, Sch Med, Dept Pediat, Greenville, NC USA. [Ng, Derek K.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD 20892 USA. [Minnick, Maria Lourdes; Furth, Susan L.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Blydt-Hansen, Tom] Univ Manitoba, Winnipeg, MB, Canada. [Warady, Bradley A.] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Furth, Susan L.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Furth, SL (reprint author), Childrens Hosp Philadelphia, Div Nephrol, 3401 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM furths@email.chop.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung and Blood Institute [U01-DK-66143, U01-DK-66174, U01-DK82194, U01-DK-66116] FX Support: The CKiD Study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Dr Moxey-Mims serves as the NIDDK project officer on the steering committee. The study received additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung and Blood Institute. Grant numbers: U01-DK-66143, U01-DK-66174, U01-DK82194, and U01-DK-66116. NR 22 TC 13 Z9 13 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2013 VL 62 IS 6 BP 1087 EP 1094 DI 10.1053/j.ajkd.2013.06.013 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 259JS UT WOS:000327523800012 PM 23932090 ER PT J AU Shea, N Prasad, V AF Shea, Neil Prasad, Vinay TI Response to the "Open Issues with Open Access Publication" Reply SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Shea, Neil] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Shea, N (reprint author), Northwestern Univ, Dept Med, Chicago, IL 60611 USA. NR 3 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 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD DEC PY 2013 VL 126 IS 12 BP E45 EP E45 DI 10.1016/j.amjmed.2013.07.039 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 257OC UT WOS:000327393300023 PM 24262747 ER PT J AU Powell, KE Zimmerman, RK Ahern, DK Lewis, AL Ramirez, AG Atienza, A Ayala, GX Elder, JP Calonge, N Chin, M Clymer, J Fielding, J Glanz, K Goetzel, R Green, LW Grossman, D Johnson, RL Kumanyika, S Orleans, T Pronk, N Ramirez, G Remington, PL Rimer, B Hesse, BW Frumkin, H Jones, BH Canham-Chervak, M Kohatsu, ND Harris, JR Koo, D Michener, L Kottke, TE Dickey, LL Maibach, E Mays, GP Halverson, PK McGinnis, JM Barry, MA Owen, N Pronk, N Sallis, JF Stokols, D Hall, KL Felitti, VJ Anda, RF Butchart, A Sethi, D Pratt, M Gruner, L AF Powell, Kenneth E. Zimmerman, Richard K. Ahern, David K. Lewis, Allison L. Ramirez, Amelie G. Atienza, Audie Ayala, Guadalupe X. Elder, John P. Calonge, Ned Chin, Marshall Clymer, John Fielding, Jonathan Glanz, Karen Goetzel, Ron Green, Lawrence W. Grossman, David Johnson, Robert L. Kumanyika, Shiriki Orleans, Tracy Pronk, Nico Ramirez, Gilbert Remington, Patrick L. Rimer, Barbara Hesse, Bradford W. Frumkin, Howard Jones, Bruce H. Canham-Chervak, Michelle Kohatsu, Neal D. Harris, Jeffrey R. Koo, Denise Michener, Lloyd Kottke, Thomas E. Dickey, Larry L. Maibach, Edward Mays, Glen P. Halverson, Paul K. McGinnis, J. Michael Barry, Michael A. Owen, Neville Pronk, Nico Sallis, James F. Stokols, Daniel Hall, Kara L. Felitti, Vincent J. Anda, Robert F. Butchart, Alexander Sethi, Dinesh Pratt, Michael Gruner, Linda TI Notes from the Field: Planting, Nurturing, and Watching Things Grow SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material ID ADVERSE CHILDHOOD EXPERIENCES; HEALTH COMMUNICATION APPLICATIONS; UNDERGRADUATE PUBLIC-HEALTH; PHYSICAL-ACTIVITY INTERVENTIONS; COMMUNITY-PREVENTIVE-SERVICES; BUILT ENVIRONMENT; POPULATION HEALTH; HOUSEHOLD DYSFUNCTION; CLINICAL PREVENTION; NEIGHBORHOOD WALKABILITY C1 [Zimmerman, Richard K.] Univ Pittsburgh, Sch Med, Dept Family Med & Clin Epidemiol, Pittsburgh, PA 15260 USA. [Ahern, David K.] Brigham & Womens Hosp, Psychiat Hlth e Technol Initiat, Boston, MA 02115 USA. [Lewis, Allison L.] Assoc Prevent Teaching & Res, Washington, DC USA. [Ramirez, Amelie G.] Univ Texas Hlth Sci Ctr San Antonio, Inst Hlth Promot Res, San Antonio, TX USA. [Atienza, Audie] NIH, Hlth Promot Res Branch, Bethesda, MD 20892 USA. [Ayala, Guadalupe X.; Elder, John P.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Hesse, Bradford W.] NCI, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. [Frumkin, Howard] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Jones, Bruce H.; Canham-Chervak, Michelle] US Army Inst Publ Hlth, Injury Prevent Program, Aberdeen Proving Ground, MD USA. [Harris, Jeffrey R.] Univ Washington, Hlth Promot Res Ctr, Seattle, WA 98195 USA. [Koo, Denise] Ctr Dis Control & Prevent, Off Director, Sci Educ & Profess Dev Program Off, Atlanta, GA 30329 USA. [Michener, Lloyd] Duke Univ, Med Ctr, Dept Community & Family Med, Duke Ctr Community Res, Durham, NC 27706 USA. [Kottke, Thomas E.] HealthPartners, Populat Hlth, Minneapolis, MN USA. [Maibach, Edward] George Mason Univ, Ctr Climate Change Commun, Fairfax, VA 22030 USA. [Mays, Glen P.] Univ Kentucky, Lexington, KY 40506 USA. [Halverson, Paul K.] Indiana Univ Purdue Univ Indianapolis, Fairbanks Sch Publ Hlth, Indianapolis, IN USA. [Barry, Michael A.] Amer Coll Prevent Med, Washington, DC USA. [Owen, Neville] Monash Univ, Baker IDI Heart & Diabet Inst, Clayton, Vic 3800, Australia. [Owen, Neville] Univ Melbourne, Melbourne, Vic 3010, Australia. [Owen, Neville] Univ Queensland, Brisbane, Qld 4072, Australia. [Pronk, Nico] Harvard Univ, Sch Publ Hlth, HealthPartners, Cambridge, MA 02138 USA. [Sallis, James F.] Univ Calif San Diego, San Diego, CA 92103 USA. [Stokols, Daniel] Univ Calif Irvine, Sch Sociol Ecol, Irvine, CA USA. [Hall, Kara L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Anda, Robert F.] ACE Interface, Fayetteville, GA USA. [Butchart, Alexander] WHO, Dept Violence & Injury Prevent & Disabil, Geneva, Switzerland. [Pratt, Michael] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. RP Powell, KE (reprint author), Care of Seidman C, UCSD, AJPM Editorial Off, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM nekllewop@hotmail.com; zimmer@pitt.edu; dahern@partners.org; ALL@aptrweb.org; ramirezag@uthscsa.edu; AtienzaA@mail.nih.gov; ayala@mail.sdsu.edu; lwgreen@comcast.net; hesseb@mail.nih.gov; frumkin@uw.edu; michelle.c.chervak.civ@mail.mil; Neal.Kohatsu@dhcs.ca.gov; dkoo@cdc.gov; tkottke@comcast.net; emaibach@gmu.edu; MMcGinnis@nas.edu; mbarry@acpm.org; neville.owen@bakeridi.edu.au; nico.p.pronk@healthpartners.com; jsallis@ucsd.edu; dstokols@uci.edu; VJFMDSDCA@mac.com; butcharta@who.int NR 123 TC 0 Z9 0 U1 3 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2013 VL 45 IS 6 BP 687 EP 702 DI 10.1016/j.amepre.2013.09.006 PG 16 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 258SG UT WOS:000327478400007 ER PT J AU Vogel, AL Hall, KL Fiore, SM Klein, JT Bennett, LM Gadlin, H Stokols, D Nebeling, LC Wuchty, S Patrick, K Spotts, EL Pohl, C Riley, WT Falk-Krzesinski, HJ AF Vogel, Amanda L. Hall, Kara L. Fiore, Stephen M. Klein, Julie T. Bennett, L. Michelle Gadlin, Howard Stokols, Daniel Nebeling, Linda C. Wuchty, Stefan Patrick, Kevin Spotts, Erica L. Pohl, Christian Riley, William T. Falk-Krzesinski, Holly J. TI The Team Science Toolkit Enhancing Research Collaboration Through Online Knowledge Sharing SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material C1 [Hall, Kara L.; Nebeling, Linda C.; Riley, William T.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Gadlin, Howard] NHLBI, Ctr Cooperat Resolut, NIH, Bethesda, MD 20892 USA. [Bennett, L. Michelle] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Spotts, Erica L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Falk-Krzesinski, Holly J.] Global Acad & Res Affairs, Chicago, IL USA. [Fiore, Stephen M.] Univ Cent Florida, Dept Philosophy, Orlando, FL 32816 USA. [Klein, Julie T.] Wayne State Univ, Dept English, Detroit, MI USA. [Patrick, Kevin] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Pohl, Christian] Swiss Fed Inst Technol, Dept Environm Syst Sci, Zurich, Switzerland. [Stokols, Daniel] Univ Calif Irvine, Sch Social Ecol, Irvine, CA USA. [Vogel, Amanda L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate CMRP, Rockville, MD 20850 USA. [Wuchty, Stefan] Univ Miami, Dept Comp Sci, Miami, FL USA. RP Vogel, AL (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate CMRP, 9609 Med Ctr Dr,Room 3E124, Rockville, MD 20850 USA. EM vogelal@mail.nih.gov OI Falk-Krzesinski, Holly/0000-0001-8112-2445; Fiore, Stephen/0000-0003-3529-1322 NR 13 TC 14 Z9 14 U1 1 U2 30 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2013 VL 45 IS 6 BP 787 EP 789 DI 10.1016/j.amepre.2013.09.001 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 258SG UT WOS:000327478400021 PM 24237924 ER PT J AU Madeleine, MM Finch, JL Lynch, CF Goodman, MT Engels, EA AF Madeleine, M. M. Finch, J. L. Lynch, C. F. Goodman, M. T. Engels, E. A. TI HPV-Related Cancers After Solid Organ Transplantation in the United States SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE HPV-related cancer; immunosuppression; organ transplant cohort; Transplant Cancer Match Study ID SQUAMOUS-CELL CARCINOMAS; HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; SKIN CANCERS; ANAL CANCER; RECIPIENTS; RISK; MALIGNANCY; WORLDWIDE; SIROLIMUS AB Transplant recipients have elevated cancer risk including risk of human papillomavirus (HPV)-associated cancers of the cervix, anus, penis, vagina, vulva and oropharynx. We examined the incidence of HPV-related cancers in 187649 US recipients in the Transplant Cancer Match Study. Standardized incidence ratios (SIRs) compared incidence rates to the general population, and incidence rate ratios (IRRs) compared rates across transplant subgroups. We observed elevated incidence of HPV-related cancers (SIRs: in situ 3.3-20.3, invasive 2.2-7.3), except for invasive cervical cancer (SIR 1.0). Incidence increased with time since transplant for vulvar, anal and penile cancers (IRRs 2.1-4.6 for 5+ vs. <2 years). Immunophenotype, characterized by decreased incidence with HLA DRB1:13 and increased incidence with B:44, contributed to susceptibility at several sites. Use of specific immunosuppressive medications was variably associated with incidence; for example, tacrolimus, was associated with reduced incidence for some anogenital cancers (IRRs 0.4-0.7) but increased incidence of oropharyngeal cancer (IRR 2.1). Thus, specific features associated with recipient characteristics, transplanted organs and medications are associated with incidence of HPV-related cancers after transplant. The absence of increased incidence of invasive cervical cancer highlights the success of cervical screening in this population and suggests a need for screening for other HPV-related cancers. C1 [Madeleine, M. M.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Madeleine, M. M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Finch, J. L.] Colorado Dept Publ Hlth & Environm, Colorado Cent Canc Registry, Denver, CO USA. [Lynch, C. F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Goodman, M. T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Madeleine, MM (reprint author), Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. EM mmadelei@fhcrc.org FU Intramural Research Program of the National Cancer Institute; National Program of Cancer Registries of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Georgia [5U58DP000817-05]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Illinois [5658DP000805-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Michigan [5U58DP000812-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New Jersey [5U58/DP000808-05]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: New York [U58DP0038789]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; SEER Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261201000034C]; SEER Program of the National Cancer Institute: Connecticut [HHSN261201000024C]; SEER Program of the National Cancer Institute: Hawaii [HHSN261201000037C, N01-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute: Iowa [HSN261201000032C, N01-PC-35143]; SEER Program of the National Cancer Institute: New Jersey [HHSN261201000027C, N01-PC-54405]; SEER Program of the National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; SEER Program of the National Cancer Institute: Utah [HHSN261201000026C]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of New Jersey; state of New York (Cancer Surveillance Improvement Initiative) [14-2491]; state of Texas; state of Washington; Fred Hutchinson Cancer Research Center in Seattle, WA; General Funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The authors gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California (Tina Clarke), Colorado, Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii, Iowa, Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey (Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Melanie Williams) and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Michael Curry, Ruth Parsons). The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries or their contractors. This research was supported in part by the Intramural Research Program of the National Cancer Institute. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP000817-05), Illinois (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP000808-05), New York (U58DP0038789), North Carolina (U58DP000832) and Texas (5U58DP000824-04). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137 and N01-PC-35139), Iowa (HSN261201000032C and N01-PC-35143), New Jersey (HHSN261201000027C and N01-PC-54405), Seattle-Puget Sound (N01-PC-35142) and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 14-2491), Texas and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, WA. This research 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. NR 30 TC 25 Z9 25 U1 0 U2 3 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 DEC PY 2013 VL 13 IS 12 BP 3202 EP 3209 DI 10.1111/ajt.12472 PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 255JN UT WOS:000327235300022 PM 24119294 ER PT J AU Colson, P De Lamballerie, X Yutin, N Asgari, S Bigot, Y Bideshi, DK Cheng, XW Federici, BA Van Etten, JL Koonin, EV La Scola, B Raoult, D AF Colson, Philippe De Lamballerie, Xavier Yutin, Natalya Asgari, Sassan Bigot, Yves Bideshi, Dennis K. Cheng, Xiao-Wen Federici, Brian A. Van Etten, James L. Koonin, Eugene V. La Scola, Bernard Raoult, Didier TI "Megavirales", a proposed new order for eukaryotic nucleocytoplasmic large DNA viruses SO ARCHIVES OF VIROLOGY LA English DT Article ID GIANT VIRUSES; EVOLUTION; MIMIVIRUS; REPLICATION; FACTORIES; VACCINIA; ORIGIN; GENES; HIGHLIGHTS; LINEAGE AB The nucleocytoplasmic large DNA viruses (NCLDVs) comprise a monophyletic group of viruses that infect animals and diverse unicellular eukaryotes. The NCLDV group includes the families Poxviridae, Asfarviridae, Iridoviridae, Ascoviridae, Phycodnaviridae, Mimiviridae and the proposed family "Marseilleviridae". The family Mimiviridae includes the largest known viruses, with genomes in excess of one megabase, whereas the genome size in the other NCLDV families varies from 100 to 400 kilobase pairs. Most of the NCLDVs replicate in the cytoplasm of infected cells, within so-called virus factories. The NCLDVs share a common ancient origin, as demonstrated by evolutionary reconstructions that trace approximately 50 genes encoding key proteins involved in viral replication and virion formation to the last common ancestor of all these viruses. Taken together, these characteristics lead us to propose assigning an official taxonomic rank to the NCLDVs as the order "Megavirales", in reference to the large size of the virions and genomes of these viruses. C1 [Colson, Philippe; La Scola, Bernard; Raoult, Didier] Aix Marseille Univ, IHU Med Infect, Fac Med & Pharm, Unite Rickettsies,URMITE UMR CNRS IRD INSERM U 72, F-13385 Marseille 05, France. [Colson, Philippe; De Lamballerie, Xavier; La Scola, Bernard; Raoult, Didier] Ctr Hosp Univ Timone, Assistance Publ Hop Marseille, IHU Med, Fed Bacteriol Hyg Virol,Pole Malad Infect & Tropi, F-13385 Marseille 05, France. [De Lamballerie, Xavier] Aix Marseille Univ, EHSP French Sch Publ Hlth, Inst Rech Dev, Fac Med,Unite Virus Emergents,UMR 190 Emergence P, F-13385 Marseille 05, France. [Bigot, Yves] INRA, CNRS, UMR 7247, PRC UMR0085, Nouzilly, France. [Yutin, Natalya; Koonin, Eugene V.] NIH, NCBI, Natl Lib Med, Bethesda, MD 20894 USA. [Asgari, Sassan] Univ Queensland, Sch Biol Sci, St Lucia, Qld 4072, Australia. Ctr INRA Nouzilly, UMR INRA CNRS 7247, PRC, F-37380 Nouzilly, France. [Bideshi, Dennis K.] Univ Calif Riverside, Mol & Dev Biol, Riverside, CA 92521 USA. [Cheng, Xiao-Wen] Miami Univ, Dept Microbiol, Oxford, OH 45056 USA. [Federici, Brian A.] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. [Van Etten, James L.] Univ Nebraska, Dept Plant Pathol, Lincoln, NE 68583 USA. [Van Etten, James L.] Univ Nebraska, Nebraska Ctr Virol, Lincoln, NE 68583 USA. RP Raoult, D (reprint author), Aix Marseille Univ, IHU Med Infect, Fac Med & Pharm, Unite Rickettsies,URMITE UMR CNRS IRD INSERM U 72, 27 Blvd Jean Moulin, F-13385 Marseille 05, France. EM didier.raoult@gmail.com RI Colson, Philippe/P-6355-2014; LA SCOLA, Bernard/P-6477-2016 OI Colson, Philippe/0000-0001-6285-0308; LA SCOLA, Bernard/0000-0001-8006-7704 FU US Department of Health and Human Services; NIH from the COBRE Program of the National Center for Research Resources [P20 RR15635] FX Natalya Yutin and Eugene V. Koonin are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). James Van Etten is partially supported by NIH Grant P20 RR15635 from the COBRE Program of the National Center for Research Resources. NR 35 TC 78 Z9 78 U1 2 U2 36 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD DEC PY 2013 VL 158 IS 12 BP 2517 EP 2521 DI 10.1007/s00705-013-1768-6 PG 5 WC Virology SC Virology GA 253XA UT WOS:000327121600010 PM 23812617 ER PT J AU Prager, AJ Peng, CR Lita, E McNally, D Kaushal, A Sproull, M Compton, K Dahut, WL Figg, WD Citrin, D Camphausen, KA AF Prager, Alisa J. Peng, Cynthia R. Lita, Elena McNally, Debbie Kaushal, Aradhana Sproull, Mary Compton, Kathryn Dahut, William L. Figg, William D. Citrin, Deborah Camphausen, Kevin A. TI Urinary aHGF, IGFBP3 and OPN as diagnostic and prognostic biomarkers for prostate cancer SO BIOMARKERS IN MEDICINE LA English DT Article DE biomarker; HGH; OPN; prostate cancer; urine ID GROWTH-FACTOR-I; HEPATOCYTE GROWTH; BINDING PROTEIN-3; PLASMA OSTEOPONTIN; FACTOR/SCATTER FACTOR; TMPRSS2-ERG FUSION; ANDROGEN RECEPTOR; ANTIGEN LEVEL; CELLS; RISK AB Aim: Serum PSA screening for prostate cancer (PCa) is controversial. Here, we identify three urinary biomarkers - aHGF, IGFBP3 and OPN - for PCa screening and prognostication. Methods: Urinary aHGF, OPN and IGFBP3 from healthy men (n = 19) and men with localized (n = 65) and metastatic (n = 36) PCa were quantified via ELISA. Mann-Whitney nonparametric t-test and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analyses were used to analyze associations. Results: Mean aHGF and IGFBP3 levels were significantly elevated in PCa patients versus controls (p = 0.0006 and p = 0.0012, respectively), and the area under the curve of the receiver operating characteristic curve (indicator of diagnostic accuracy) for aHGF and IGFBP3 was 0.75 and 0.74, respectively. OPN levels were significantly higher in metastatic groups (p = 0.0060) versus localized and controls (area under the curve = 0.68). Conclusion: Urinary aHGF and IGFBP3 exhibit the capacity for diagnostic discrimination for PCa, whereas OPN may indicate presence of metastatic disease. C1 [Prager, Alisa J.; Peng, Cynthia R.; Sproull, Mary; Citrin, Deborah; Camphausen, Kevin A.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lita, Elena; McNally, Debbie; Kaushal, Aradhana] NCI, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Compton, Kathryn; Figg, William D.] NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. [Dahut, William L.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Camphausen, KA (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov RI Figg Sr, William/M-2411-2016 NR 56 TC 3 Z9 3 U1 0 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PD DEC PY 2013 VL 7 IS 6 BP 831 EP 841 DI 10.2217/bmm.13.112 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 255QB UT WOS:000327253800003 PM 24266816 ER PT J AU Huang, CY Qin, J AF Huang, Chiung-Yu Qin, Jing TI Semiparametric estimation for the additive hazards model with left-truncated and right-censored data SO BIOMETRIKA LA English DT Article DE Canadian Study of Health and Aging; Composite likelihood; Estimating equation; Martingale; Prevalent sampling ID NONPARAMETRIC-ESTIMATION; REGRESSION-MODELS; LIKELIHOOD; SURVIVAL AB Survival data from prevalent cases collected under a cross-sectional sampling scheme are subject to left-truncation. When fitting an additive hazards model to left-truncated data, the conditional estimating equation method (Lin & Ying, 1994), obtained by modifying the risk sets to account for left-truncation, can be very inefficient, as the marginal likelihood of the truncation times is not used in the estimation procedure. In this paper, we use a pairwise pseudolikelihood to eliminate nuisance parameters from the marginal likelihood and, by combining the marginal pairwise pseudo-score function and the conditional estimating function, propose an efficient estimator for the additive hazards model. The proposed estimator is shown to be consistent and asymptotically normally distributed with a sandwich-type covariance matrix that can be consistently estimated. Simulation studies show that the proposed estimator is more efficient than its competitors. A data analysis illustrates application of the method. C1 [Huang, Chiung-Yu] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Oncol Biostat & Bioinformat, Baltimore, MD 21205 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Huang, CY (reprint author), Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Oncol Biostat & Bioinformat, Baltimore, MD 21205 USA. EM cyhuang@jhmi.edu; jingqin@niaid.nih.gov FU National Health Research and Development Program of Health Canada Project; Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program; Bayer Incorporated; British Columbia Health Research Foundation FX The authors thank Professors Christina Wolfson, Masoud Asgharian and Ian McDowell for kindly sharing the Canadian Study of Health and Aging data. The core study was funded by the National Health Research and Development Program of Health Canada Project. Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, Bayer Incorporated, and the British Columbia Health Research Foundation Projects. The authors also thank the referees, associate editor, editor, and Dr. Dean Follmann for their comments, which have helped to improve the presentation of this article. This work was conducted when the first author was a mathematical statistician at the National Institute of Allergy and Infectious Diseases. NR 26 TC 2 Z9 3 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-3444 EI 1464-3510 J9 BIOMETRIKA JI Biometrika PD DEC PY 2013 VL 100 IS 4 BP 877 EP 888 DI 10.1093/biomet/ast039 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 262DL UT WOS:000327714200007 PM 26246622 ER PT J AU Vincent, DT Ibrahim, YF Espey, MG Suzuki, YJ AF Vincent, Duncan T. Ibrahim, Yasmine F. Espey, Michael Graham Suzuki, Yuichiro J. TI The role of antioxidants in the era of cardio-oncology SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Review DE Antioxidants; Cancer; Cardioprotection; Cardiotoxicity; Chemotherapy; Free radicals; Reactive oxygen species ID ADVANCED BREAST-CANCER; CHRONIC DOXORUBICIN CARDIOTOXICITY; ADRIAMYCIN-INDUCED CARDIOMYOPATHY; CISPLATIN-INDUCED CARDIOTOXICITY; ACUTE LYMPHOBLASTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; ALPHA-LIPOIC ACID; VITAMIN-E; MITOCHONDRIAL TOXICITY; TAXANE CHEMOTHERAPIES AB Although most chemotherapeutic drugs have the potential to exert cardiotoxicity, these drugs have been chosen for use in cancer treatment because survival and curability benefits outweigh the risk of these complications. Anthracyclines, for example, are a powerful class of chemotherapeutic agents; however, their use is restricted by dose-related cardiotoxicity. Experimental evidence strongly supports the role of reactive oxygen species in this process, suggesting that antioxidants may be effective in protecting the heart from toxicity. Clinical use of antioxidants to protect the heart during anthracycline chemotherapy has been controversial due to the potential for reduced cytotoxic efficacy toward cancer cells. Results from randomized clinical trials addressing whether antioxidants either reduce the incidence of clinical heart failure among patients undergoing anthracycline-based chemotherapy or reduce the response rates to anthracycline-based chemotherapy have been unclear. While anthracyclines are by far the most well-studied antitumor agents with cardiotoxic properties, evidence now shows that reactive oxygen species may play roles in cardiotoxicity induced by other chemotherapeutic agents such as cyclophosphamide, cisplatin, 5-fluorouracil, and trastuzumab. Thus, in the new era of combination therapy and long-term survival of cancer patients, the use of antioxidants to support cancer therapy should be revisited. C1 [Vincent, Duncan T.; Ibrahim, Yasmine F.; Suzuki, Yuichiro J.] Georgetown Univ, Med Ctr, Dept Physiol & Pharmacol, Washington, DC 20057 USA. [Espey, Michael Graham] NIDDK, Off Sci Director, Bethesda, MD 20892 USA. RP Suzuki, YJ (reprint author), Georgetown Univ, Med Ctr, Dept Physiol & Pharmacol, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM ys82@georgetown.edu FU NHLBI NIH HHS [R01 HL072844] NR 99 TC 8 Z9 10 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD DEC PY 2013 VL 72 IS 6 BP 1157 EP 1168 DI 10.1007/s00280-013-2260-4 PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 257LX UT WOS:000327387000001 PM 23959462 ER PT J AU Chudasama, Y Daniels, TE Gorrin, DP Rhodes, SEV Rudebeck, PH Murray, EA AF Chudasama, Yogita Daniels, Teresa E. Gorrin, Daniel P. Rhodes, Sarah E. V. Rudebeck, Peter H. Murray, Elisabeth A. TI The Role of the Anterior Cingulate Cortex in Choices based on Reward Value and Reward Contingency SO CEREBRAL CORTEX LA English DT Article DE action-reversal; monkey; object-reversal; reward value ID MEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; RHESUS-MONKEY; FRONTAL-CORTEX; MACAQUE MONKEY; REINFORCER DEVALUATION; DECISION-MAKING; AMYGDALA; LESIONS; SELECTION AB Although several studies have emphasized the role of the anterior cingulate cortex (ACC) in associating actions with reward value, its role in guiding choices on the basis of changes in reward value has not been assessed. Accordingly, we compared rhesus monkeys with ACC lesions and controls on object- and action-based reinforcer devaluation tasks. Monkeys were required to associate an object or an action with one of two reward outcomes, and we assessed the monkeys shift in choices of objects or actions after changes in the value of 1 outcome. No group differences emerged on either task. For comparison, we tested the same monkeys on their ability to make choices guided by reward contingency in object- and action-based reversal learning tasks. Monkeys with ACC lesions were impaired in using rewarded trials to sustain the selection of the correct object during object reversal learning. They were also impaired in using errors to guide choices in action reversal learning. These data indicate that the role of the ACC is not restricted to linking specific actions with reward outcomes, as previously reported. Instead, the data suggest a more general role for the ACC in using information about reward and nonreward to sustain effective choice behavior. C1 [Chudasama, Yogita] McGill Univ, Dept Psychol, Montreal, PQ H3A 1B1, Canada. [Daniels, Teresa E.; Gorrin, Daniel P.; Rhodes, Sarah E. V.; Rudebeck, Peter H.; Murray, Elisabeth A.] NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Chudasama, Y (reprint author), McGill Univ, Dept Psychol, 1205 Dr Penfield Ave, Montreal, PQ H3A 1B1, Canada. EM yogita.chudasama@mcgill.ca OI Rudebeck, Peter/0000-0002-1411-7555; Murray, Elisabeth/0000-0003-1450-1642 FU Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health at the National Institutes of Health. NR 58 TC 15 Z9 15 U1 2 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD DEC PY 2013 VL 23 IS 12 BP 2884 EP 2898 DI 10.1093/cercor/bhs266 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 258AY UT WOS:000327431400010 PM 22944530 ER PT J AU Manzur, HE Alvarez, J Babul, C Maldonado, PE AF Manzur, Hachi E. Alvarez, Joel Babul, Cecilia Maldonado, Pedro E. TI Synchronization Across Sensory Cortical Areas by Electrical Microstimulation is Sufficient for Behavioral Discrimination SO CEREBRAL CORTEX LA English DT Article DE coding; cortex; microstimulation; sensory; synchronization ID CAT VISUAL-CORTEX; OSCILLATORY NEURONAL RESPONSES; STRIATE CORTEX; INTRACORTICAL MICROSTIMULATION; GAMMA OSCILLATIONS; MOTOR CORTEX; NEOCORTICAL NEURONS; CEREBRAL-CORTEX; OLFACTORY-BULB; AWAKE MACAQUE AB The temporal correlation hypothesis proposes that cortical neurons engage in synchronized activity, thus configuring a general mechanism to account for a range of cognitive processes from perceptual binding to consciousness. However, most studies supporting this hypothesis have only provided correlational, but not causal evidence. Here, we used electrical microstimulation of the visual and somatosensory cortices of the rat in both hemispheres, to test whether rats could discriminate synchronous versus asynchronous patterns of stimulation applied to the same cortical sites. To disambiguate synchrony from other related parameters, our experiments independently manipulated the rate and intensity of stimulation, the spatial locations of stimulation, the exact temporal sequence of stimulation patterns, and the degree of synchrony across stimulation sites. We found that rats reliably distinguished between 2 microstimulation patterns, differing in the spatial arrangement of cortical sites stimulated synchronously. Also, their performance was proportional to the level of synchrony in the microstimulation patterns. We demonstrated that rats can recognize artificial current patterns containing precise synchronization features, thus providing the first direct evidence that artificial synchronous activity can guide behavior. Such precise temporal information can be used as feedback signals in machine interface arrangements. C1 [Manzur, Hachi E.; Alvarez, Joel; Babul, Cecilia; Maldonado, Pedro E.] Univ Chile, Biomed Neurosci Inst, Santiago 8380453, Chile. [Manzur, Hachi E.] NIA, Neural Circuits & Cognit Unit, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Maldonado, Pedro E.] Univ Chile, Fac Med, Program Physiol & Biophys, Casilla Santiago, Chile. RP Maldonado, PE (reprint author), Univ Chile, Fac Med, Program Physiol & Biophys, Independencia 1027, Santiago 8380453, Chile. EM pedro@neuro.med.uchile.cl OI Maldonado, Pedro/0000-0001-9895-7684 FU Fondecyt [1090101]; Iniciativa Cientifica Milenio; Conicyt; Conciyt Anillo [ACT 66] FX This study was supported in part by Fondecyt 1090101 to P. M., Iniciativa Cientifica Milenio and a Conicyt Doctoral fellowship and Conciyt Anillo ACT 66 to H. M. NR 84 TC 2 Z9 2 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD DEC PY 2013 VL 23 IS 12 BP 2976 EP 2986 DI 10.1093/cercor/bhs288 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 258AY UT WOS:000327431400018 PM 22989583 ER PT J AU Jain, L Raju, TNK AF Jain, Lucky Raju, Tonse N. K. TI Late Preterm and Early Term Births Preface SO CLINICS IN PERINATOLOGY LA English DT Editorial Material ID MORTALITY; PREGNANCY C1 [Jain, Lucky] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Jain, Lucky] Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Jain, L (reprint author), Emory Univ, Sch Med, 2015 Uppergate Dr, Atlanta, GA 30322 USA. EM ljain@emory.edu; rajut@mail.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0095-5108 EI 1557-9840 J9 CLIN PERINATOL JI Clin. Perinatol. PD DEC PY 2013 VL 40 IS 4 BP XIX EP XX DI 10.1016/j.clp.2013.07.013 PG 2 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 259XQ UT WOS:000327560000002 PM 24182963 ER PT J AU Raju, TNK AF Raju, Tonse N. K. TI Moderately Preterm, Late Preterm and Early Term Infants: Research Needs SO CLINICS IN PERINATOLOGY LA English DT Article DE Preterm; Immaturity; Respiratory distress; Apnea; Hypothermia; Hypoglycemia; Jaundice; Infection ID RESPIRATORY MORBIDITY; NEONATAL OUTCOMES; COLD STRESS; BRAIN; RISK; GESTATION; DELIVERY; FETUS C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. RP Raju, TNK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, 6100 Execut Blvd,Room 4803, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 32 TC 9 Z9 9 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0095-5108 EI 1557-9840 J9 CLIN PERINATOL JI Clin. Perinatol. PD DEC PY 2013 VL 40 IS 4 BP 791 EP + DI 10.1016/j.clp.2013.07.010 PG 8 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 259XQ UT WOS:000327560000015 PM 24182962 ER PT J AU Alexander, VM Choyke, PL Kobayashi, H AF Alexander, V. M. Choyke, P. L. Kobayashi, H. TI Fluorescent Molecular Imaging: Technical Progress and Current Preclinical and Clinical Applications in Urogynecologic Diseases SO CURRENT MOLECULAR MEDICINE LA English DT Article DE Gynecologic cancer; molecular imaging; near infrared; urologic cancer ID TARGETED CONTRAST AGENT; IN-VIVO; INDOCYANINE GREEN; PROSTATE-CANCER; OVARIAN-CANCER; QUANTUM DOTS; MONOCLONAL-ANTIBODY; INTRAOPERATIVE ASSESSMENT; ADVERSE REACTIONS; PEPTIDE PROBES AB Many molecular imaging probes have been developed in recent years that hold great promise for both diagnostic and therapeutic functions in urogynecologic disease. Historically, optical probe designs were based on either endogenous or exogenous fluorophores. More recently, organic fluorophore probes have been engineered to target specific tissues and emit fluorescence only upon binding to targets. Several different photochemical mechanisms of activation exist. This review presents a discussion of the history and development of molecular imaging probe designs and provides an overview of successful preclinical and clinical models employing molecular probes for in vivo imaging of urogynecologic cancers. C1 [Alexander, V. M.; Choyke, P. L.; Kobayashi, H.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, NIH, Bldg 10,Room B3B69,MSC 1088, Bethesda, MD 20892 USA. EM pchoyke@mail.nih.gov NR 97 TC 1 Z9 1 U1 1 U2 18 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 EI 1875-5666 J9 CURR MOL MED JI Curr. Mol. Med. PD DEC PY 2013 VL 13 IS 10 BP 1568 EP 1578 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 258GV UT WOS:000327448200007 PM 24206135 ER PT J AU Bornstein, MH Jager, J Putnick, DL AF Bornstein, Marc H. Jager, Justin Putnick, Diane L. TI Sampling in developmental science: Situations, shortcomings, solutions, and standards SO DEVELOPMENTAL REVIEW LA English DT Article DE Sampling; Methodology; Developmental science ID SOCIOECONOMIC-STATUS; DEPRESSIVE SYMPTOMS; UNITED-STATES; GENDER-DIFFERENCES; RACIAL-DIFFERENCES; FAMILY-STRUCTURE; PUBLIC-HEALTH; SUBSTANCE USE; RACE; ADOLESCENCE AB Sampling is a key feature of every study in developmental science. Although sampling has far-reaching implications, too little attention is paid to sampling. Here, we describe, discuss, and evaluate four prominent sampling strategies in developmental science: population-based probability sampling, convenience sampling, quota sampling, and homogeneous sampling. We then judge these sampling strategies by five criteria: whether they yield representative and generalizable estimates of a study's target population, whether they yield representative and generalizable estimates of subsamples within a study's target population, the recruitment efforts and costs they entail, whether they yield sufficient power to detect subsample differences, and whether they introduce "noise" related to variation in subsamples and whether that "noise" can be accounted for statistically. We use sample composition of gender, ethnicity, and socioeconomic status to illustrate and assess the four sampling strategies. Finally, we tally the use of the four sampling strategies in five prominent developmental science journals and make recommendations about best practices for sample selection and reporting. Published by Elsevier Inc. C1 [Bornstein, Marc H.; Jager, Justin; Putnick, Diane L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Publ Hlth Serv, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockledge 1,Suite 8030,6705 Rockledge Dr,MSC 7971, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS [ZIA HD001119-27] NR 46 TC 19 Z9 19 U1 2 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2297 EI 1090-2406 J9 DEV REV JI Dev. Rev. PD DEC PY 2013 VL 33 IS 4 BP 357 EP 370 DI 10.1016/j.dr.2013.08.003 PG 14 WC Psychology, Developmental SC Psychology GA 256CE UT WOS:000327286500004 PM 25580049 ER PT J AU Lipska, KJ Inzucchi, SE Van Ness, PH Gill, TM Kanaya, A Strotmeyer, ES Koster, A Johnson, KC Goodpaster, BH Harris, T De Rekeneire, N AF Lipska, Kasia J. Inzucchi, Silvio E. Van Ness, Peter H. Gill, Thomas M. Kanaya, Alka Strotmeyer, Elsa S. Koster, Annemarie Johnson, Karen C. Goodpaster, Bret H. Harris, Tamara De Rekeneire, Nathalie CA Health Abc Study TI Elevated HbA(1c) and Fasting Plasma Glucose in Predicting Diabetes Incidence Among Older Adults Are two better than one? SO DIABETES CARE LA English DT Article ID GLYCATED HEMOGLOBIN; ODDS RATIO; RISK; A1C; PERFORMANCE; HEALTH; CLASSIFICATION; DIAGNOSIS; MARKER; COHORT AB OBJECTIVETo determine which measuresimpaired fasting glucose (IFG), elevated HbA(1c), or bothbest predict incident diabetes in older adults.RESEARCH DESIGN AND METHODSFrom the Health, Aging, and Body Composition study, we selected individuals without diabetes, and we defined IFG (100-125 mg/dL) and elevated HbA(1c) (5.7-6.4%) per American Diabetes Association guidelines. Incident diabetes was based on self-report, use of antihyperglycemic medicines, or HbA(1c) 6.5% during 7 years of follow-up. Logistic regression analyses were adjusted for age, sex, race, site, BMI, smoking, blood pressure, and physical activity. Discrimination and calibration were assessed for models with IFG and with both IFG and elevated HbA(1c).RESULTSAmong 1,690 adults (mean age 76.5, 46% men, 32% black), 183 (10.8%) developed diabetes over 7 years. Adjusted odds ratios of diabetes were 6.2 (95% CI 4.4-8.8) in those with IFG (versus those with fasting plasma glucose [FPG] <100 mg/dL) and 11.3 (7.8-16.4) in those with elevated HbA(1c) (versus those with HbA(1c) <5.7%). When FPG and HbA(1c) were considered together, odds ratios were 3.5 (1.9-6.3) in those with IFG only, 8.0 (4.8-13.2) in those with elevated HbA(1c) only, and 26.2 (16.3-42.1) in those with both IFG and elevated HbA(1c) (versus those with normal FPG and HbA(1c)). Addition of elevated HbA(1c) to the model with IFG resulted in improved discrimination and calibration.CONCLUSIONSOlder adults with both IFG and elevated HbA(1c) have a substantially increased odds of developing diabetes over 7 years. Combined screening with FPG and HbA(1c) may identify older adults at very high risk for diabetes. C1 [Lipska, Kasia J.; Inzucchi, Silvio E.] Yale Univ, Sch Med, Dept Internal Med, Endocrinol Sect, New Haven, CT 06510 USA. [Van Ness, Peter H.; Gill, Thomas M.; De Rekeneire, Nathalie] Yale Univ, Sch Med, Dept Internal Med, Geriatr Sect, New Haven, CT 06510 USA. [Kanaya, Alka] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Strotmeyer, Elsa S.; Goodpaster, Bret H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Koster, Annemarie] Maastricht Univ, Dept Social Med, CAPHRI, Maastricht, Netherlands. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Goodpaster, Bret H.] Univ Pittsburgh, Grad Sch Publ Hlth, Div Endocrinol & Metab, Pittsburgh, PA USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Lipska, KJ (reprint author), Yale Univ, Sch Med, Dept Internal Med, Endocrinol Sect, New Haven, CT 06510 USA. EM kasia.lipska@yale.edu RI Strotmeyer, Elsa/F-3015-2014; Koster, Annemarie/E-7438-2010 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050, T32AG1934, R03 AG045086, K24AG021507]; National Institute of Nursing Research (NINR) [R01-NR012459]; National Institutes of Health, NIA; Pepper Center Career Development Award [P30 AG21342] FX This research was supported by National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA grant R01-AG028050; and National Institute of Nursing Research (NINR) grant R01-NR012459 and in part by the Intramural Research Program of the National Institutes of Health, NIA. K.J.L. was supported by NIA training grant T32AG1934 and is currently supported by the Pepper Center Career Development Award (P30 AG21342) and the Grants for Early Medical/Surgical Specialists' Transition to Aging Research (R03 AG045086) from the NIA. T. M. G. is the recipient of a Midcareer Investigator Award in Patient-Oriented Research (K24AG021507) from the NIA. The study was conducted at the Yale Claude D. Pepper Older Americans Independence Center (P30AG21342). NR 34 TC 13 Z9 15 U1 3 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2013 VL 36 IS 12 BP 3923 EP 3929 DI 10.2337/dc12-2631 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 255AL UT WOS:000327211500039 PM 24135387 ER PT J AU Yau, RK Strotmeyer, ES Resnick, HE Sellmeyer, DE Feingold, KR Cauley, JA Vittinghoff, E De Rekeneire, N Harris, TB Nevitt, MC Cummings, SR Shorr, RI Schwartz, AV AF Yau, Rebecca K. Strotmeyer, Elsa S. Resnick, Helaine E. Sellmeyer, Deborah E. Feingold, Kenneth R. Cauley, Jane A. Vittinghoff, Eric De Rekeneire, Nathalie Harris, Tamara B. Nevitt, Michael C. Cummings, Steven R. Shorr, Ronald I. Schwartz, Ann V. TI Diabetes and Risk of Hospitalized Fall Injury Among Older Adults SO DIABETES CARE LA English DT Article ID BODY-COMPOSITION; ELDERLY RESIDENTS; GLYCEMIC CONTROL; FRACTURE RISK; HEALTH ABC; WOMEN; MELLITUS; PREDICTORS; PEOPLE; TYPE-1 AB OBJECTIVETo determine whether older adults with diabetes are at increased risk of an injurious fall requiring hospitalization.RESEARCH DESIGN AND METHODSThe longitudinal Health, Aging, and Body Composition Study included 3,075 adults aged 70-79 years at baseline. Hospitalizations that included ICD-9-Clinical Modification codes for a fall and an injury were identified. The effect of diabetes with and without insulin use on the rate of first fall-related injury hospitalization was assessed using proportional hazards models.RESULTSAt baseline, 719 participants had diabetes, and 117 of them were using insulin. Of the 293 participants who were hospitalized for a fall-related injury, 71 had diabetes, and 16 were using insulin. Diabetes was associated with a higher rate of injurious fall requiring hospitalization (hazard ratio [HR] 1.48 [95% CI 1.12-1.95]) in models adjusted for age, race, sex, BMI, and education. In those participants using insulin, compared with participants without diabetes, the HR was 3.00 (1.78-5.07). Additional adjustment for potential intermediaries, such as fainting in the past year, standing balance score, cystatin C level, and number of prescription medications, accounted for some of the increased risk associated with diabetes (1.41 [1.05-1.88]) and insulin-treated diabetes (2.24 [1.24-4.03]). Among participants with diabetes, a history of falling, poor standing balance score, and A1C level 8% were risk factors for an injurious fall requiring hospitalization.CONCLUSIONSOlder adults with diabetes, in particular those using insulin, are at greater risk of an injurious fall requiring hospitalization than those without diabetes. Among those with diabetes, poor glycemic control may increase the risk of an injurious fall. C1 [Yau, Rebecca K.] Ctr Dis Control & Prevent, Council State & Terr Epidemiologists Appl Epidemi, Atlanta, GA 30333 USA. [Yau, Rebecca K.] Univ N Carolina, Injury Prevent Res Ctr, Chapel Hill, NC USA. [Strotmeyer, Elsa S.; Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Resnick, Helaine E.] Univ Maryland, Sch Med, Dept Geriatr, Baltimore, MD 21201 USA. [Resnick, Helaine E.] Gerontol Res Educ & Training Ctr, Baltimore, MD USA. [Resnick, Helaine E.] Resnick Chodorow & Associates, Silver Spring, MD USA. [Sellmeyer, Deborah E.] Johns Hopkins Sch Med, Div Endocrinol, Baltimore, MD USA. [Feingold, Kenneth R.] Univ Calif San Francisco, Dept Med, Div Endocrinol, San Francisco, CA USA. [Vittinghoff, Eric; Nevitt, Michael C.; Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [De Rekeneire, Nathalie] Yale Univ, Sch Med, Dept Internal Med, Geriatr Sect, New Haven, CT 06510 USA. [Harris, Tamara B.] NIA, Lab Epidemiol, Bethesda, MD 20892 USA. [Cummings, Steven R.] Calif Pacific Med Ctr Res Inst, San Francisco, CA USA. [Shorr, Ronald I.] North Florida South Georgia Vet Hlth Syst, Ctr Geriatr Res Educ & Clin, Gainesville, FL USA. [Shorr, Ronald I.] Univ Florida, Dept Aging & Geriatr, Gainesville, FL USA. RP Yau, RK (reprint author), Ctr Dis Control & Prevent, Council State & Terr Epidemiologists Appl Epidemi, Atlanta, GA 30333 USA. EM rebeccayau@unc.edu RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036; Cauley, Jane A/0000-0003-0752-4408 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute of Nursing Research [R01-NR012459]; Applied Epidemiology Fellowship Program; Centers for Disease Control and Prevention [5U38HM000414]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; National Institute on Aging grant R01-AG028050; and National Institute of Nursing Research grant R01-NR012459. This research was also supported by an appointment to the Applied Epidemiology Fellowship Program administered by the Council of State and Territorial Epidemiologists and funded by Centers for Disease Control and Prevention Cooperative Agreement number 5U38HM000414. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 39 TC 16 Z9 17 U1 1 U2 19 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2013 VL 36 IS 12 BP 3985 EP 3991 DI 10.2337/dc13-0429 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 255AL UT WOS:000327211500047 PM 24130352 ER PT J AU Dize, L West, S Quinn, TC Gaydos, CA AF Dize, Laura West, Sheila Quinn, Thomas C. Gaydos, Charlotte A. TI Pooling ocular swab specimens from Tanzania for testing by Roche Amplicor and Aptima Combo 2 assays for the detection of Chlamydia trachomatis: accuracy and cost-savings SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article DE Chlamydia trachomatis; Trachoma; Pooling; Cost-savings ID NEISSERIA-GONORRHOEAE; RANDOMIZED-TRIAL; SAMPLES; URINE; INFECTION; PROGRAMS; STRATEGY AB Ocular swabs collected in Tanzania were evaluated by Amplicor CT PCR and Aptima Combo2 assays for the detection of Chlamydia trachomatis to determine if pooling could be used to reduce the cost of detection. Pooling would be an accurate method and has thus far resulted in a cost-savings of 62.2%. (C) 2013 Elsevier Inc. All rights reserved. C1 [Dize, Laura; West, Sheila; Quinn, Thomas C.; Gaydos, Charlotte A.] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21218 USA. [Dize, Laura; West, Sheila; Quinn, Thomas C.; Gaydos, Charlotte A.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Dize, L (reprint author), Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21218 USA. EM Ldize2@jhmi.edu FU Intramural NIH HHS [ZIA AI000358-32] NR 16 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0732-8893 EI 1879-0070 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD DEC PY 2013 VL 77 IS 4 BP 289 EP 291 DI 10.1016/j.diagmicrobio.2013.08.005 PG 3 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 257WW UT WOS:000327419500003 PM 24079951 ER PT J AU Whirledge, S Cidlowski, JA AF Whirledge, Shannon Cidlowski, John A. TI A Role for Glucocorticoids in Stress-Impaired Reproduction: Beyond the Hypothalamus and Pituitary SO ENDOCRINOLOGY LA English DT Review ID BETA-HYDROXYSTEROID DEHYDROGENASE; RAT LEYDIG-CELLS; GONADOTROPIN-RELEASING-HORMONE; MESSENGER-RIBONUCLEIC-ACID; FOLLICLE-STIMULATING-HORMONE; IN-VITRO FERTILIZATION; TESTICULAR GERM-CELLS; OVARIAN 11-BETA-HYDROXYSTEROID DEHYDROGENASE; INTRAUTERINE GROWTH RESTRICTION; ENDOMETRIAL STROMAL CELLS AB In addition to the well-characterized role of the sex steroid receptors in regulating fertility and reproduction, reproductive events are also mediated by the hypothalamic-pituitary-adrenal axis in response to an individual's environment. Glucocorticoid secretion in response to stress contributes to the well-characterized suppression of the hypothalamic-pituitary-gonadal axis through central actions in the hypothalamus and pituitary. However, both animal and in vitro studies indicate that other components of the reproductive system are also regulated by glucocorticoids. Furthermore, in the absence of stress, it appears that homeostatic glucocorticoid signaling plays a significant role in reproduction and fertility in all tissues comprising the hypothalamic-pituitary-gonadal axis. Indeed, as central regulators of the immune response, glucocorticoids are uniquely poised to integrate an individual's infectious, inflammatory, stress, nutritional, and metabolic status through glucocorticoid receptor signaling in target tissues. Endocrine signaling between tissues regulating the immune and stress response and those determining reproductive status provides an evolutionary advantage, facilitating the trade-off between reproductive investment and offspring fitness. This review focuses on the actions of glucocorticoids in tissues important for fertility and reproduction, highlighting recent studies that show glucocorticoid signaling plays a significant role throughout the hypothalamic-pituitary-gonadal axis and characterizing these effects as permissive or inhibitory in terms of facilitating reproductive success. C1 [Whirledge, Shannon; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 251 TC 19 Z9 20 U1 4 U2 41 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD DEC PY 2013 VL 154 IS 12 BP 4450 EP 4468 DI 10.1210/en.2013-1652 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 259RY UT WOS:000327545200004 PM 24064362 ER PT J AU Mok, K Laaksovirta, H Tienari, PJ Peuralinna, T Myllykangas, L Chio, A Traynor, BJ Nalls, MA Gurunlian, N Shatunov, A Restagno, G Mora, G Leigh, PN Shaw, CE Morrison, KE Shaw, PJ Al-Chalabi, A Hardy, J Orrell, RW AF Mok, Kin Laaksovirta, Hannu Tienari, Pentti J. Peuralinna, Terhi Myllykangas, Liisa Chio, Adriano Traynor, Bryan J. Nalls, Michael A. Gurunlian, Nicole Shatunov, Aleksey Restagno, Gabriella Mora, Gabriele Leigh, P. Nigel Shaw, Chris E. Morrison, Karen E. Shaw, Pamela J. Al-Chalabi, Ammar Hardy, John Orrell, Richard W. TI Homozygosity analysis in amyotrophic lateral sclerosis SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE amyotrophic lateral sclerosis; homozygosity; recessive ID GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; HEXANUCLEOTIDE REPEAT; SUPEROXIDE-DISMUTASE; MUTATIONS; ALS; POPULATION; GENE; TRAFFICKING; PROTEIN AB Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length <2 Mb were identified, and 3568 rare segments remained after filtering 'common' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P = 0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P = 1 x 10(-5)), a greater proportion of cases harboured homozygosity (P = 2 x 10(-5))(,) a longer average length of segment (P = 1 x 10(-5)), a longer total genome coverage (P = 1 x 10(-5)), and a higher rate of these segments overlapped with RefSeq gene regions (P = 1 = 10 = 5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9-4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS. C1 [Mok, Kin; Gurunlian, Nicole; Hardy, John; Orrell, Richard W.] UCL, Inst Neurol, Dept Mol Neurosci, Reta Lila Weston Res Labs, London NW3 2PF, England. [Mok, Kin; Gurunlian, Nicole; Hardy, John; Orrell, Richard W.] UCL, Inst Neurol, Dept Clin Neurosci, London NW3 2PF, England. [Laaksovirta, Hannu] Univ Helsinki, Cent Hosp, Biomedicum, Dept Neurol,Mol Neurol Res Program, Helsinki, Finland. [Laaksovirta, Hannu; Tienari, Pentti J.; Peuralinna, Terhi; Traynor, Bryan J.; Nalls, Michael A.] NIA, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. [Laaksovirta, Hannu; Tienari, Pentti J.; Peuralinna, Terhi; Traynor, Bryan J.; Nalls, Michael A.] NIA, Neuromuscular Dis Res Grp, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Myllykangas, Liisa] Univ Helsinki, Dept Pathol, Haartman Inst, Helsinki, Finland. [Myllykangas, Liisa] HUSLAB, Helsinki, Finland. [Myllykangas, Liisa] Folkhalsan Inst Genet, Helsinki, Finland. [Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Chio, Adriano] Azienda Osped Univ San Giovanni Battista, Turin, Italy. [Shatunov, Aleksey; Shaw, Chris E.; Al-Chalabi, Ammar] Kings Coll London, Med Res Council Ctr Neurodegenerat Res, Inst Psychiat, London WC2R 2LS, England. [Restagno, Gabriella] Azienda Osped OIRM St Anna, Mol Genet Lab, Turin, Italy. [Mora, Gabriele] Fdn Salvatore Mangeri, IRCCS Sci Inst Milan, Milan, Italy. [Leigh, P. Nigel] Univ Sussex, Trafford Ctr Biomed Res, Brighton & Sussex Med Sch, Falmer, England. [Morrison, Karen E.] Univ Birmingham, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Morrison, Karen E.] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp, Birmingham, W Midlands, England. [Shaw, Pamela J.] Univ Sheffield, Dept Neurosci, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England. RP Orrell, RW (reprint author), UCL, Inst Neurol, Dept Clin Neurosci, Rowland Hill St, London NW3 2PF, England. EM r.orrell@ucl.ac.uk RI Al-Chalabi, Ammar/E-5361-2010; Hardy, John/C-2451-2009; Traynor, Bryan/G-5690-2010; Tienari, Pentti/A-4893-2012; Mok, Kin/F-5860-2012; OI Al-Chalabi, Ammar/0000-0002-4924-7712; Chio, Adriano/0000-0001-9579-5341 FU NIH; National Institute on Aging [Z01-AG000949-02]; National Institute of Neurological Disorders and Stroke; Extramural NIH grants [R01AG031278, R01AG038791]; European Community [259867]; Motor Neurone Disease Association of Great Britain; ALS Association; Angel Fund; ALS Therapy Alliance; Wellcome Trust; Reta Lila Weston Foundation; MRC; Microsoft Research Foundation; ALS Association, Helsinki University Central Hospital; Finnish Academy, Ministero della Salute, Progetti Finalizzati; Fondazione Vialli e Mauro for ALS; Federazione Italiana Giuoco Calcio; NIHR specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM); Institute of Psychiatry, King's College London; National Institute for Health Research FX This work was supported in part by the Intramural Research Programs of the NIH, the National Institute on Aging (Z01-AG000949-02), and the National Institute of Neurological Disorders and Stroke. Extramural NIH grants R01AG031278 and R01AG038791 supported some family assessments. The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259867. We thank the Motor Neurone Disease Association of Great Britain for several grants relating to this work (RWO, AAC, PJS, HM), the ALS Association, The Angel Fund, the ALS Therapy Alliance, and the Wellcome Trust (PJS) for support. This work was also funded by the Reta Lila Weston Foundation, and by an MRC returning scientist (JH) and fellowship (SPB) award, by Microsoft Research Foundation, the ALS Association, Helsinki University Central Hospital, the Finnish Academy, Ministero della Salute, Progetti Finalizzati 2007, Fondazione Vialli e Mauro for ALS, and Federazione Italiana Giuoco Calcio. The authors thank the NIHR specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry, King's College London, and the National Institute for Health Research-funded University College London / University College London Hospitals Biomedical Research Centre. NR 40 TC 10 Z9 10 U1 2 U2 6 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 DEC PY 2013 VL 21 IS 12 BP 1429 EP 1435 DI 10.1038/ejhg.2013.59 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 257AK UT WOS:000327355100017 PM 23612577 ER PT J AU DeCherney, AH AF DeCherney, Alan H. TI From partner's desk to iPad SO FERTILITY AND STERILITY LA English DT Editorial Material C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP DeCherney, AH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. NR 0 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2013 VL 100 IS 6 BP 1492 EP 1494 DI 10.1016/j.fertnstert.2013.10.004 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 259NG UT WOS:000327533000007 ER PT J AU Trabert, B Lamb, EJ Scoccia, B Moghissi, KS Westhoff, CL Niwa, S Brinton, LA AF Trabert, Britton Lamb, Emmet J. Scoccia, Bert Moghissi, Kamran S. Westhoff, Carolyn L. Niwa, Shelley Brinton, Louise A. TI Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort SO FERTILITY AND STERILITY LA English DT Article DE Ovarian cancer; risk; infertility; clomiphene citrate; gonadotropins ID FERTILITY DRUGS; WOMEN; STIMULATION; BREAST; TUMORS AB Objective: To examine the relationship of ovulation-inducing drugs and ovarian cancer. Design: Retrospective cohort study, with additional follow-up since initial report. Setting: Five large reproductive endocrinology practices. Patient(s): In a retrospective cohort of 9,825 women evaluated for infertility at five clinical sites in the United States between 1965 and 1988 with follow-up through 2010, we examined the relationship of ovulation-inducing drugs and ovarian cancer (n = 85). Intervention(s): None. Main Outcome Measure(s): Hazard rate ratios (RR) and 95% confidence intervals (CI) for ovarian cancer. Result(s): Among women evaluated for infertility, there was no association of ovarian cancer risk with ever use of clomiphene citrate (CC) (adjusted RR 1.34, 95% CI 0.86-2.07) or gonadotropins (RR 1.00, 95% CI 0.48-2.08) and no evidence that any of several more detailed subgroups of usage were related to an increased risk with one exception: women who used CC and remained nulligravid did demonstrate much higher risks than those who successfully conceived compared with nonusers (respectively, RR 3.63, 95% CI 1.36-9.72 vs. RR 0.88, 95% CI 0.47-1.63). Conclusion(s): Our overall results were reassuring and consistent with other studies. A reason for an association between CC use and ovarian cancer among persistently nulligravid women remains to be determined. Given the large and increasing number of women treated with ovulation-inducing drugs, the increased risk of ovarian cancer among the subset of women who remained nulligravid should be further monitored. (Fertil Steril (R) 2013;100:1660-6. (C)2013 by American Society for Reproductive Medicine.) C1 [Trabert, Britton; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lamb, Emmet J.] Stanford Univ, Dept Obstet & Gynecol, Stanford, CA 94305 USA. [Scoccia, Bert] Univ Illinois, Dept Obstet & Gynecol, Chicago, IL 60612 USA. [Moghissi, Kamran S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Westhoff, Carolyn L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Niwa, Shelley] Westat Corp, Rockville, MD USA. RP Trabert, B (reprint author), 9609 Med Ctr Dr,Room 7-E228,MSC 9774, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov RI Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015 OI Brinton, Louise/0000-0003-3853-8562; FU National Cancer Institute, National Institutes of Health FX Supported by the intramural research program of the National Cancer Institute, National Institutes of Health. NR 21 TC 11 Z9 12 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2013 VL 100 IS 6 BP 1660 EP 1666 DI 10.1016/j.fertnstert.2013.08.008 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 259NG UT WOS:000327533000036 PM 24011610 ER PT J AU Filiberto, AC Mumford, SL Pollack, AZ Zhang, CL Yeung, EH Schliep, KC Perkins, NJ Wactawski-Wende, J Schisterman, EF AF Filiberto, Amanda C. Mumford, Sunni L. Pollack, Anna Z. Zhang, Cuilin Yeung, Edwina H. Schliep, Karen C. Perkins, Neil J. Wactawski-Wende, Jean Schisterman, Enrique F. TI Usual dietary isoflavone intake and reproductive function across the menstrual cycle SO FERTILITY AND STERILITY LA English DT Article DE Isoflavone; anovulation; sex hormones; nutrition ID HORMONE-BINDING GLOBULIN; PREMENOPAUSAL WOMEN; MEDITERRANEAN DIET; SOY PROTEIN; POSTMENOPAUSAL WOMEN; US ADULTS; ADHERENCE; RISK; MEN; METABOLITES AB Objective: To assess the association of total isoflavone intake with ovulatory function, including sporadic anovulation in healthy premenopausal women. Design: Prospective cohort study. Setting: University. Patient(s): Participants included 259 healthy regularly menstruating women aged 18-44 years. Intervention(s): None. Main Outcome Measure(s): Serum concentrations of E-2, free E-2, P, LH, FSH, and SHBG and sporadic anovulation in healthy premenopausal women. Result(s): Isoflavone intake was not associated with E-2, free E-2, P, LH, and FSH concentrations. Consumption in the highest quartile (Q4: 1.6-78.8 mg/d) was significantly associated with greater SHBG concentrations (beta = 0.09; 95% confidence interval [CI] 0.02-0.16), compared with the first quartile (Q1: 0.0-0.3 mg/d). Conclusion(s): Isoflavone intake was not associated with sporadic anovulation (Q4 vs. Q1: odds ratio 0.87, 95% CI 0.32-1.66). Dietary isoflavone intake among young premenopausal women was not related to sex hormone concentrations or anovulation, but was associated with minimally increased SHBG concentrations. These results suggest potential endocrine effects with no subsequent effects on ovulation, easing concerns regarding their impacts on fertility. (Fertil Steril (R) 2013;100:1727-34. (C)2013 by American Society for Reproductive Medicine.) C1 [Filiberto, Amanda C.; Mumford, Sunni L.; Pollack, Anna Z.; Zhang, Cuilin; Yeung, Edwina H.; Schliep, Karen C.; Perkins, Neil J.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Schliep, Karen C.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. EM schistee@mail.nih.gov RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health FX Supported by the Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health. NR 32 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2013 VL 100 IS 6 BP 1727 EP 1734 DI 10.1016/j.fertnstert.2013.08.002 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 259NG UT WOS:000327533000046 PM 23998910 ER PT J AU Thompson, AJ Scholz, SW Singleton, AB Hardwick, A McFarland, NR Okun, MS AF Thompson, Amanda J. Scholz, Sonja W. Singleton, Andrew B. Hardwick, Angela McFarland, Nikolaus R. Okun, Michael S. TI Variability in clinical phenotypes of heterozygous and homozygous cases of Parkin-related Parkinson's disease SO INTERNATIONAL JOURNAL OF NEUROSCIENCE LA English DT Article DE Parkin; Parkinson's disease; levodopa-equivalent dose (LED); dyskinesias; PARK 2 ID STIMULATION AB Parkin mutations are a common cause of early-onset Parkinson's disease. To study the clinical features and treatment responses of patients with homozygous or heterozygous Parkin mutations, we performed a retrospective chart review in six early-onset parkinsonism patients with pathogenic Parkin mutations. The clinical phenotypes observed in this cohort, all drawn from different families, were variable. All patients had a slowly progressive form of parkinsonism that responded well to dopaminergic therapy with the exception of one advanced case. Homozygous patients had an earlier age at disease onset than heterozygous patients. Two of our patients underwent bilateral deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus leading to a sustained positive response. Our observations support an earlier age of onset for homozygous cases and possible beneficial effects of DBS in Parkin-related parkinsonism. C1 [Thompson, Amanda J.; Hardwick, Angela; McFarland, Nikolaus R.; Okun, Michael S.] Univ Florida, Ctr Movement Disorders & Neurorestorat, Dept Neurol, Gainesville, FL 32607 USA. [Thompson, Amanda J.; Hardwick, Angela; McFarland, Nikolaus R.; Okun, Michael S.] Univ Florida, Ctr Movement Disorders & Neurorestorat, Dept Neurosurg, Gainesville, FL 32607 USA. [Scholz, Sonja W.] Georgetown Univ, Dept Neurosci, Washington, DC USA. [Scholz, Sonja W.; Singleton, Andrew B.] NIH, Neurogenet Lab, Bethesda, MD 20892 USA. RP Okun, MS (reprint author), Univ Florida, Ctr Movement Disorders & Neurorestorat, Dept Neurol, Gainesville, FL 32607 USA. EM okun@neurology.ufl.edu RI Singleton, Andrew/C-3010-2009; OI McFarland, Nikolaus/0000-0002-8699-8857; Okun, Michael/0000-0002-6247-9358; Scholz, Sonja/0000-0002-6623-0429 FU NIH; NPF; Michael J. Fox Foundation; Parkinson Alliance; Smallwood Foundation; UF Foundation; USF CME office; PeerView; Vanderbilt University; Medtronic; ANS/St. Jude FX The authors alone are responsible for the content and writing of the article. Dr. Okun serves as a consultant for the National Parkinson Foundation, and has received research grants from NIH, NPF, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, and the UF Foundation. Dr. Okun has previously received honoraria, but in the past >36 months has received no support from industry including travel. Dr. Okun has received royalties for publications with Demos, Manson, and Cambridge (movement disorders books). Dr. Okun has participated in CME activities on movement disorders sponsored by the USF CME office, PeerView, and by Vanderbilt University. The institution and not Dr. Okun receives grants from Medtronic and ANS/St. Jude, and the PI has no financial interest in these grants. Dr. Okun has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. NR 7 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0020-7454 EI 1563-5279 J9 INT J NEUROSCI JI Int. J. Neurosci. PD DEC PY 2013 VL 123 IS 12 BP 847 EP 849 DI 10.3109/00207454.2013.810626 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 255RV UT WOS:000327258400004 PM 23767969 ER PT J AU Nichols, SL Bethel, J Garvie, PA Patton, DE Thornton, S Kapogiannis, BG Ren, WJ Major-Wilson, H Puga, A Woods, SP AF Nichols, Sharon L. Bethel, James Garvie, Patricia A. Patton, Doyle E. Thornton, Sarah Kapogiannis, Bill G. Ren, Weijia Major-Wilson, Hanna Puga, Ana Woods, Steven P. TI Neurocognitive Functioning in Antiretroviral Therapy-Naive Youth With Behaviorally Acquired Human Immunodeficiency Virus SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE HIV; Adolescent; Neurocognitive functioning; Substance use; HIV-associated neurocognitive disorder ID HIV-INFECTION; NEUROPSYCHOLOGICAL IMPAIRMENT; MEDICATION ADHERENCE; DISORDERS; MEMORY; INDIVIDUALS; ADOLESCENCE; HIV/AIDS; DEMENTIA; WORKING AB Purpose: Youth living with human immunodeficiency virus (HIV) account for over one third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. Human immunodeficiency virus-associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy. Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here, we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use. Methods: A total of 220 participants, age 18-24 years, who were naive to treatment (except for prevention of mother-to-child HIV transmission; n = 3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery. Results: Sixty-seven percent of youth met criteria for HAND (96.4% were asymptomatic and 3.5% were syndromic); deficits in episodic memory and fine-motor skills emerged as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high-risk alcohol use were uniquely associated with neurocognitive deficits. Conclusions: Over two thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e. g., nonadherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy. (C) 2013 Society for Adolescent Health and Medicine. All rights reserved. C1 [Nichols, Sharon L.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Bethel, James; Thornton, Sarah; Ren, Weijia] Westat Corp, Rockville, MD USA. [Patton, Doyle E.; Puga, Ana] Childrens Diagnost & Treatment Ctr Inc, Ft Lauderdale, FL USA. [Kapogiannis, Bill G.] NIH, Bethesda, MD 20892 USA. [Major-Wilson, Hanna] Univ Miami, Dept Pediat, Div Adolescent Med, Miami, FL 33152 USA. [Woods, Steven P.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Nichols, SL (reprint author), Univ Calif San Diego, Dept Neurosci, 9500 Gilman Dr,0935, La Jolla, CA 92093 USA. EM slnichols@ucsd.edu FU Adolescent Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health through the National Institute of Child Health and Human Development [U01-HD040533]; National Institutes of Drug Abuse; National Institutes of Drug Abuse [R01 DA DA031017]; National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [U01 A1068632]; ATN Coordinating Center at the University of Alabama at Birmingham FX This work was supported by the Adolescent Trials Network for HIV/AIDS Interventions (ATN; Grant U01-HD040533) from the National Institutes of Health through the National Institute of Child Health and Human Development (B. Kapogiannis, C. Worrell), with supplemental funding from the National Institutes of Drug Abuse (N. Borek, D. Lawrence) and Mental Health (P. Brouwers, S. Allison), and Grant R01 DA DA031017 from the National Institutes of Drug Abuse. The protocol was co-endorsed by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group. Support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) [U01 A1068632]. The study was scientifically reviewed by the ATN's Behavioral Leadership Group. Network, scientific, and logistical support was provided by the ATN Coordinating Center (C. Wilson, C. Partlow) at the University of Alabama at Birmingham. Network operations and data management support was provided by the ATN Data and Operations Center at Westat, Inc. (J. Korelitz, B. Driver). Please note that listing in the acknowledgments section does not imply endorsement of the findings and conclusions of this article. The authors acknowledge the contribution of the investigators and staff at the following ATN 071 and IMPAACT sites that participated in this study (listed in order of Site Principal Investigator, Study Coordinator, Psychologist): University of South Florida (Patricia Emmanuel, M. D., Priscilla Julian, RN, Tiffany Chenneville, Ph.D.); Children's Hospital of Los Angeles (Marvin Belzer, M. D., Michelle Bradford, B. A., Anita Hamilton, Ph.D., ABPP-CN); Children's National Medical Center (Lawrence D'Angelo, M. D., Connie Trexler, RN, Donna Marschall, Ph.D.); University of Pennsylvania and the Children's Hospital of Philadelphia (Mary Tanney, M. P. H., M.S.N., C.P.N.P., Linda Hawkins, M. S., Ed.D.; Jerilynn Radcliffe, Ph.D.); Stroger Hospital and the CORE Center (Jaime Martinez, M. D., Kelly Bojan, D.N.P., Harold Fuentes, Psy.D.); University Pediatric Hospital (Irma Febo, M. D., Hazel Ayala-Flores, B.S.N., Nydia Scalley-Trifilio, M. A.); Montefiore Medical Center (Donna Futterman, M. D., Elizabeth Bruce, M. D., Erica Weiss, M. A.); Mount Sinai Medical Center, Adolescent Health Center (John Steever, M. D., Mary Geiger, M. P. H., Marijane Lehr, Ph.D.); University of California, San Francisco (Barbara Moscicki, M. D., Lisa Irish, B.S.N., Rita Jeremy, Ph.D.); Tulane Medical Center (Sue Ellen Abdalian, M. D., Leslie Kozina, RN, Patricia Sirois, Ph.D.); University of Maryland (Vicki Tepper, Ph.D., Reshma Gorle, M. P. H., Terry Lee-Wilk, Ph.D.); University of Miami School of Medicine (Lawrence Friedman, M. D., Donna Maturo, M.S.N., Anai Cuadra, Ph.D.); Children's Diagnostic and Treatment Center (Ana Puga, M. D., Amy Inman, B. S., Doyle Patton, Ph.D.); St Jude Children's Research Hospital (Patricia Flynn, M. D., Mary Dillard, B.S.N, Patricia Garvie, Ph.D., Megan Wilkins, Ph.D.); Lurie Children's Hospital (Robert Garofalo, M. D., M. P. H., Ann Sanders, M. P. H., Andrea Boyd, Ph.D.); University of Southern California (Andrea Kovacs, M. D., Michelle Aranda, M. P. H., Maribel Mejia, Ph.D.); Children's Hospital of Michigan (Ellen Moore, M. D., Ayanna Walters, RN, Salome Cockern, Ph.D.); Children's Hospital of Denver (Elizabeth McFarland, M. D., Kerry Hahn, B. S.; , CCRP, Robin McEvoy, Ph.D.); Howard University (Sohail Rana, M. D., Meseret Deressa, M. P. H, Eshauna Padilla, M. A.); and Johns Hopkins University (Allison George Agwu, M. D., Todd Noletto, M. P. H., Laura Margolis, Ph.D.). The authors sincerely thank additional ATN 071 Protocol Team Members (Pim Brouwers, Ph.D., Tiandong Li, Ph.D., Craig Wilson, M. D.), the ATN Community Advisory Board, and the youth who participated in the study. An oral presentation of portions of this study was made at the bi-annual Adolescent Medicine Trials Network for HIV/AIDS Intervention Meeting in Bethesda, Maryland, on April 11, 2011. The authors extend sincere gratitude to Pim Brouwers, Ph.D., for his comments on earlier versions of the manuscript, and Tiandong Li, Ph.D., for statistical analysis and consultation. NR 42 TC 11 Z9 11 U1 1 U2 9 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 DEC PY 2013 VL 53 IS 6 BP 763 EP 771 DI 10.1016/j.jadohealth.2013.07.006 PG 9 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 258TJ UT WOS:000327481300015 PM 23972941 ER PT J AU Myers, VH Mcvay, MA Champagne, CM Hollis, JF Coughlin, JW Funk, KL Gullion, CM Jerome, GJ Loria, CM Samuel-Hodge, CD Stevens, VJ Svetkey, LP Brantley, PJ AF Myers, Valerie H. McVay, Megan A. Champagne, Catherine M. Hollis, Jack F. Coughlin, Janelle W. Funk, Kristine L. Gullion, Christina M. Jerome, Gerald J. Loria, Catherine M. Samuel-Hodge, Carmen D. Stevens, Victor J. Svetkey, Laura P. Brantley, Phillip J. TI Weight loss history as a predictor of weight loss: results from Phase I of the weight loss maintenance trial SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Weight loss history; Previous weight; Weight loss method; Behavioral; Lifestyle; Greatest weight loss ID DIABETES PREVENTION PROGRAM; DIETARY-SUPPLEMENTS; PHYSICAL-ACTIVITY; PRETREATMENT PREDICTORS; MISSING DATA; OBESITY; REDUCTION; WOMEN; BEHAVIOR; INTERVENTIONS AB Past studies have suggested that weight loss history is associated with subsequent weight loss. However, questions remain whether method and amount of weight lost in previous attempts impacts current weight loss efforts. This study utilized data from the Weight Loss Maintenance Trial to examine the association between weight loss history and weight loss outcomes in a diverse sample of high-risk individuals. Multivariate regression analysis was conducted to determine which specific aspects of weight loss history predict change in weight during a 6-month weight loss intervention. Greater weight loss was predicted by fewer previous weight loss attempts with assistance (p = 0.03), absence of previous dietary/herbal weight loss supplement use (p = 0.01), and greater maximum weight loss in previous attempts (p < 0.001). Future interventions may benefit from assessment of weight loss history and tailoring of interventions based on past weight loss behaviors and outcomes. C1 [Myers, Valerie H.; McVay, Megan A.; Champagne, Catherine M.; Brantley, Phillip J.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Hollis, Jack F.; Funk, Kristine L.; Gullion, Christina M.; Stevens, Victor J.] Kaiser Permanente Ctr Hlth Res, Portland, OR 97227 USA. [Coughlin, Janelle W.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Jerome, Gerald J.] Towson Univ, Towson, MD 21252 USA. [Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. [Samuel-Hodge, Carmen D.] Univ N Carolina, Gillings Sch Publ Hlth, Chapel Hill, NC 27599 USA. [Samuel-Hodge, Carmen D.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Svetkey, Laura P.] Duke Univ, Med Ctr, Durham, NC 27705 USA. RP Myers, VH (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM valerie.myers@pbrc.edu; meganamcvay@gmail.com; catherine.champagne@pbrc.edu; Jack.Hollis@kpchr.org; jwilder3@jhmi.edu; Kristine.Funk@kpchr.org; Christina.Gullion@kpchr.org; GJerome@towson.edu; loriac@nih.gov; carmen_samuel@unc.edu; victor.j.stevens@kpchr.org; svetk001@mc.duke.edu; brantlpj@pbrc.edu OI Jerome, Gerald/0000-0003-0612-2626 FU NHLBI NIH HHS [5-U01 HL68920, 5-HL 68955, 5-U01 HL68676, 5-U01 HL68790, U01 HL068676, U01 HL068734, U01 HL068790, U01 HL068920, U01 HL068955]; PHS HHS [5-U01 68734] NR 35 TC 3 Z9 3 U1 1 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 EI 1573-3521 J9 J BEHAV MED JI J. Behav. Med. PD DEC PY 2013 VL 36 IS 6 BP 574 EP 582 DI 10.1007/s10865-012-9450-0 PG 9 WC Psychology, Clinical SC Psychology GA 255BL UT WOS:000327214100004 PM 22907176 ER PT J AU Peabody, NC White, BH AF Peabody, Nathan C. White, Benjamin H. TI Eclosion gates progression of the adult ecdysis sequence of Drosophila SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE hormones; behavior; innate; circuit ID IMAGINAL ECDYSIS; WING EXPANSION; INSECT ECDYSIS; BEHAVIORAL SEQUENCE; DECISION NETWORK; CELL-DEATH; BURSICON; HORMONE; ROLES; MELANOGASTER AB Animal behavior is often organized into stereotyped sequences that promote the goals of reproduction, development and survival. However, for most behaviors, the neural mechanisms that govern the order of execution of the motor programs within a sequence are poorly understood. An important model in understanding the hormonal determinants of behavioral sequencing is the ecdysis sequence, which is performed by insects at each developmental transition, or molt. The adult ecdysis sequence in Drosophila includes the emergence of the insect from the pupal case followed by expansion and hardening of the wings. Wing expansion is governed by the hormone bursicon, and stimulation of the bursicon-expressing neurons in newly eclosed flies induces rapid wing expansion. Here we show that that such stimulation delivered prior to eclosion has no immediate effect, but does cause rapid wing expansion after eclosion if the stimulus is delivered within 40 min of that event. We observe a similar delayed effect upon stimulation of a single pair of bursicon-expressing neurons previously identified as command neurons for wing expansion. We conclude that command neuron stimulation enables the motor output pathway for wing expansion, but that this pathway is blocked prior to eclosion. By manipulating the time of eclosion, we demonstrate that some physiological process tightly coupled to adult ecdysis releases the block on wing expansion. Eclosion thus serves as a behavioral checkpoint and complements hormonal mechanisms to ensure that wing expansion strictly follows eclosion in the ecdysis sequence. C1 [Peabody, Nathan C.; White, Benjamin H.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP White, BH (reprint author), NIMH, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM benjaminwhite@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health [1ZIA-MH-002800-07] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health (Project 1ZIA-MH-002800-07 to B. H. W.). Deposited in PMC for release after 12 months. NR 25 TC 0 Z9 0 U1 0 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 EI 1477-9145 J9 J EXP BIOL JI J. Exp. Biol. PD DEC PY 2013 VL 216 IS 23 BP 4395 EP 4402 DI 10.1242/jeb.091595 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 258YZ UT WOS:000327495900020 PM 24031052 ER PT J AU Slaughter, J Wei, CS Korzeniewski, SJ Lu, Q Beck, JS Khoo, SK Brovont, A Maurer, J Martin, D Lenski, M Paneth, N AF Slaughter, Jaime Wei, Changshuai Korzeniewski, Steven J. Lu, Qing Beck, John S. Khoo, Sok Kean Brovont, Ariel Maurer, Joel Martin, Denny Lenski, Madeleine Paneth, Nigel TI High correlations in gene expression between paired umbilical cord blood and neonatal blood of healthy newborns on Guthrie cards SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Archived newborn blood spots; genes and transcripts; genome-wide; messenger RNAs; oligonucleotide microarrays ID DISEASE; SPOTS AB Objective: To examine the correlation in genes expressed in paired umbilical cord blood (UCB) and newborn blood (NB). Method: Total mRNA and mRNA of three gene sets (inflammatory, hypoxia, and thyroidal response) was assessed using microarray in UCB and NB spotted on Guthrie cards from 7 mother/infant pairs. Results: The average gene expression correlation between paired UCB and NB samples was 0.941 when all expressed genes were considered, and 0.949 for three selected gene sets. Conclusion: The high correlation of UCB and NB gene expression suggest that either source may be useful for examining gene expression in the perinatal period. C1 [Slaughter, Jaime; Wei, Changshuai; Lu, Qing; Brovont, Ariel; Lenski, Madeleine; Paneth, Nigel] Michigan State Univ, Coll Human Med, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Korzeniewski, Steven J.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Korzeniewski, Steven J.] NICHHD, Perinatal Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Beck, John S.; Khoo, Sok Kean] Van Andel Inst, Lab Microarray Technol, Grand Rapids, MI USA. [Maurer, Joel; Martin, Denny] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, E Lansing, MI 48824 USA. [Paneth, Nigel] Michigan State Univ, Coll Human Med, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. RP Paneth, N (reprint author), Michigan State Univ, 909 Fee Rd Room 218, E Lansing, MI 48824 USA. EM paneth@msu.edu RI Wei, Changshuai/A-7750-2015; OI Wei, Changshuai/0000-0003-0148-6797; Slaughter-Acey, Jaime/0000-0002-8897-1244 FU Wayne State University Perinatal Initiative; NIH [R01 NS055101]; [T32 HD046377] FX The authors have no conflicts of interests. This research was supported in part by the Wayne State University Perinatal Initiative and funded by NIH R01 NS055101 to Dr. Paneth. Dr. Slaughter is funded by T32 HD046377. NR 10 TC 2 Z9 2 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD DEC PY 2013 VL 26 IS 18 BP 1765 EP 1767 DI 10.3109/14767058.2013.804050 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 256OA UT WOS:000327321900001 PM 23668672 ER PT J AU Mehta, GU Sheehan, JP Vance, ML AF Mehta, Gautam U. Sheehan, Jason P. Vance, Mary Lee TI Effect of stereotactic radio surgery before bilateral adrenalectomy for Cushing's disease on the incidence of Nelson's syndrome SO JOURNAL OF NEUROSURGERY LA English DT Article DE adrenalectomy; Cushing's disease; Gamma Knife; Nelson's syndrome; stereotactic radiosurgery; pituitary surgery ID GAMMA-KNIFE SURGERY; PITUITARY-ADENOMAS; RADIOSURGERY; TUMOR AB Object. Nelson's syndrome (NS) is a significant and frequent risk for patients with Cushing's disease (CD) who undergo bilateral adrenalectomy. A recent study has shown tumor progression in 47% of patients at risk for NS. The authors sought to define the rate of NS in patients who were treated with Gamma Knife stereotactic radiosurgery (GK SRS) prior to bilateral adrenalectomy. Methods. Consecutive patients with CD who were treated with GK SRS after pituitary surgery but before bilateral adrenalectomy were included. Serial MRI sequences were analyzed to evaluate for pituitary tumor growth. Clinical evaluations were performed to screen for NS. Follow-up for adrenocorticotropic hormone levels and hormone studies of other pituitary axes was performed. Results. Twenty consecutive patients were followed with neuroimaging and clinically for a median of 5.4 years (range 0.6-12 years). One patient (5%) developed pituitary tumor growth consistent with NS 9 months after adrenalectomy. By Kaplan-Meier analysis, progression-free survival was 94.7% at 1, 3, and 7 years. No predisposing factors were identified for the tumor progression. Two patients developed new pituitary dysfunction and no patient developed cranial neuropathy or visual deficit after GK SRS. Conclusions. These findings suggest that GK SRS not only serves a role as second-line therapy for CD, but that it also provides prophylaxis for NS when used before bilateral adrenalectomy. C1 [Mehta, Gautam U.; Sheehan, Jason P.] Univ Virginia Hlth Syst, Dept Neurosurg, Charlottesville, VA 22908 USA. [Vance, Mary Lee] Univ Virginia Hlth Syst, Dept Med, Charlottesville, VA 22908 USA. [Mehta, Gautam U.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Vance, ML (reprint author), Univ Virginia Hlth Syst, Dept Med, Charlottesville, VA 22908 USA. EM mlv@virginia.edu OI Mehta, Gautam/0000-0002-8009-6430 FU Intramural NIH HHS NR 24 TC 10 Z9 10 U1 1 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2013 VL 119 IS 6 BP 1493 EP 1497 DI 10.3171/2013.7.JNS13389 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 257EU UT WOS:000327367200021 PM 23952749 ER PT J AU Guo, F Simons-Morton, BG Klauer, SE Ouimet, MC Dingus, TA Lee, SE AF Guo, Feng Simons-Morton, Bruce G. Klauer, Sheila E. Ouimet, Marie Claude Dingus, Thomas A. Lee, Suzanne E. TI Variability in Crash and Near-Crash Risk among Novice Teenage Drivers: A Naturalistic Study SO JOURNAL OF PEDIATRICS LA English DT Article ID SENSATION-SEEKING; DRIVING BEHAVIOR; PERSONALITY; PASSENGERS; INVOLVEMENT; PERFORMANCE; EXPERIENCE; SIMULATOR AB Objective Using video monitoring technologies, we investigated teenage driving risk variation during the first 18 months of independent driving. Study design Driving data were collected on 42 teenagers whose vehicles were instrumented with sophisticated video and data recording devices. Surveys on demographic and personality characteristics were administered at baseline. Drivers were classified into 3 risk groups using a K-mean clustering method based on crash and near-crash (CNC) rate. The change in CNC rates over time was evaluated by mixed-effect Poisson models. Results Compared with the first 3 months after licensure (first quarter), the CNC rate for participants during the third, fourth, and fifth quarters decreased significantly to 59%, 62%, and 48%, respectively. Three distinct risk groups were identified with CNC rates of 21.8 (high-risk), 8.3 (moderate-risk), and 2.1 (low-risk) per 10 000 km traveled. High-and low-risk drivers showed no significant change in CNC rates throughout the 18-month study period. CNC rates for moderate-risk drivers decreased substantially from 8.8 per 10 000 km in the first quarter to 0.8 and 3.2 in the fourth and fifth quarters, respectively. The 3 groups were not distinguishable with respect to personality characteristics. Conclusion Teenage CNC rates varied substantially, with distinct high-, moderate-, and low-risk groups. Risk declined over time only in the moderate-risk group. The high-risk drivers appeared to be insensitive to experience, with CNC rates consistently high throughout the 18-month study period, and the moderate-risk group appeared to learn from experience. C1 [Guo, Feng] Virginia Tech, Dept Stat, Blacksburg, VA 24061 USA. [Guo, Feng; Klauer, Sheila E.; Dingus, Thomas A.; Lee, Suzanne E.] Virginia Tech, Transportat Inst, Blacksburg, VA 24061 USA. [Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Longueuil, PQ, Canada. [Dingus, Thomas A.] Virginia Tech, Charles E Via Jr Dept Civil & Environm Engn, Blacksburg, VA 24061 USA. RP Guo, F (reprint author), Virginia Tech, Transportat Inst, 3500 Transportat Res Plaza, Blacksburg, VA 24061 USA. EM feng.guo@vt.edu OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-5-3405]; National Highway Traffic Safety Administration; career grant from the Quebec Health Research Fund (Fonds de recherche du Quebec-Sante) FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01-HD-5-3405) and by the National Highway Traffic Safety Administration. M.O. was supported by a career grant from the Quebec Health Research Fund (Fonds de recherche du Quebec-Sante). The authors declare no conflicts of interest. NR 32 TC 6 Z9 6 U1 0 U2 11 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 DEC PY 2013 VL 163 IS 6 BP 1670 EP 1676 DI 10.1016/j.jpeds.2013.07.025 PG 7 WC Pediatrics SC Pediatrics GA 259RE UT WOS:000327543200032 PM 23992677 ER PT J AU McGuire, PJ Lee, HS Summar, ML AF McGuire, Peter J. Lee, Hye-Seung Summar, Marshall L. CA Urea Cycle Disorders Consoritum TI Infectious Precipitants of Acute Hyperammonemia Are Associated with Indicators of Increased Morbidity in Patients with Urea Cycle Disorders SO JOURNAL OF PEDIATRICS LA English DT Article ID MULTICENTER; MANAGEMENT; MORTALITY AB Objective To prospectively characterize acute hyperammonemic episodes in patients with urea cycle disorders (UCDs) in terms of precipitating factors, treatments, and use of medical resources. Study design This was a prospective, longitudinal observational study of hyperammonemic episodes in patients with UCD enrolled in the National Institutes of Health-sponsored Urea Cycle Disorders Consortium Longitudinal Study. An acute hyperammonemic event was defined as plasma ammonia level >100 mu mol/L. Physician-reported data regarding the precipitating event and laboratory and clinical variables were recorded in a central database. Results In our study population, 128 patients with UCD experienced a total of 413 hyperammonemia events. Most patients experienced between 1 and 3 (65%) or between 4 and 6 (23%) hyperammonemia events since study inception, averaging fewer than 1 event/year. The most common identifiable precipitant was infection (33%), 24% of which were upper/lower respiratory tract infections. Indicators of increased morbidity were seen with infection, including increased hospitalization rates (P = .02), longer hospital stays (+2.0 days; P = .003), and increased use of intravenous ammonia scavengers (+45%-52%; P = .003-.03). Conclusion Infection is the most common precipitant of acute hyperammonemia in patients with UCD and is associated with indicators of increased morbidity (ie, hospitalization rate, length of stay, and use of intravenous ammonia scavengers). These findings suggest that the catabolic and immune effects of infection may be a target for clinical intervention in inborn errors of metabolism. C1 [McGuire, Peter J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Lee, Hye-Seung] Univ S Florida, Dept Pediat, Pediat Epidemiol Ctr, Tampa, FL 33620 USA. [Summar, Marshall L.] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. RP McGuire, PJ (reprint author), NHGRI, NIH, 49 Convent Dr,Room 4A62, Bethesda, MD 20892 USA. EM peter.mcguire@nih.gov FU NIH FX We wish to recognize the efforts of Dr Danuta Krotoski (National Institutes of Health [NIH]) for programmatic support for the UCDC, and Dr Mary Lou Oster-Granite (NIH) for scientific support. We also thank Cindy LeMons (Executive Director, National Urea Cycle Disorders Foundation) for support and direction, and Dr Les Biesecker (who is funded by the NIH, serves as an advisor to the Illumina Corp, receives royalties from Genentech Corp, and receives compensation for editorial duties by Wiley-Blackwell Corp) for his guidance and the support of the Physician Scientist Development Program at National Human Genome Research Institute. NR 13 TC 13 Z9 13 U1 0 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 DEC PY 2013 VL 163 IS 6 BP 1705 EP U254 DI 10.1016/j.jpeds.2013.08.029 PG 7 WC Pediatrics SC Pediatrics GA 259RE UT WOS:000327543200037 PM 24084106 ER PT J AU Kramer, RM Zeng, YH Sahni, N Kueltzo, LA Schwartz, RM Srivastava, IK Crane, L Joshi, SB Volkin, DB Middaugh, CR AF Kramer, Ryan M. Zeng, Yuhong Sahni, Neha Kueltzo, Lisa A. Schwartz, Richard M. Srivastava, Indresh K. Crane, Lindsey Joshi, Sangeeta B. Volkin, David B. Middaugh, C. Russell TI Development of a Stable Virus-Like Particle Vaccine Formulation against Chikungunya Virus and Investigation of the Effects of Polyanions SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE stabilization; thermal analysis; vaccines; particle size; physical stability; physicochemical properties; preformulation; spectroscopy; protein formulation ID INDIAN-OCEAN; INFECTION; OUTBREAK; PH; TRAVELERS; DISEASES; COHORT; FEVER AB Chikungunya virus (CHIKV) is an alphavirus that infects millions of people every year, especially in the developing world. The selective expression of recombinant CHIKV capsid and envelope proteins results in the formation of self-assembled virus-like particles (VLPs) that have been shown to protect nonhuman primates against infection from multiple strains of CHIKV. This study describes the characterization, excipient screening, and optimization of CHIKV VLP solution conditions toward the development of a stable parenteral formulation. The CHIKV VLPs were found to be poorly soluble at pH 6 and below. Circular dichroism, intrinsic fluorescence, and static and dynamic light scattering measurements were therefore performed at neutral pH, and results consistent with the formation of molten globule structures were observed at elevated temperatures. A library of generally recognized as safe excipients was screened for their ability to physically stabilize CHIKV VLPs using a high-throughput turbidity-based assay. Sugars, sugar alcohols, and polyanions were identified as potential stabilizers and the concentrations and combinations of select excipients were optimized. The effects of polyanions were further studied, and while all polyanions tested stabilized CHIKV VLPs against aggregation, the effects of polyanions on conformational stability varied. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4305-4314, 2013 C1 [Kramer, Ryan M.; Zeng, Yuhong; Sahni, Neha; Crane, Lindsey; Joshi, Sangeeta B.; Volkin, David B.; Middaugh, C. Russell] Univ Kansas, Macromol & Vaccine Stabilizat Ctr, Dept Pharmaceut Chem, Lawrence, KS 66047 USA. [Kueltzo, Lisa A.; Schwartz, Richard M.] NIAID, Vaccine Prod Program, Vaccine Res Ctr, NIH, Gaithersburg, MD 20878 USA. [Srivastava, Indresh K.] Prot Sci Corp, Meriden, CT 06450 USA. RP Middaugh, CR (reprint author), Univ Kansas, Macromol & Vaccine Stabilizat Ctr, Dept Pharmaceut Chem, Lawrence, KS 66047 USA. EM Middaugh@Ku.Edu FU National Cancer Institute, National Institutes of Health [HHSN26120080001E] 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 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. NR 24 TC 11 Z9 11 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3549 EI 1520-6017 J9 J PHARM SCI-US JI J. Pharm. Sci. PD DEC PY 2013 VL 102 IS 12 BP 4305 EP 4314 DI 10.1002/jps.23749 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 254UM UT WOS:000327193300010 PM 24129946 ER PT J AU Sinha, BK Kumar, A Bhattacharjee, S Espey, MG Mason, RP AF Sinha, Birandra K. Kumar, Ashutosh Bhattacharjee, Suchandra Espey, Michael G. Mason, Ronald P. TI Effect of Nitric Oxide on the Anticancer Activity of the Topoisomerase-Active Drugs Etoposide and Adriamycin in Human Melanoma Cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CISPLATIN-INDUCED APOPTOSIS; FREE-RADICAL FORMATION; BREAST TUMOR-CELLS; CATALYZED METABOLISM; NITROGEN-OXIDES; O-DEMETHYLATION; CANCER CELLS; DNA; CYTOTOXICITY; MACROPHAGES AB Nitric oxide ((NO)-N-center dot) was originally identified as an innate cytotoxin. However, in tumors it can enhance resistance to chemotherapy and exacerbate cancer progression. Our previous studies indicated that (NO)-N-center dot/(NO)-N-center dot-derived species react with etoposide (VP-16) in vitro and form products that show significantly reduced activity toward HL60 cells and lipopolysaccharide (LPS)-induced macrophages. Here, we further confirm the hypothesis that (NO)-N-divided by generation contributes to VP-16 resistance by examining interactions of (NO)-N-center dot with VP-16 in inducible nitric-oxide synthase (iNOS)-expressing human melanoma A375 cells. Inhibition of iNOS catalysis by N-6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) in human melanoma A375 cells reversed VP-16 resistance, leading to increased DNA damage and apoptosis. Furthermore, we found that coculturing A375 melanoma cells with LPS-induced macrophage RAW cells also significantly reduced VP-16 cytotoxicity and DNA damage in A375 cells. We also examined the interactions of (NO)-N-center dot with another topoisomerase active drug, Adriamycin, in A375 cells. In contrast, to VP-16, (NO)-N-center dot caused no significant modulation of cytotoxicity or Adriamycin-dependent apoptosis, suggesting that (NO)-N-center dot does not interact with Adriamycin. Our studies support the hypothesis that (NO)-N-center dot oxidative chemistry can detoxify VP-16 through direct nitrogen oxide radical attack. Our results provide insights into the pharmacology and anticancer mechanisms of VP-16 that may ultimately contribute to increased resistance, treatment failure, and induction of secondary leukemia in VP-16-treated patients. C1 [Sinha, Birandra K.; Kumar, Ashutosh; Bhattacharjee, Suchandra; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Espey, Michael G.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Sinha, BK (reprint author), NIEHS, Res Triangle Pk, NC 27709 USA. EM sinha1@niehs.nih.gov FU National Institutes of Health [National Institute of Environmental Health Sciences] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences]. NR 59 TC 7 Z9 7 U1 0 U2 7 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 DEC PY 2013 VL 347 IS 3 BP 607 EP 614 DI 10.1124/jpet.113.207928 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 258IQ UT WOS:000327453200009 PM 24049059 ER PT J AU Oosthuyzen, W Sime, NEL Ivy, JR Turtle, EJ Street, JM Pound, J Bath, LE Webb, DJ Gregory, CD Bailey, MA Dear, JW AF Oosthuyzen, Wilna Sime, Nicole E. L. Ivy, Jessica R. Turtle, Emma J. Street, Jonathan M. Pound, John Bath, Louise E. Webb, David J. Gregory, Christopher D. Bailey, Matthew A. Dear, James W. TI Quantification of human urinary exosomes by nanoparticle tracking analysis SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID VESICLES; CELLS; BIOMARKERS; DISCOVERY; DISTINCT; DISEASE AB Exosomes are vesicles that are released from the kidney into urine. They contain protein and RNA from the glomerulus and all sections of the nephron and represent a reservoir for biomarker discovery. Current methods for the identification and quantification of urinary exosomes are time consuming and only semi-quantitative. Nanoparticle tracking analysis (NTA) counts and sizes particles by measuring their Brownian motion in solution. In this study, we applied NTA to human urine and identified particles with a range of sizes. Using antibodies against the exosomal proteins CD24 and aquaporin 2 (AQP2), conjugated to a fluorophore, we could identify a subpopulation of CD24- and AQP2-positive particles of characteristic exosomal size. Extensive pre-NTA processing of urine was not necessary. However, the intra-assay variability in the measurement of exosome concentration was significantly reduced when an ultracentrifugation step preceded NTA. Without any sample processing, NTA tracked exosomal AQP2 upregulation induced by desmopressin stimulation of kidney collecting duct cells. Nanoparticle tracking analysis was also able to track changes in exosomal AQP2 concentration that followed desmopressin treatment of mice and a patient with central diabetes insipidus. When urine was stored at room temperature, 4 degrees C or frozen, nanoparticle concentration was reduced; freezing at -80 degrees C with the addition of protease inhibitors produced the least reduction. In conclusion, with appropriate sample storage, NTA has potential as a tool for the characterization and quantification of extracellular vesicles in human urine. C1 [Oosthuyzen, Wilna; Sime, Nicole E. L.; Ivy, Jessica R.; Turtle, Emma J.; Webb, David J.; Bailey, Matthew A.; Dear, James W.] Univ Edinburgh, British Heart Fdn Ctr Cardiovasc Sci, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland. [Street, Jonathan M.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. [Pound, John; Gregory, Christopher D.] Univ Edinburgh, MRC Ctr Inflammat Res, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland. [Bath, Louise E.] Royal Hosp Sick Children, Natl Hlth Serv Lothian, Edinburgh Ctr Endocrinol, Edinburgh EH9 1LF, Midlothian, Scotland. RP Dear, JW (reprint author), Univ Edinburgh, British Heart Fdn Ctr Cardiovasc Sci, Queens Med Res Inst, 47 Little France Crescent, Edinburgh EH16 4TJ, Midlothian, Scotland. EM james.dear@ed.ac.uk OI Gregory, Chris/0000-0002-7553-0132 FU British Heart Foundation Centre of Research Excellence Award; NHS Research Scotland (NRS), through NHS Lothian; Diabetes Research and Wellness Foundation; NC3R FX The authors acknowledge the contribution of the British Heart Foundation Centre of Research Excellence Award. J.W.D. acknowledges the financial support of NHS Research Scotland (NRS), through NHS Lothian. Funding was received from the Diabetes Research and Wellness Foundation and NC3R. NR 16 TC 31 Z9 33 U1 4 U2 43 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD DEC 1 PY 2013 VL 591 IS 23 BP 5833 EP 5842 DI 10.1113/jphysiol.2013.264069 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 259FC UT WOS:000327511800010 PM 24060994 ER PT J AU Detterbeck, FC Asamura, H Crowley, J Falkson, C Giaccone, G Giroux, D Huang, J Kim, J Kondo, K Lucchi, M Marino, M Marom, EM Nicholson, A Okumura, M Ruffini, E van Schil, P Stratton, K AF Detterbeck, Frank C. Asamura, Hisao Crowley, John Falkson, Conrad Giaccone, Giuseppe Giroux, Dori Huang, James Kim, Jhingook Kondo, Kazuya Lucchi, Marco Marino, Mirella Marom, Edith M. Nicholson, Andrew Okumura, Meinoshin Ruffini, Enrico van Schil, Paul Stratton, Kelly CA Staging Prognostic Factors Comm TI The IASLC/ITMIG Thymic Malignancies Staging Project Development of a Stage Classification for Thymic Malignancies SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Thymoma; Thymic carcinoma; Staging of stage classification ID FORTHCOMING 7TH EDITION; IASLC LUNG-CANCER; INTERNATIONAL-ASSOCIATION; TNM CLASSIFICATION; TUMORS; PROPOSALS; THYMOMAS; SYSTEM; NODE AB The lack of an official-stage classification system for thymic malignancies is an issue that hampers progress in this rare disease. A collaborative effort by the International Association for the Study of Lung Cancer and the International Thymic Malignancies Interest Group is underway to develop proposals for such a system. A database of more than 10,000 cases worldwide has been assembled to provide a solid basis for analysis. This report outlines the structure of the effort and the process that has been designed. C1 [Detterbeck, Frank C.] Yale Univ, Dept Thorac Surg, Yale New Haven Hosp, Sch Med, New Haven, CT 06510 USA. [Asamura, Hisao; Stratton, Kelly] Natl Canc Ctr, Tokyo, Japan. [Falkson, Conrad] Queens Univ, Kingston, ON K7L 3N6, Canada. [Giaccone, Giuseppe] NCI, Bethesda, MD 20892 USA. [Huang, James] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kim, Jhingook] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Kondo, Kazuya] Univ Tokushima, Tokushima 770, Japan. [Lucchi, Marco] Univ Pisa, Pisa, Italy. [Marino, Mirella] Regina Elena Inst Canc Res, Rome, Italy. [Marino, Mirella; Marom, Edith M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Nicholson, Andrew] Royal Brompton Hosp, London SW3 6LY, England. [Okumura, Meinoshin] Osaka Univ, Osaka, Japan. [Ruffini, Enrico] Univ Torino, Turin, Italy. [van Schil, Paul] Univ Antwerp Hosp, Antwerp, Belgium. RP Detterbeck, FC (reprint author), Yale Univ, Dept Surg, Div Thorac Surg, Sch Med, BB2 333 Cedar St, New Haven, CT 06510 USA. EM frank.detterbeck@yale.edu RI Spaggiari, Lorenzo/G-7915-2012; Kondo, Kazuya/J-9163-2012; Nowak, Anna/B-2487-2013; Giaccone, Giuseppe/E-8297-2017; OI Lim, Eric/0000-0002-9078-3226; Brunelli, Alessandro/0000-0002-6505-1656; Nowak, Anna/0000-0002-9317-9526; Giaccone, Giuseppe/0000-0002-5023-7562; Rami-Porta, Ramon/0000-0003-3366-7664; Van Schil, Paul/0000-0002-1962-8821; Huang, James/0000-0001-5495-3577; Bertolaccini, Luca/0000-0002-1153-3334; Venuta, Federico/0000-0001-9296-877X; LUCCHI, MARCO/0000-0001-9909-6820 NR 18 TC 28 Z9 30 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD DEC PY 2013 VL 8 IS 12 BP 1467 EP 1473 DI 10.1097/JTO.0000000000000017 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 257XG UT WOS:000327420500013 PM 24389429 ER PT J AU Shuch, B Ricketts, CJ Vocke, CD Komiya, T Middelton, LA Kauffman, EC Merino, MJ Metwalli, AR Dennis, P Linehan, WM AF Shuch, Brian Ricketts, Christopher J. Vocke, Cathy D. Komiya, Takefumi Middelton, Lindsay A. Kauffman, Eric C. Merino, Maria J. Metwalli, Adam R. Dennis, Phillip Linehan, W. Marston TI Germline PTEN Mutation Cowden Syndrome: An Underappreciated Form of Hereditary Kidney Cancer SO JOURNAL OF UROLOGY LA English DT Article DE carcinoma, renal cell; hamartoma syndrome, multiple; genetic diseases, inborn ID RENAL-CELL CARCINOMA; HAMARTOMA-TUMOR-SYNDROME; GENETIC-BASIS; DISEASE; FREQUENCY; COMPLEX AB Purpose: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. Materials and Methods: Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. Results: Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. Conclusions: Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome. C1 [Shuch, Brian; Ricketts, Christopher J.; Vocke, Cathy D.; Middelton, Lindsay A.; Kauffman, Eric C.; Metwalli, Adam R.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Komiya, Takefumi] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dennis, Phillip] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Bldg 10 CRC Room 1-5940, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 29 TC 22 Z9 22 U1 0 U2 2 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 DEC PY 2013 VL 190 IS 6 BP 1990 EP 1998 DI 10.1016/j.juro.2013.06.012 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 258EC UT WOS:000327441000007 PM 23764071 ER PT J AU Diaz, AW Hoang, AN Turkbey, B Hong, CW Truong, H Sterling, T Rais-Bahrami, S Siddiqui, MM Stamatakis, L Vourganti, S Nix, J Logan, J Harris, C Weintraub, M Chua, C Merino, MJ Choyke, P Wood, BJ Pinto, PA AF Diaz, Annerleim Walton Hoang, Anthony N. Turkbey, Baris Hong, Cheng William Hong Truong Sterling, Todd Rais-Bahrami, Soroush Siddiqui, M. Minhaj Stamatakis, Lambros Vourganti, Srinivas Nix, Jeffrey Logan, Jennifer Harris, Colette Weintraub, Michael Chua, Celene Merino, Maria J. Choyke, Peter Wood, Bradford J. Pinto, Peter A. TI Can Magnetic Resonance-Ultrasound Fusion Biopsy Improve Cancer Detection in Enlarged Prostates? SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; prostatic hyperplasia; magnetic resonance imaging; ultrasonography ID NEEDLE-BIOPSY; GLAND VOLUME; MRI; POPULATION; EXPERIENCE; GUIDANCE; SYSTEM AB Purpose: Patients with an enlarged prostate and suspicion of prostate cancer pose a diagnostic dilemma. The prostate cancer detection rate of systematic 12-core transrectal ultrasound guided biopsy is between 30% and 40%. For prostates greater than 40 cc this decreases to 30% or less. Magnetic resonance-ultrasound fusion biopsy has shown superior prostate cancer detection rates. We defined the detection rate of magnetic resonance-ultrasound fusion biopsy in men with an enlarged prostate gland. Materials and Methods: We retrospectively analyzed the records of patients who underwent multiparametric prostate magnetic resonance imaging followed by magnetic resonance-ultrasound fusion biopsy at our institution. Whole prostate volumes were calculated using magnetic resonance imaging reconstructions. Detection rates were analyzed with respect to age, prostate specific antigen and whole prostate volumes. Multivariable logistic regression was used to assess these parameters as independent predictors of prostate cancer detection. Results: We analyzed 649 patients with a mean +/- SD age of 61.8 +/- 7.9 years and a median prostate specific antigen of 6.65 ng/ml (IQR 4.35-11.0). Mean whole prostate volume was 58.7 +/- 34.3 cc. The overall detection rate of the magnetic resonance-ultrasound fusion platform was 55%. For prostates less than 40 cc the detection rate was 71.1% compared to 57.5%, 46.9%, 46.9% 33.3%, 36.4% and 30.4% for glands 40 to 54.9, 55 to 69.9, 70 to 84.9, 85 to 99.9, 100 to 114.9 and 115 cc or greater, respectively (p < 0.0001). Multivariable logistic regression showed a significant inverse association of magnetic resonance imaging volume with prostate cancer detection, controlling for age and prostate specific antigen. Conclusions: Transrectal ultrasound guided and fusion biopsy cancer detection rates decreased with increasing prostate volume. However, magnetic resonance-ultrasound fusion biopsy had a higher prostate cancer detection rate compared to that of transrectal ultrasound guided biopsy in the literature. Magnetic resonance-ultrasound fusion biopsy represents a promising solution for patients with suspicion of prostate cancer and an enlarged prostate. C1 [Diaz, Annerleim Walton; Hoang, Anthony N.; Hong Truong; Sterling, Todd; Rais-Bahrami, Soroush; Siddiqui, M. Minhaj; Stamatakis, Lambros; Vourganti, Srinivas; Nix, Jeffrey; Logan, Jennifer; Harris, Colette; Weintraub, Michael; Chua, Celene; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Hong, Cheng William; Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, CRC, 10 Ctr Dr,MSC 1210,Bldg 10,Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Siddiqui, Mohummad/0000-0002-4484-6820; Rais-Bahrami, Soroush/0000-0001-9466-9925 NR 29 TC 18 Z9 19 U1 0 U2 9 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 DEC PY 2013 VL 190 IS 6 BP 2020 EP 2025 DI 10.1016/j.juro.2013.05.118 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 258EC UT WOS:000327441000016 ER PT J AU Blasche, S Wuchty, S Rajagopala, SV Uetz, P AF Blasche, Sonja Wuchty, Stefan Rajagopala, Seesandra V. Uetz, Peter TI The Protein Interaction Network of Bacteriophage Lambda with Its Host, Escherichia coli SO JOURNAL OF VIROLOGY LA English DT Article ID C-TERMINAL DOMAIN; PHAGE-LAMBDA; RNA-POLYMERASE; DNA-REPLICATION; DEPENDENT ACTIVATION; POINT MUTATIONS; FIS PROTEIN; IN-VIVO; INITIATION; COMPLEX AB Although most of the 73 open reading frames (ORFs) in bacteriophage lambda have been investigated intensively, the function of many genes in host-phage interactions remains poorly understood. Using yeast two-hybrid screens of all lambda ORFs for interactions with its host Escherichia coli, we determined a raw data set of 631 host-phage interactions resulting in a set of 62 high-confidence interactions after multiple rounds of retesting. These links suggest novel regulatory interactions between the E. coli transcriptional network and lambda proteins. Targeted host proteins and genes required for lambda infection are enriched among highly connected proteins, suggesting that bacteriophages resemble interaction patterns of human viruses. Lambda tail proteins interact with both bacterial fimbrial proteins and E. coli proteins homologous to other phage proteins. Lambda appears to dramatically differ from other phages, such as T7, because of its unusually large number of modified and processed proteins, which reduces the number of host-virus interactions detectable by yeast two-hybrid screens. C1 [Blasche, Sonja] German Canc Res Ctr, Genom & Prote Core Facil, Heidelberg, Germany. [Wuchty, Stefan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Rajagopala, Seesandra V.] J Craig Venter Inst, Rockville, MD USA. [Uetz, Peter] Virginia Commonwealth Univ, Ctr Study Biol Complex, Richmond, VA 23284 USA. RP Uetz, P (reprint author), Virginia Commonwealth Univ, Ctr Study Biol Complex, Richmond, VA 23284 USA. EM peter@uetz.us RI Uetz, Peter/A-7119-2012; OI Uetz, Peter/0000-0001-6194-4927; Rajagopala, Seesandra/0000-0001-7176-5770 FU National Institutes of Health [R01GM79710]; European Union [HEALTH-F3-2009-223101]; National Institutes of Health/Department of Health and Human Services, Intramural Research program of the National Library of Medicine FX This project was partly funded by National Institutes of Health grant R01GM79710 and the European Union (grant HEALTH-F3-2009-223101, AntipathoGN). Research at the National Center for Biotechnology Information was supported by the National Institutes of Health/Department of Health and Human Services as part of the Intramural Research program of the National Library of Medicine. NR 67 TC 3 Z9 3 U1 6 U2 14 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 DEC PY 2013 VL 87 IS 23 BP 12745 EP 12755 DI 10.1128/JVI.02495-13 PG 11 WC Virology SC Virology GA 254RG UT WOS:000327183800023 PM 24049175 ER PT J AU Kerr, PJ Rogers, MB Fitch, A DePasse, JV Cattadori, IM Twaddle, AC Hudson, PJ Tscharke, DC Read, AF Holmes, EC Ghedin, E AF Kerr, Peter J. Rogers, Matthew B. Fitch, Adam DePasse, Jay V. Cattadori, Isabella M. Twaddle, Alan C. Hudson, Peter J. Tscharke, David C. Read, Andrew F. Holmes, Edward C. Ghedin, Elodie TI Genome Scale Evolution of Myxoma Virus Reveals Host-Pathogen Adaptation and Rapid Geographic Spread SO JOURNAL OF VIROLOGY LA English DT Article ID ORYCTOLAGUS-CUNICULUS L; RABBIT FIBROMA VIRUS; EUROPEAN RABBITS; EASTERN AUSTRALIA; PROTEIN; SEQUENCE; RECOMBINANT; POPULATIONS; VIRULENCE; RESPONSES AB The evolutionary interplay between myxoma virus (MYXV) and the European rabbit (Oryctolagus cuniculus) following release of the virus in Australia in 1950 as a biological control is a classic example of host-pathogen coevolution. We present a detailed genomic and phylogeographic analysis of 30 strains of MYXV, including the Australian progenitor strain Standard Laboratory Strain (SLS), 24 Australian viruses isolated from 1951 to 1999, and three isolates from the early radiation in Britain from 1954 and 1955. We show that in Australia MYXV has spread rapidly on a spatial scale, with multiple lineages cocirculating within individual localities, and that both highly virulent and attenuated viruses were still present in the field through the 1990s. In addition, the detection of closely related virus lineages at sites 1,000 km apart suggests that MYXV moves freely in geographic space, with mosquitoes, fleas, and rabbit migration all providing means of transport. Strikingly, despite multiple introductions, all modern viruses appear to be ultimately derived from the original introductions of SLS. The rapidity of MYXV evolution was also apparent at the genomic scale, with gene duplications documented in a number of viruses. Duplication of potential virulence genes may be important in increasing the expression of virulence proteins and provides the basis for the evolution of novel functions. Mutations leading to loss of open reading frames were surprisingly frequent and in some cases may explain attenuation, but no common mutations that correlated with virulence or attenuation were identified. C1 [Kerr, Peter J.] CSIRO Ecosyst Sci, Canberra, ACT, Australia. [Rogers, Matthew B.; Fitch, Adam; DePasse, Jay V.; Twaddle, Alan C.; Ghedin, Elodie] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Pittsburgh, PA 15260 USA. [Rogers, Matthew B.; Ghedin, Elodie] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA USA. [Cattadori, Isabella M.; Hudson, Peter J.; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Tscharke, David C.] Australian Natl Univ, Res Sch Biol, Canberra, ACT, Australia. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ghedin, E (reprint author), Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Pittsburgh, PA 15260 USA. EM elg21@pitt.edu RI Tscharke, David/C-9133-2009; OI Tscharke, David/0000-0001-6825-9172; Holmes, Edward/0000-0001-9596-3552 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01 AI093804]; NHMRC Australia Fellowship; ARC Future Fellowship FX This work was funded in part by grant R01 AI093804 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. E.C.H. is funded by an NHMRC Australia Fellowship. D.C.T. is funded by an ARC Future Fellowship. NR 60 TC 16 Z9 16 U1 3 U2 46 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 DEC PY 2013 VL 87 IS 23 BP 12900 EP 12915 DI 10.1128/JVI.02060-13 PG 16 WC Virology SC Virology GA 254RG UT WOS:000327183800036 PM 24067966 ER PT J AU Breed, MW Jordan, APO Aye, PP Sugimoto, C Alvarez, X Kuroda, MJ Pahar, B Keele, BF Hoxie, JA Lackner, AA AF Breed, Matthew W. Jordan, Andrea P. O. Aye, Pyone P. Sugimoto, Chie Alvarez, Xavier Kuroda, Marcelo J. Pahar, Bapi Keele, Brandon F. Hoxie, James A. Lackner, Andrew A. TI A Single Amino Acid Mutation in the Envelope Cytoplasmic Tail Restores the Ability of an Attenuated Simian Immunodeficiency Virus Mutant To Deplete Mucosal CD4(+) T Cells SO JOURNAL OF VIROLOGY LA English DT Article ID ACUTE SIV INFECTION; GASTROINTESTINAL-TRACT; IMMUNE ACTIVATION; MASSIVE INFECTION; VIRAL REPLICATION; RHESUS MACAQUES; HIV DISEASE; EXPRESSION; OCCURS; HOSTS AB Disruption of the conserved motif GYxxO in the simian immunodeficiency virus (SIV) SIVmac239 envelope (Env) cytoplasmic tail resulted in a virus (Delta GY) that exhibited a high plasma peak but uniquely failed to acutely deplete mucosal CD4(+) T cells. Here, we show that Delta GY containing a flanking S727P mutation that was acquired in Delta GY-infected macaques reacquired the ability to rapidly deplete CD4(+) T cells in lamina propria. This suggests that the GYxxO motif and S727P each contribute to SIV's targeting to mucosal tissues. C1 [Breed, Matthew W.; Aye, Pyone P.; Sugimoto, Chie; Alvarez, Xavier; Kuroda, Marcelo J.; Pahar, Bapi; Lackner, Andrew A.] Tulane Natl Primate Res Ctr, Covington, LA USA. [Jordan, Andrea P. O.; Hoxie, James A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Keele, Brandon F.] Frederick Natl Lab Canc Res, SAIC Frederick, Frederick, MD USA. RP Lackner, AA (reprint author), Tulane Natl Primate Res Ctr, Covington, LA USA. EM lackner@tulane.edu OI Pahar, Bapi/0000-0003-1949-973X FU National Institutes of Health [RR000164/P51OD011104, RR000168, RO1 AI074362, RO1 AI097059, AI045008, RR021309 (T32)]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by National Institutes of Health grants RR000164/P51OD011104 (TNPRC) and RR000168 (NEPRC), RO1 AI074362 (J.A.H.), RO1 AI097059 (M.J.K.), AI045008 (Penn CFAR), and RR021309 (T32) and was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 28 TC 2 Z9 2 U1 0 U2 0 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 DEC PY 2013 VL 87 IS 23 BP 13048 EP 13052 DI 10.1128/JVI.02126-13 PG 5 WC Virology SC Virology GA 254RG UT WOS:000327183800051 PM 24027336 ER PT J AU Balinsky, CA Schmeisser, H Ganesan, S Singh, K Pierson, TC Zoon, KC AF Balinsky, Corey A. Schmeisser, Hana Ganesan, Sundar Singh, Kavita Pierson, Theodore C. Zoon, Kathryn C. TI Nucleolin Interacts with the Dengue Virus Capsid Protein and Plays a Role in Formation of Infectious Virus Particles SO JOURNAL OF VIROLOGY LA English DT Article ID JAPANESE ENCEPHALITIS-VIRUS; SURFACE-EXPRESSED NUCLEOLIN; INHIBITS HIV-INFECTION; N-TERMINAL REGION; CORE PROTEIN; NUCLEAR-LOCALIZATION; ANTIPROLIFERATIVE ACTIVITY; ENDOPLASMIC-RETICULUM; VIRAL REPLICATION; BINDING PROPERTY AB Dengue virus (DENV) is a mosquito-transmitted flavivirus that can cause severe disease in humans and is considered a reemerging pathogen of significant importance to public health. The DENV capsid (C) protein functions as a structural component of the infectious virion; however, it may have additional functions in the virus replicative cycle. Here, we show that the DENV C protein interacts and colocalizes with the multifunctional host protein nucleolin (NCL). Furthermore, we demonstrate that this interaction can be disrupted by the addition of an NCL binding aptamer (AS1411). Knockdown of NCL with small interfering RNA (siRNA) or treatment of cells with AS1411 results in a significant reduction of viral titers after DENV infection. Western blotting and quantitative RT-PCR (qRT-PCR) analysis revealed no differences in viral RNA or protein levels at early time points postinfection, suggesting a role for NCL in viral morphogenesis. We support this hypothesis by showing that treatment with AS1411 alters the migration characteristics of the viral capsid, as visualized by native electrophoresis. Here, we identify a critical interaction between DENV C protein and NCL that represents a potential new target for the development of antiviral therapeutics. C1 [Balinsky, Corey A.; Schmeisser, Hana; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. [Ganesan, Sundar] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Singh, Kavita] NIAID, Struct Biol Unit, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, Cytokine Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). NR 82 TC 19 Z9 19 U1 1 U2 15 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 DEC PY 2013 VL 87 IS 24 BP 13094 EP 13106 DI 10.1128/JVI.00704-13 PG 13 WC Virology SC Virology GA 258EZ UT WOS:000327443300002 PM 24027323 ER PT J AU Kew, C Lui, PY Chan, CP Liu, X Au, SWN Mohr, I Jin, DY Kok, KH AF Kew, Chun Lui, Pak-Yin Chan, Chi-Ping Liu, Xiang Au, Shannon Wing Ngor Mohr, Ian Jin, Dong-Yan Kok, Kin-Hang TI Suppression of PACT-Induced Type I Interferon Production by Herpes Simplex Virus 1 Us11 Protein SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; BINDING-PROTEIN; RIG-I; ALPHA/BETA-INTERFERON; PKR ACTIVATION; NS1 PROTEIN; INHIBITION; PATHWAY; PHOSPHORYLATION; FACILITATE AB Herpes simplex virus 1 (HSV-1) Us11 protein is a double-stranded RNA-binding protein that suppresses type I interferon production through the inhibition of the cytoplasmic RNA sensor RIG-I. Whether additional cellular mediators are involved in this suppression remains to be determined. In this study, we report on the requirement of cellular double-stranded RNA-binding protein PACT for Us11-mediated perturbation of type I interferon production. Us11 associates with PACT tightly to prevent it from binding with and activating RIG-I. The Us11-deficient HSV-1 was indistinguishable from the Us11-proficient virus in the suppression of interferon production when PACT was compromised. More importantly, HSV-1-induced activation of interferon production was abrogated in PACT knockout murine embryonic fibroblasts. Our findings suggest a new mechanism for viral evasion of innate immunity through which a viral double-stranded RNA-binding protein interacts with PACT to circumvent type I interferon production. This mechanism might also be used by other PACT-binding viral interferon-antagonizing proteins such as Ebola virus VP35 and influenza A virus NS1. C1 [Kew, Chun; Lui, Pak-Yin; Chan, Chi-Ping; Jin, Dong-Yan; Kok, Kin-Hang] Univ Hong Kong, Li Ka Shing Fac Med, Dept Biochem, Pokfulam, Hong Kong, Peoples R China. [Liu, Xiang] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Au, Shannon Wing Ngor] Chinese Univ Hong Kong, Fac Sci, Sch Life Sci, Shatin, Hong Kong, Peoples R China. [Mohr, Ian] NYU, Sch Med, Dept Microbiol, Inst Canc, New York, NY 10016 USA. RP Jin, DY (reprint author), Univ Hong Kong, Li Ka Shing Fac Med, Dept Biochem, Pokfulam, Hong Kong, Peoples R China. EM dyjin@hku.hk; khkok@hku.hk RI Liu, Xiang/F-5731-2014 FU Hong Kong Health and Medical Research Fund [10091202, 12111312]; Hong Kong Research Grants Council [HKU7677/10 M, HKU1/CRF/11G]; SK Yee Medical Research Fund FX This work was supported by the Hong Kong Health and Medical Research Fund (10091202 and 12111312), Hong Kong Research Grants Council (HKU7677/10 M and HKU1/CRF/11G), and SK Yee Medical Research Fund (2011). NR 41 TC 16 Z9 16 U1 1 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 DEC PY 2013 VL 87 IS 24 BP 13141 EP 13149 DI 10.1128/JVI.02564-13 PG 9 WC Virology SC Virology GA 258EZ UT WOS:000327443300007 PM 24067967 ER PT J AU Handisurya, A Day, PM Thompson, CD Buck, CB Pang, YYS Lowy, DR Schiller, JT AF Handisurya, Alessandra Day, Patricia M. Thompson, Cynthia D. Buck, Christopher B. Pang, Yuk-Ying S. Lowy, Douglas R. Schiller, John T. TI Characterization of Mus musculus Papillomavirus 1 Infection In Situ Reveals an Unusual Pattern of Late Gene Expression and Capsid Protein Localization SO JOURNAL OF VIROLOGY LA English DT Article ID MICROMYS-MINUTUS; MOUSE MODEL; VIRAL-DNA; DIFFERENTIATION; CARCINOMAS; CLONING; BINDING; VIRUS; SKIN; NEUTRALIZATION AB Full-length genomic DNA of the recently identified laboratory mouse papillomavirus 1 (MusPV1) was synthesized in vitro and was used to establish and characterize a mouse model of papillomavirus pathobiology. MusPV1 DNA, whether naked or encapsidated by MusPV1 or human papillomavirus 16 (HPV 16) capsids, efficiently induced the outgrowth of papillomas as early as 3 weeks after application to abraded skin on the muzzles and tails of athymic NCr nude mice. High concentrations of virions were extracted from homogenized papillomatous tissues and were serially passaged for > 10 generations. Neutralization by L1 antisera confirmed that infectious transmission was capsid mediated. Unexpectedly, the skin of the murine back was much less susceptible to virion-induced papillomas than the muzzle or tail. Although reporter pseudovirions readily transduced the skin of the back, infection with native MusPV1 resulted in less viral genome amplification and gene expression on the back, including reduced expression of the L1 protein and very low expression of the L2 protein, results that imply skin region-specific control of postentry aspects of the viral life cycle. Unexpectedly, L1 protein on the back was predominantly cytoplasmic, while on the tail the abundant L1 was cytoplasmic in the lower epithelial layers and nuclear in the upper layers. Nuclear localization of L1 occurred only in cells that coexpressed the minor capsid protein, L2. The pattern of L1 protein staining in the infected epithelium suggests that L1 expression occurs earlier in the MusPV1 life cycle than in the life cycle of high-risk HPV and that virion assembly is regulated by a previously undescribed mechanism. C1 [Handisurya, Alessandra; Day, Patricia M.; Thompson, Cynthia D.; Buck, Christopher B.; Pang, Yuk-Ying S.; Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. EM schillej@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Austrian Science Fund FWF (Erwin Schroedinger Fellowship project) [J3012-B13] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Austrian Science Fund FWF (Erwin Schroedinger Fellowship project J3012-B13, to A.H.). NR 44 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2013 VL 87 IS 24 BP 13214 EP 13225 DI 10.1128/JVI.02162-13 PG 12 WC Virology SC Virology GA 258EZ UT WOS:000327443300014 PM 24067981 ER PT J AU Chakrabarti, BK Feng, Y Sharma, SK McKee, K Hedestam, GBK LaBranche, CC Montefiori, DC Mascola, JR Wyatt, RT AF Chakrabarti, Bimal K. Feng, Yu Sharma, Shailendra Kumar McKee, Krisha Hedestam, Gunilla B. Karlsson LaBranche, Celia C. Montefiori, David C. Mascola, John R. Wyatt, Richard T. TI Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; B-CELL RESPONSES; CD4-BINDING SITE; ENV TRIMERS; CD4 BINDING; SUBTYPE-B; GP120; PROTEIN; TYPE-1; POTENT AB Host cell-mediated proteolytic cleavage of the human immunodeficiency virus type 1 (HIV-1) gp160 precursor glycoprotein into gp120 and gp41 subunits is required to generate fusion-competent envelope glycoprotein (Env) spikes. The gp120-directed broadly neutralizing monoclonal antibodies (bNabs) isolated from HIV-infected individuals efficiently recognize fully cleaved JRFL Env spikes; however, nonneutralizing gp120-directed monoclonal antibodies isolated from infected or vaccinated subjects recognize only uncleaved JRFL spikes. Therefore, as an immunogen, cleaved spikes that selectively present desired neutralizing epitopes to B cells may elicit cross-reactive neutralizing antibodies. Accordingly, we inoculated nonhuman primates (NHPs) with plasmid DNA encoding transmembrane-anchored, cleaved JRFL Env or by electroporation (EP). Priming with DNA expressing soluble, uncleaved gp140 trimers was included as a comparative experimental group of NHPs. DNA inoculation was followed by boosts with soluble JRFL gp140 trimers, and control NHPs were inoculated with soluble JRFL protein trimers without DNA priming. In the TZM-bl assay, elicitation of neutralizing antibodies against HIV-1 tier 1 isolates was robust following the protein boost. Neutralization of tier 2 isolates was detected, but only in animals primed with plasmid DNA and boosted with trimeric protein. Using the more sensitive A3R5 assay, consistent neutralization of both clade B and C tier 2 isolates was detected from all regimens assessed in the current study, exceeding levels achieved by our previous vaccine regimens in primates. Together, these data suggest a potential advantage of B cell priming followed by a rest interval and protein boosting to present JRFL Env spikes to the immune system to better generate HIV-1 cross-clade neutralizing antibodies. C1 [Chakrabarti, Bimal K.; Feng, Yu; Sharma, Shailendra Kumar; Wyatt, Richard T.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [McKee, Krisha; Mascola, John R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [LaBranche, Celia C.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Wyatt, Richard T.] Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. RP Wyatt, RT (reprint author), Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM bchakrabarti@iavi.org; rwyatt@iavi.org FU IAVI intramural research; NIH intramural research program; SIDA; Bill and Melinda Gates Foundation; Scripps CHAVI-ID FX This work was supported primarily by IAVI intramural research, as well as by the NIH intramural research program, SIDA, The Bill and Melinda Gates Foundation, and the Scripps CHAVI-ID. NR 58 TC 33 Z9 33 U1 0 U2 12 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 DEC PY 2013 VL 87 IS 24 BP 13239 EP 13251 DI 10.1128/JVI.01247-13 PG 13 WC Virology SC Virology GA 258EZ UT WOS:000327443300016 PM 24067980 ER PT J AU Keller, PW Huang, RK England, MR Waki, K Cheng, NQ Heymann, JB Craven, RC Freed, EO Steven, AC AF Keller, Paul W. Huang, Rick K. England, Matthew R. Waki, Kayoko Cheng, Naiqian Heymann, J. Bernard Craven, Rebecca C. Freed, Eric O. Steven, Alasdair C. TI A Two-Pronged Structural Analysis of Retroviral Maturation Indicates that Core Formation Proceeds by a Disassembly-Reassembly Pathway Rather than a Displacive Transition SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS CAPSID PROTEIN; HELICAL STRUCTURE; HIV-1 MATURATION; TERMINAL DOMAIN; SPACER PEPTIDE; GAG PROTEIN; IMMUNODEFICIENCY; RESOLUTION; CLEAVAGE; VIRIONS AB Retrovirus maturation involves sequential cleavages of the Gag polyprotein, initially arrayed in a spherical shell, leading to formation of capsids with polyhedral or conical morphology. Evidence suggests that capsids assemble de novo inside maturing virions from dissociated capsid (CA) protein, but the possibility persists of a displacive pathway in which the CA shell remains assembled but is remodeled. Inhibition of the final cleavage between CA and spacer peptide SP1/SP blocks the production of mature capsids. We investigated whether retention of SP might render CA assembly incompetent by testing the ability of Rous sarcoma virus (RSV) CA-SP to assemble in vitro into icosahedral capsids. Capsids were indeed assembled and were indistinguishable from those formed by CA alone, indicating that SP was disordered. We also used cryo-electron tomography to characterize HIV-1 particles produced in the presence of maturation inhibitor PF-46396 or with the cleavage-blocking CA5 mutation. Inhibitor-treated virions have a shell that resembles the CA layer of the immature Gag shell but is less complete. Some CA protein is generated but usually not enough for a mature core to assemble. We propose that inhibitors like PF-46396 bind to the Gag lattice where they deny the protease access to the CA-SP1 cleavage site and prevent the release of CA. CA5 particles, which exhibit no cleavage at the CA-SP1 site, have spheroidal shells with relatively thin walls. It appears that this lattice progresses displacively toward a mature-like state but produces neither conical cores nor infectious virions. These observations support the disassembly- reassembly pathway for core formation. C1 [Keller, Paul W.; Huang, Rick K.; Cheng, Naiqian; Heymann, J. Bernard; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [England, Matthew R.; Craven, Rebecca C.] Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA USA. [Waki, Kayoko; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov OI Heymann, Bernard/0000-0002-8872-5326 FU NIAMS; NCI; NIH [CA100322, 2 T32 CA60395]; PA Department of Health FX This work was supported by the Intramural Research Programs of NIAMS and NCI, by the NIH Intramural AIDS Targeted Antiviral Program, by NIH CA100322, NIH training grant 2 T32 CA60395, and by the PA Department of Health (R.C.C.). NR 57 TC 31 Z9 31 U1 2 U2 11 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 DEC PY 2013 VL 87 IS 24 BP 13655 EP 13664 DI 10.1128/JVI.01408-13 PG 10 WC Virology SC Virology GA 258EZ UT WOS:000327443300053 PM 24109217 ER PT J AU Lee, PD Mukherjee, S Edeling, MA Dowd, KA Austin, SK Manhart, CJ Diamond, MS Fremont, DH Pierson, TC AF Lee, Phong D. Mukherjee, Swati Edeling, Melissa A. Dowd, Kimberly A. Austin, S. Kyle Manhart, Carolyn J. Diamond, Michael S. Fremont, Daved H. Pierson, Theodore C. TI The Fc Region of an Antibody Impacts the Neutralization of West Nile Viruses in Different Maturation States SO JOURNAL OF VIROLOGY LA English DT Article ID BORNE ENCEPHALITIS-VIRUS; PROTEIN DOMAIN-III; ENVELOPE PROTEIN; DENGUE-VIRUS; CRYSTAL-STRUCTURE; MEMBRANE-FUSION; MEDIATED NEUTRALIZATION; DISSEMINATED INFECTION; MONOCLONAL-ANTIBODY; REACTIVE EPITOPES AB Flavivirus-infected cells secrete a structurally heterogeneous population of viruses because of an inefficient virion maturation process. Flaviviruses assemble as noninfectious, immature virions composed of trimers of envelope (E) and precursor membrane (prM) protein heterodimers. Cleavage of prM is a required process during virion maturation, although this often remains incomplete for infectious virus particles. Previous work demonstrated that the efficiency of virion maturation could impact antibody neutralization through changes in the accessibility of otherwise cryptic epitopes on the virion. In this study, we show that the neutralization potency of monoclonal antibody (MAb) E33 is sensitive to the maturation state of West Nile virus (WNV), despite its recognition of an accessible epitope, the domain III lateral ridge (DIII-LR). Comprehensive epitope mapping studies with 166 E protein DIII-LR variants revealed that the functional footprint of MAb E33 on the E protein differs subtly from that of the well-characterized DIII-LR MAb E16. Remarkably, aromatic substitutions at E protein residue 306 ablated the maturation state sensitivity of E33 IgG, and the neutralization efficacy of E33 Fab fragments was not affected by changes in the virion maturation state. We propose that E33 IgG binding on mature virions orients the Fc region in a manner that impacts subsequent antibody binding to nearby sites. This Fc-mediated steric constraint is a novel mechanism by which the maturation state of a virion modulates the efficacy of the humoral immune response to flavivirus infection. C1 [Lee, Phong D.; Mukherjee, Swati; Dowd, Kimberly A.; Manhart, Carolyn J.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Fremont, Daved H.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Edeling, Melissa A.; Austin, S. Kyle; Diamond, Michael S.; Fremont, Daved H.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Austin, S. Kyle; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM piersontc@niaid.nih.gov FU Intramural Research Program of the National Institutes of Allergy and Infectious Diseases FX This work was funded by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases. NR 71 TC 10 Z9 10 U1 0 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 DEC PY 2013 VL 87 IS 24 BP 13729 EP 13740 DI 10.1128/JVI.02340-13 PG 12 WC Virology SC Virology GA 258EZ UT WOS:000327443300059 PM 24109224 ER PT J AU Yoshida, T Koyanagi, Y Strebel, K AF Yoshida, Takeshi Koyanagi, Yoshio Strebel, Klaus TI Functional Antagonism of Rhesus Macaque and Chimpanzee BST-2 by HIV-1 Vpu Is Mediated by Cytoplasmic Domain Interactions SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PIG-TAILED MACAQUES; TYPE-1 VPU; CELL-SURFACE; TRANSMEMBRANE DOMAIN; PROTEIN INTERACTIONS; RESTRICTION FACTOR; PARTICLE RELEASE; LIVING CELLS; MOLECULAR-CLONING AB Human immunodeficiency virus type 1 (HIV-1) Vpu enhances the release of viral particles from infected cells by interfering with the function of BST-2/tetherin, a cellular protein inhibiting virus release. The Vpu protein encoded by NL4-3, a widely used HIV-1 laboratory strain, antagonizes human BST-2 but not monkey or murine BST-2, leading to the conclusion that BST-2 antagonism by Vpu is species specific. In contrast, we recently identified several primary Vpu isolates, such as Vpu of HIV-1DH12, capable of antagonizing both human and rhesus BST-2. Here we report that while Vpu interacts with human BST-2 primarily through their respective transmembrane domains, antagonism of rhesus BST-2 by Vpu involved an interaction of their cytoplasmic domains. Importantly, a Vpu mutant carrying two mutations in its transmembrane domain (A(14)L and W(22)A), rendering it incompetent for interaction with human BST-2, was able to interact with human BST-2 carrying the rhesus BST-2 cytoplasmic domain and partially neutralized the ability of this BST-2 variant to inhibit viral release. Bimolecular fluorescence complementation analysis to detect Vpu-BST-2 interactions suggested that the physical interaction of Vpu with rhesus or chimpanzee BST-2 involves a 5-residue motif in the cytoplasmic domain of BST-2 previously identified as important for the antagonism of monkey and great ape BST-2 by simian immunodeficiency virus (SIV) Nef. Thus, our study identifies a novel mechanism of antagonism of monkey and great ape BST-2 by Vpu that targets the same motif in BST-2 used by SIV Nef and might explain the expanded host range observed for Vpu isolates in our previous study. C1 [Yoshida, Takeshi; Strebel, Klaus] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Koyanagi, Yoshio] Kyoto Univ, Inst Virus Res, Lab Viral Pathogenesis, Sakyo Ku, Kyoto 606, Japan. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Ministry of Health, Labor and Welfare of Japan [24115008, 24390112] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (K.S.) and by grants from the Grants in-Aid for Scientific Research (24115008 and 24390112) and Research on HIV/AIDS from the Ministry of Health, Labor and Welfare of Japan (to Y.K.). NR 76 TC 2 Z9 3 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2013 VL 87 IS 24 BP 13825 EP 13836 DI 10.1128/JVI.02567-13 PG 12 WC Virology SC Virology GA 258EZ UT WOS:000327443300068 PM 24109238 ER PT J AU Rahmberg, AR Neidermyer, WJ Breed, MW Alvarez, X Midkiff, CC Piatak, M Lifson, JD Evans, DT AF Rahmberg, Andrew R. Neidermyer, William J., Jr. Breed, Matthew W. Alvarez, Xavier Midkiff, Cecily C. Piatak, Michael, Jr. Lifson, Jeffrey D. Evans, David T. TI Tetherin Upregulation in Simian Immunodeficiency Virus-Infected Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; IN-VIVO; VPU; SIV; ADAPTATION; RESISTANCE; RESPONSES; RELEASE; BST2 AB Here we show that simian immunodeficiency virus (SIV) infection of rhesus macaques results in rapid upregulation of tetherin (BST-2 or CD317) on peripheral blood lymphocytes, including the CD4(+) CCR5(+) T cell targets of virus infection, with a peak of induction that coincides with peak alpha interferon (IFN-alpha) levels in plasma, and that tetherin remains above baseline levels throughout chronic infection. These observations are consistent with a role for tetherin in innate immunity to immunodeficiency virus infection. C1 [Rahmberg, Andrew R.; Neidermyer, William J., Jr.; Evans, David T.] Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Dept Microbiol & Immunobiol, Southborough, MA 01772 USA. [Breed, Matthew W.; Alvarez, Xavier; Midkiff, Cecily C.] Tulane Natl Primate Res Ctr, Div Comparat Pathol, Covington, LA USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] SAIC Frederick, Natl Canc Inst Frederick, Frederick, MD USA. RP Evans, DT (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. EM david_evans@hms.harvard.edu FU Public Health Service [AI098485, AI087498, AI071306]; National Institutes of Health [RR000164, RR000168/OD011103]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by Public Health Service grants AI098485, AI087498, and AI071306, National Institutes of Health grants RR000164 (TNPRC) and RR000168/OD011103, and, in part, federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 25 TC 7 Z9 8 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2013 VL 87 IS 24 BP 13917 EP 13921 DI 10.1128/JVI.01757-13 PG 5 WC Virology SC Virology GA 258EZ UT WOS:000327443300078 PM 24109219 ER PT J AU Cai, YY Yu, SQ Mazur, S Dong, L Janosko, K Zhang, TF Muller, MA Hensley, LE Bavari, S Jahrling, PB Radoshitzky, SR Kuhn, JH AF Cai, Yingyun Yu, Shuiqing Mazur, Steven Dong, Lian Janosko, Krisztina Zhang, Tengfei Mueller, Marcel A. Hensley, Lisa E. Bavari, Sina Jahrling, Peter B. Radoshitzky, Sheli R. Kuhn, Jens H. TI Nonhuman Transferrin Receptor 1 Is an Efficient Cell Entry Receptor for Ocozocoautla de Espinosa Virus SO JOURNAL OF VIROLOGY LA English DT Article ID HEMORRHAGIC-FEVER ARENAVIRUSES; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; JUNIN VIRUS; GLYCOPROTEINS; INFECTION; MEXICO; MICE AB Ocozocoautla de Espinosa virus (OCEV) is a novel, uncultured arenavirus. We found that the OCEV glycoprotein mediates entry into grivet and bat cells through transferrin receptor 1 (TfR1) binding but that OCEV glycoprotein precursor (GPC)-pseudotyped retroviruses poorly entered 53 human cancer cell lines. Interestingly, OCEV and Tacaribe virus could use bat, but not human, TfR1. Replacing three human TfR1 amino acids with their bat ortholog counterparts transformed human TfR1 into an efficient OCEV and Tacaribe virus receptor. C1 [Cai, Yingyun; Yu, Shuiqing; Mazur, Steven; Janosko, Krisztina; Zhang, Tengfei; Hensley, Lisa E.; Jahrling, Peter B.; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. [Dong, Lian; Bavari, Sina; Radoshitzky, Sheli R.] US Army Med Res Inst Infect Dis, Frederick, MD USA. [Mueller, Marcel A.] Univ Bonn, Inst Virol, Med Ctr, Bonn, Germany. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. EM sheli.r.radoshitzky.ctr@mail.mil; kuhnjens@mail.nih.gov RI Kuhn, Jens H./B-7615-2011; OI Kuhn, Jens H./0000-0002-7800-6045; Mueller, Marcel/0000-0003-2242-5117 FU NIAID [HHSN272200700016I]; Joint Science and Technology Office for Chemical and Biological Defense [TMTI0048_09_RD_T] FX Y.C. and J.H.K. performed this work as employees of Tunnell Consulting, Inc., S. M. as an employee of MRI Global, T.Z. as an employee of Lovelace, and S.Y. and K.J. as employees of Battelle Memorial Institute, all under Battelle's prime contract with NIAID under contract number HHSN272200700016I. This work was in part funded by the Joint Science and Technology Office for Chemical and Biological Defense (proposal number TMTI0048_09_RD_T to S.B.). NR 27 TC 3 Z9 3 U1 1 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 DEC PY 2013 VL 87 IS 24 BP 13930 EP 13935 DI 10.1128/JVI.02701-13 PG 6 WC Virology SC Virology GA 258EZ UT WOS:000327443300081 PM 24109228 ER PT J AU Zhu, ZY Qin, HR Chen, WZ Zhao, Q Shen, XY Schutte, R Wang, YP Ofek, G Streaker, E Prabakaran, P Fouda, GG Liao, HX Owens, J Louder, M Yang, YP Klaric, KA Moody, MA Mascola, JR Scott, JK Kwong, PD Montefiori, D Haynes, BF Tomaras, GD Dimitrov, DS AF Zhu, Zhongyu Qin, Haiyan Rebekah Chen, Weizao Zhao, Qi Shen, Xiaoying Schutte, Robert Wang, Yanping Ofek, Gilad Streaker, Emily Prabakaran, Ponraj Fouda, Genevieve G. Liao, Hua-Xin Owens, John Louder, Mark Yang, Yongping Klaric, Kristina-Ana Moody, M. Anthony Mascola, John R. Scott, Jamie K. Kwong, Peter D. Montefiori, David Haynes, Barton F. Tomaras, Georgia D. Dimitrov, Dimiter S. TI Cross-Reactive HIV-1-Neutralizing Human Monoclonal Antibodies Identified from a Patient with 2F5-Like Antibodies (vol 85, pg 11401, 2011) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Zhu, Zhongyu] NCI, Frederick, MD 21701 USA. Human Vaccine Inst, Durham, NC USA. SAIC, Frederick, MD USA. Vaccine Res Ctr, Bethesda, MD USA. Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. RP Zhu, ZY (reprint author), NCI, Frederick, MD 21701 USA. RI Tomaras, Georgia/J-5041-2016 NR 1 TC 0 Z9 0 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2013 VL 87 IS 24 BP 13936 EP 13936 DI 10.1128/JVI.02726-13 PG 1 WC Virology SC Virology GA 258EZ UT WOS:000327443300082 ER PT J AU Witkowski, B Amaratunga, C Khim, N Sreng, S Chim, P Kim, S Lim, P Mao, S Sopha, C Sam, B Anderson, JM Duong, S Chuor, CM Taylor, WRJ Suon, S Mercereau-Puijalon, O Fairhurst, RM Menard, D AF Witkowski, Benoit Amaratunga, Chanaki Khim, Nimol Sreng, Sokunthea Chim, Pheaktra Kim, Saorin Lim, Pharath Mao, Sivanna Sopha, Chantha Sam, Baramey Anderson, Jennifer M. Duong, Socheat Chuor, Char Meng Taylor, Walter R. J. Suon, Sella Mercereau-Puijalon, Odile Fairhurst, Rick M. Menard, Didier TI Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies SO LANCET INFECTIOUS DISEASES LA English DT Article ID PARASITE CLEARANCE; WESTERN CAMBODIA; SUSCEPTIBILITY; SENSITIVITY; ARTESUNATE; PROVINCE; RATES AB Background Artemisinin resistance in Plasmodium falciparum lengthens parasite clearance half-life during artemisinin monotherapy or artemisinin-based combination therapy. Absence of in-vitro and ex-vivo correlates of artemisinin resistance hinders study of this phenotype. We aimed to assess whether an in-vitro ring-stage survival assay (RSA) can identify culture-adapted P falciparum isolates from patients with slow-clearing or fast-clearing infections, to investigate the stage-dependent susceptibility of parasites to dihydroaitemisinin in the in-vitro RSA, and to assess whether an ex-vivo RSA can identify artemisinin-resistant P falciparum infections. Methods We culture-adapted parasites from patients with long and short parasite clearance half-lives from a study done in Pursat, Cambodia, in 2010 (registered with ClinicalTrials.gov, number NCT00341003) and used novel in-vitro survival assays to explore the stage-dependent susceptibility of slow-clearing and fast-clearing parasites to dihydroartemisinin. In 2012, we implemented the RSA in prospective parasite clearance studies in Pursat, Preah Vihear, and Ratanakiri, Cambodia (NCT01736319), to measure the ex-vivo responses of parasites from patients with malaria. Continuous variables were compared with the Mann-Whitney U test. Correlations were analysed with the Spearman correlation test. Findings In-vitro survival rates of culture-adapted parasites from 13 slow-clearing and 13 fast-clearing infections differed significantly when assays were done on 0-3 h ring-stage parasites (10.88% vs 0"23%; p=0.007). Ex-vivo survival rates significantly correlated with in-vivo parasite clearance half-lives (n=30, r=0.74, 95% CI 0.50-0.87; p<0.0001). Interpretation The in-vitro RSA of 0-3 h ring-stage parasites provides a platform for the molecular characterisation of artemisinin resistance. The ex-vivo RSA can be easily implemented where surveillance for artemisinin resistance is needed. Funding Institut Pasteur du Cambodge and the Intramural Research Program, NIAID, NIH. C1 [Witkowski, Benoit; Khim, Nimol; Chim, Pheaktra; Kim, Saorin; Lim, Pharath; Menard, Didier] Inst Pasteur Cambodge, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia. [Amaratunga, Chanaki; Lim, Pharath; Anderson, Jennifer M.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Sreng, Sokunthea; Lim, Pharath; Duong, Socheat; Chuor, Char Meng; Suon, Sella] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Mao, Sivanna] Sampov Mean Referral Hosp, Pursat, Cambodia. [Sopha, Chantha] Makara 16 Referral Hosp, Preah Vihear, Cambodia. [Sam, Baramey] Ratanakiri Referral Hosp, Ratanakiri, Cambodia. [Taylor, Walter R. J.] Hop Cantonal Univ Geneva, Serv Med Int & Humanitaire, Geneva, Switzerland. [Mercereau-Puijalon, Odile] Inst Pasteur, Parasite Mol Immunol Unit, Paris, France. RP Menard, D (reprint author), Inst Pasteur Cambodge, 5 Blvd Monivong BP 983, Phnom Penh, Cambodia. EM rfairhurst@niaid.nih.gov; dmenard@pasteur-kh.org RI Menard, Didier/O-3294-2013 OI Menard, Didier/0000-0003-1357-4495 FU Institut Pasteur du Cambodge; NIAID, NIH; International Division, Institut Pasteur; French Ministry of Foreign Affairs; Laboratoire d'excellence IBEID (Agence Nationale de la Recherche, France) FX Institut Pasteur du Cambodge and the Intramural Research Program, NIAID, NIH.; We thank Robert Gwadz, Savuth Koeuth, Francois Nosten, Eng Ly Pech, Thomas Wellems, and Chongjun Zhou for their efforts in support of this work. This study was funded by the Intramural Research Program, NIAID, NIH, and by grants from Institut Pasteur du Cambodge (Institut Pasteur, International Division and Banque Natixis) and Laboratoire d'excellence IBEID (Agence Nationale de la Recherche, France). BW is supported by a postdoctoral fellowship from the International Division, Institut Pasteur, and DM by the French Ministry of Foreign Affairs. NR 34 TC 123 Z9 125 U1 25 U2 54 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD DEC PY 2013 VL 13 IS 12 BP 1043 EP 1049 DI 10.1016/S1473-3099(13)70252-4 PG 7 WC Infectious Diseases SC Infectious Diseases GA 256AZ UT WOS:000327283400026 PM 24035558 ER PT J AU Corbex, M Harford, JB AF Corbex, Marilys Harford, Joe B. TI Perspectives on breast cancer in Arab populations SO LANCET ONCOLOGY LA English DT Letter ID MIDDLE-INCOME COUNTRIES C1 [Corbex, Marilys] Inst Trop Med, Dept Publ Hlth, B-2000 Antwerp, Belgium. [Harford, Joe B.] NCI, Ctr Global Hlth, NIH, Rockville, MD 20850 USA. RP Corbex, M (reprint author), Inst Trop Med, Dept Publ Hlth, B-2000 Antwerp, Belgium. EM harfordj@mail.nih.gov NR 5 TC 3 Z9 3 U1 0 U2 2 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 DEC PY 2013 VL 14 IS 13 BP E582 EP E582 PG 1 WC Oncology SC Oncology GA 259PU UT WOS:000327539600001 PM 24275130 ER PT J AU Mousoulis, C Xu, X Reiter, DA Neu, CP AF Mousoulis, Charilaos Xu, Xin Reiter, David A. Neu, Corey P. TI Single cell spectroscopy: Noninvasive measures of small-scale structure and function SO METHODS LA English DT Article DE Spectroscopy; Single cells; Nuclear magnetic resonance; Fluorescence microscopy; Atomic force microscopy ID ATOMIC-FORCE MICROSCOPY; NUCLEAR-MAGNETIC-RESONANCE; RAMAN SCATTERING MICROSCOPY; RESOLUTION NMR-SPECTROSCOPY; FLUORESCENCE MICROSCOPY; LIVE CELLS; LIVING CELLS; ILLUMINATION MICROSCOPY; PROTEIN-PHOSPHORYLATION; INFRARED-SPECTROSCOPY AB The advancement of spectroscopy methods attained through increases in sensitivity, and often with the coupling of complementary techniques, has enabled real-time structure and function measurements of single cells. The purpose of this review is to illustrate, in light of advances, the strengths and the weaknesses of these methods. Included also is an assessment of the impact of the experimental setup and conditions of each method on cellular function and integrity. A particular emphasis is placed on noninvasive and nondestructive techniques for achieving single cell detection, including nuclear magnetic resonance, in addition to physical, optical, and vibrational methods. (C) 2013 Elsevier Inc. All rights reserved. C1 [Mousoulis, Charilaos; Xu, Xin; Neu, Corey P.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Reiter, David A.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21225 USA. RP Neu, CP (reprint author), Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. EM cpneu@purdue.edu RI Xu, Xin/B-1975-2014 OI Xu, Xin/0000-0002-4876-5710 FU Showalter Trust Fund; Intramural program of the National Institutes of Health (NIH), National Institute on Aging [NIH R21 AR064178] FX This research was funded in part by the Showalter Trust Fund, the Intramural program of the National Institutes of Health (NIH), National Institute on Aging, and NIH R21 AR064178. The authors have no financial conflicts of interest to declare. NR 135 TC 1 Z9 1 U1 0 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD DEC 1 PY 2013 VL 64 IS 2 BP 119 EP 128 DI 10.1016/j.ymeth.2013.07.025 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260AM UT WOS:000327567400005 PM 23886910 ER PT J AU Kidder, BL Hu, GQ Yu, ZX Liu, CY Zhao, KJ AF Kidder, Benjamin L. Hu, Gangqing Yu, Zu-Xi Liu, Chengyu Zhao, Keji TI Extended Self-Renewal and Accelerated Reprogramming in the Absence of Kdm5b SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EMBRYONIC STEM-CELLS; CORE TRANSCRIPTIONAL NETWORK; HISTONE DEMETHYLASE; HUMAN GENOME; REGULATES PLURIPOTENCY; ACTIVE GENES; ES CELLS; METHYLATION; MOUSE; EXPRESSION AB Embryonic stem (ES) cell pluripotency is thought to be regulated in part by H3K4 methylation. However, it is unclear how H3K4 demethylation contributes to ES cell function and participates in induced pluripotent stem (iPS) cell reprogramming. Here, we show that KDM5B, which demethylates H3K4, is important for ES cell differentiation and presents a barrier to the reprogramming process. Depletion of Kdm5b leads to an extension in the self-renewal of ES cells in the absence of LIF. Transcriptome analysis revealed the persistent expression of pluripotency genes and underexpression of developmental genes during differentiation in the absence of Kdm5b, suggesting that KDM5B plays a key role in cellular fate changes. We also observed accelerated reprogramming of differentiated cells in the absence of Kdm5b, demonstrating that KDM5B is a barrier to the reprogramming process. Expression analysis revealed that mesenchymal master regulators associated with the epithelial-to-mesenchymal transition (EMT) are downregulated during reprogramming in the absence of Kdm5b. Moreover, global analysis of H3K4me3/2 revealed that enhancers of fibroblast genes are rapidly deactivated in the absence of Kdm5b, and genes associated with EMT lose H3K4me3/2 during the early reprogramming process. These findings provide functional insight into the role for KDM5B in regulating ES cell differentiation and as a barrier to the reprogramming process. C1 [Kidder, Benjamin L.; Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Kidder, BL (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM benjamin.kidder@nih.gov; zhaok@nhlbi.nih.gov RI HU, GANGQING/K-5849-2012 NR 54 TC 13 Z9 13 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2013 VL 33 IS 24 BP 4793 EP 4810 DI 10.1128/MCB.00692-13 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 259RO UT WOS:000327544200003 PM 24100015 ER PT J AU Lamichhane, TN Mattijssen, S Maraia, RJ AF Lamichhane, Tek N. Mattijssen, Sandy Maraia, Richard J. TI Human Cells Have a Limited Set of tRNA Anticodon Loop Substrates of the tRNA Isopentenyltransferase TRIT1 Tumor Suppressor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SELENOCYSTEINE TRANSFER; LUNG-CANCER; RECOGNITION; DIMETHYLALLYLTRANSFERASE; TRANSLATION; METHYLATION; EXPRESSION; INHIBITION; NUCLEOSIDE; EFFICIENCY AB Human TRIT1 is a tRNA isopentenyltransferase (IPTase) homologue of Escherichia coli MiaA, Saccharomyces cerevisiae Mod5, Schizosaccharomyces pombe Tit1, and Caenorhabditis elegans GRO-1 that adds isopentenyl groups to adenosine 37 (i6A37) of substrate tRNAs. Prior studies indicate that i6A37 increases translation fidelity and efficiency in codon-specific ways. TRIT1 is a tumor suppressor whose mutant alleles are associated with cancer progression. We report the systematic identification of i6A37-containing tRNAs in a higher eukaryote, performed using small interfering RNA knockdown and other methods to examine TRIT1 activity in HeLa cells. Although several potential substrates contained the IPTase recognition sequence A36A37-A38 in the anticodon loop, only tRNA(Ser)AGA, tRNA(Ser)CGA, tRNA(Ser)UGA, and selenocysteine tRNA with UCA (tRNA([Ser]Sec)UCA) contained i6A37. This subset is a significantly more restricted than that for two distant yeasts (S. cerevisiae and S. pombe), the only other organisms comprehensively examined. Unlike the fully i6A37-modified tRNAs for Ser, tRNA([Ser]Sec)UCA is partially (similar to 40%) modified. Exogenous selenium and other treatments that decreased the i6A37 content of tRNA([Ser]Sec)UCA led to increased levels of the tRNA([Ser]Sec)UCA. Of the human mitochondrion (mt)-encoded tRNAs with A36A37-A38, only mt tRNAs tRNASerUGA and tRNA(Trp)UCA contained detectable i6A37. Moreover, while tRNA(Ser) levels were unaffected by TRIT1 knockdown, the tRNA([Ser]Sec)UCA level was increased and the mt tRNA(Ser)UGA level was decreased, suggesting that TRIT1 may control the levels of some tRNAs as well as their specific activity. C1 [Lamichhane, Tek N.; Mattijssen, Sandy; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Washington, DC USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov FU Intramural Research Program of the NICHD, NIH FX This work was supported by the Intramural Research Program of the NICHD, NIH. NR 41 TC 9 Z9 9 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2013 VL 33 IS 24 BP 4900 EP 4908 DI 10.1128/MCB.01041-13 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 259RO UT WOS:000327544200011 PM 24126054 ER PT J AU Zhang, XX Sun, ZC Guo, JX Wang, Z Wu, CX Niu, G Ma, Y Kiesewetter, DO Chen, XY AF Zhang, Xiao-Xiang Sun, Zhongchan Guo, Jinxia Wang, Zhe Wu, Chenxi Niu, Gang Ma, Ying Kiesewetter, Dale O. Chen, Xiaoyuan TI Comparison of F-18-labeled CXCR4 antagonist peptides for PET imaging of CXCR4 expression SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE CXCR4; PET imaging; CXCR4 antagonist peptides; F-18-labeling ID CHEMOKINE RECEPTOR CXCR4; CELL-DERIVED FACTOR-1; POSITRON-EMISSION-TOMOGRAPHY; HIGH SELECTIVITY INDEXES; HUMAN CANCER XENOGRAFTS; FACTOR-I; TUMOR; METASTASIS; LIGAND; T140 AB CXCR4 is overexpressed on tumor cells from many types of human cancers. A high level of CXCR4 expression often correlates with poor prognosis, chemotherapy resistance, and metastasis. The development of CXCR4-specific radiotracers for positron emission tomography (PET) imaging will allow in vivo evaluation of receptor expression level for diagnosis or therapeutic evaluation. Two new F-18-labeled radiotracers based on an Ac-TC14012 peptide, [F-18]FP-Ac-TC14012 and [F-18]FB-Ac-TC14012, were synthesized and characterized. The affinities of the 2-fluoropropionate (FP)-conjugated or 4-fluorobenzoate (FB)-conjugated peptides to CXCR4-transfected Chinese hamster ovarian (CHO) cells were evaluated in a competitive binding assay with [I-125]CXCL12 radioligand. The cell uptake and retention of [F-18]FP-labeled and [F-18]FB-labeled peptides were measured. The tumor targetability and pharmacokinetics of these two tracers were also evaluated by microPET imaging and biodistribution studies. The labeled peptides retained high binding affinity to CXCR4 and showed much higher uptake in CXCR4-positive CHO cells than in CXCR4-negative cells in vitro. The smaller and more hydrophilic [F-18]FP prosthetic group resulted in higher affinity and lower nonspecific cell uptake compared to the [F-18]FB-labeled peptide. Both radiotracers showed much higher accumulation in CXCR4-positive than CXCR4-negative tumor xenografts in mice and allowed clear visualization of CXCR4 expression by PET. Among the two, [F-18]FP-Ac-TC14012 showed higher tumor uptake and better tumor-to-background contrast. Unlike their N-terminal 4-F-benzoate analogs, these two tracers had minimal blood retention, likely due to reduced red blood cell binding. Metabolic organs, such as the liver and kidney, also showed high uptake. When blocked with low-dose cold peptide (10 mu g), the tumor uptake was significantly increased, most likely due to the increased concentration in blood circulation, as evidenced by decreased liver uptake. These results demonstrate that the [F-18]FP-labeled Ac-TC14012 peptide with high tumor uptake, low nonspecific binding, and good tumor-to-background contrast promises [F-18]FP-Ac-TC14012 as a PET tracer for in vivo PET imaging of CXCR4 expression. C1 [Zhang, Xiao-Xiang; Guo, Jinxia; Wang, Zhe; Wu, Chenxi; Niu, Gang; Ma, Ying; Kiesewetter, Dale O.; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Sun, Zhongchan] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiol, Xian 710032, Shaanxi, Peoples R China. [Sun, Zhongchan] Fourth Mil Med Univ, Xijing Hosp, Mol Imaging Program, Xian 710032, Shaanxi, Peoples R China. [Guo, Jinxia; Wang, Zhe] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Kiesewetter, DO (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM dkiesewetter@mail.nih.gov; shawn.chen@nih.gov FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National Research Council Research Associateship Award at NIH/NIBIB FX We want to thank the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) for the funding support. This work was performed while X-X Zhang held a National Research Council Research Associateship Award at NIH/NIBIB. NR 41 TC 14 Z9 14 U1 0 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD DEC PY 2013 VL 15 IS 6 BP 758 EP 767 DI 10.1007/s11307-013-0640-0 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 255CH UT WOS:000327216300014 PM 23636490 ER PT J AU Zhang, XX Sun, ZC Guo, JX Wang, Z Wu, CX Niu, G Ma, Y Kiesewetter, DO Chen, XY AF Zhang, Xiao-Xiang Sun, Zhongchan Guo, Jinxia Wang, Zhe Wu, Chenxi Niu, Gang Ma, Ying Kiesewetter, Dale O. Chen, Xiaoyuan TI Comparison of F-18-labeled CXCR4 antagonist peptides for PET imaging of CXCR4 expression (vol 15, pg 758, 2013) SO MOLECULAR IMAGING AND BIOLOGY LA English DT Correction C1 [Zhang, Xiao-Xiang; Guo, Jinxia; Wang, Zhe; Wu, Chenxi; Niu, Gang; Ma, Ying; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Sun, Zhongchan] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiol & Mol Imaging Program, Xian 710032, Shaanxi, Peoples R China. [Guo, Jinxia; Wang, Zhe] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Kiesewetter, DO (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM dkiesewetter@mail.nih.gov; shawn.chen@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD DEC PY 2013 VL 15 IS 6 BP 788 EP 788 DI 10.1007/s11307-013-0650-y PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 255CH UT WOS:000327216300018 ER PT J AU Antonioli, L Blandizzi, C Pacher, P Hasko, G AF Antonioli, Luca Blandizzi, Corrado Pacher, Pal Hasko, Gyoergy TI Immunity, inflammation and cancer: a leading role for adenosine SO NATURE REVIEWS CANCER LA English DT Review ID REGULATORY T-CELLS; ENDOTHELIAL GROWTH-FACTOR; ACTIVATED PROTEIN-KINASE; TUMOR-ASSOCIATED MACROPHAGES; HUMAN-MELANOMA CELLS; NF-KAPPA-B; CL-IB-MECA; NUCLEOSIDE TRANSPORTER FAMILY; RECEPTOR MEDIATES APOPTOSIS; SYNERGISTIC UP-REGULATION AB Cancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in regulating the complex interplay among immune, inflammatory, endothelial and cancer cells during the course of neoplastic disease. C1 [Antonioli, Luca; Blandizzi, Corrado] Univ Pisa, Dept Clin & Expt Med, I-56126 Pisa, Italy. [Antonioli, Luca; Hasko, Gyoergy] Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Antonioli, Luca; Hasko, Gyoergy] Rutgers New Jersey Med Sch, Ctr Immun & Inflammat, Newark, NJ 07103 USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Labs Physiol Studies, NIH, Bethesda, MD 20892 USA. [Hasko, Gyoergy] Univ Debrecen, Med & Hlth Sci Ctr, Dept Med Chem, H-4032 Debrecen, Hungary. RP Hasko, G (reprint author), Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. EM haskoge@njms.rutgers.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU US National Institutes of Health (NIH) [R01GM66189]; Hungarian Scientific Research Fund grants (Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA)) [CK 78275, K 109178]; NIH, the National Institute on Alcohol Abuse and Alcoholism; Nexus award "Marcello Tonini"; Inflammatory Bowel Disease (IBD) Research Foundation FX This work was supported by US National Institutes of Health (NIH) grant R01GM66189 (to G. H.), Hungarian Scientific Research Fund grants (Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA)) CK 78275 (to G. H.) and K 109178 (to G. H.), the Intramural Research Program of the NIH, the National Institute on Alcohol Abuse and Alcoholism (to P. P.), the Nexus award "Marcello Tonini" (to L. A.) and by the Inflammatory Bowel Disease (IBD) Research Foundation (mini grant 2012) (to L.A.). NR 215 TC 106 Z9 111 U1 10 U2 71 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD DEC PY 2013 VL 13 IS 12 BP 842 EP 857 DI 10.1038/nrc3613 PG 16 WC Oncology SC Oncology GA 259RA UT WOS:000327542800008 PM 24226193 ER PT J AU Morgan, IG Cotch, MF AF Morgan, Ian G. Cotch, Mary Frances TI Birth Order and Myopia: What are the Messages to Readers? SO OPHTHALMIC EPIDEMIOLOGY LA English DT Editorial Material ID REFRACTIVE ERROR; VISUAL IMPAIRMENT; SOUTHERN CHINA; CHILDREN; ADOLESCENCE C1 [Morgan, Ian G.] Australian Natl Univ, Res Sch Biol, Canberra, ACT, Australia. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Morgan, IG (reprint author), Australian Natl Univ, Res Sch Biol, Canberra, ACT, Australia. EM ian.morgan@anu.edu.au RI Morgan, Ian/D-1190-2009; OI Morgan, Ian/0000-0002-4548-3574; Cotch, Mary Frances/0000-0002-2046-4350 FU Intramural NIH HHS [Z99 EY999999] NR 17 TC 2 Z9 2 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0928-6586 EI 1744-5086 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD DEC PY 2013 VL 20 IS 6 BP 333 EP 334 DI 10.3109/09286586.2013.860994 PG 2 WC Ophthalmology SC Ophthalmology GA 256OC UT WOS:000327322100001 PM 24229068 ER PT J AU Dalal, MD Morgans, CW Duvoisin, RM Gamboa, EA Jeffrey, BG Garg, SJ Chan, CC Sen, HN AF Dalal, Monica D. Morgans, Catherine W. Duvoisin, Robert M. Gamboa, Elizabeth A. Jeffrey, Brett G. Garg, Sunir J. Chan, Chi-Chao Sen, H. Nida TI Diagnosis of Occult Melanoma Using Transient Receptor Potential Melastatin 1 (TRPM1) Autoantibody Testing A Novel Approach SO OPHTHALMOLOGY LA English DT Article ID UNKNOWN PRIMARY SITE; BIPOLAR CELLS; CUTANEOUS MELANOMA; RETINOPATHY MAR AB Purpose: To report the first case of melanoma-associated retinopathy (MAR) and underlying occult melanoma diagnosed based on the presence of serum transient receptor potential melastatin 1 (TRPM1) autoantibodies. Design: Interventional case report with basic science correlation. Participants: One patient with MAR. Intervention: Testing for the presence of serum TRPM1 autoantibodies. Main Outcome Measures: Diagnosis of an occult melanoma involving the axillary lymph nodes (unknown primary site) and MAR based on the presence of TRPM1 autoantibodies in the patient's serum. Results: The patient's clinical exam was remarkable for mild intraocular inflammation in both eyes and retinal hemorrhages with an apparent choroidal neovascularization in the left eye, which was confirmed by fluorescein angiography and indocyanine green angiography testing. Humphrey visual field 30-2 SITA-fast (Humphrey Visual Field Analyzer, Carl Zeiss Meditec, Inc, Dublin, CA) demonstrated diffuse depression in both eyes out of proportion to the clinical exams, prompting electroretinography testing that revealed an electronegative response. Dark-adapted thresholds were markedly elevated and mediated by cones. Due to concern for MAR, a systemic work-up for melanoma was performed by the primary care physician that was unrevealing. Given our continued clinical suspicion for MAR, the patient's serum was sent for evaluation for TRPM1 autoantibodies. The patient's serum applied to normal human retina exhibited positivity in the inner nuclear layer. Application of the patient's serum to wild-type and TRPM1 knockout mouse retina revealed strongly labeled bipolar cells in the wild-type retina, but not in the TRPM1 knockout retina, indicating TRPM1-dependent immunoreactivity. The antigen was confirmed as TRPM1 by labeling of TRPM1-transfected human embryonic kidney 293 cells. Additional systemic work-up prompted by this finding resulted in identification of an occult metastatic melanoma involving the axillary lymph nodes with an unknown primary site. The patient underwent surgical excision of the occult melanoma without evidence of other sites of metastases. He also received intravenous immunoglobulin therapy and his vision has stabilized. Conclusions: This is the first reported case of a melanoma-associated retinopathy diagnosed utilizing the innovative approach of testing for serum TRPM1 autoantibodies. (C) 2013 by the American Academy of Ophthalmology. C1 [Dalal, Monica D.; Jeffrey, Brett G.; Chan, Chi-Chao; Sen, H. Nida] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Morgans, Catherine W.; Duvoisin, Robert M.; Gamboa, Elizabeth A.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Garg, Sunir J.] Wills Eye Inst, Retina Serv, Philadelphia, PA USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,Room 10D42, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU National Eye Institute Intramural Research Program, Bethesda, Maryland FX Supported by the National Eye Institute Intramural Research Program, Bethesda, Maryland. The sponsor or funding organization had no role in the design or conduct of this research. NR 19 TC 5 Z9 6 U1 0 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 DEC PY 2013 VL 120 IS 12 BP 2560 EP 2564 DI 10.1016/j.ophtha.2013.07.037 PG 5 WC Ophthalmology SC Ophthalmology GA 255OL UT WOS:000327249600040 PM 24053997 ER PT J AU Domalpally, A Danis, RP White, J Narkar, A Clemons, T Ferris, F Chew, E AF Domalpally, Amitha Danis, Ronald P. White, James Narkar, Ashwini Clemons, Traci Ferris, Fredrick Chew, Emily TI Circularity Index as a Risk Factor for Progression of Geographic Atrophy SO OPHTHALMOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; NATURAL-HISTORY; CLINICAL-TRIALS; EYE DISEASE; AREA AB Objective: To develop a parameter that can assess the relative rate of progression of geographic atrophy (GA) based on the hypothesis that noncircular configuration of the atrophic lesion may be a risk factor for enlargement. Design: Cohort study. Participants: Digitized color photographs of 593 eyes with GA from the Age-Related Eye Disease Study (AREDS). Methods: A novel parameter called the "Geographic Atrophy Circularity Index" (GACI) was developed on the basis of area and perimeter measurements to categorize the irregularity of the shape of GA. The GACI ranges from 0.0 to 1.0 and is categorized into 3 groups: 0.25 (very irregular), 0.25 to <0.75 (partly irregular), and >= 0.75 (circular). Main Outcome Measures: Growth rate of GA. Results: The mean growth rate in the 3 categories was 0.40 (+/- 0.18), 0.36 (+/- 0.30), and 0.21 (+/- 0.22) mm/year, respectively (P<0.001). By adjusting for known confounders, baseline area, duration of GA, and configuration, GACI categories were significantly associated with increased growth rate of GA (P<0.001). Conclusions: The GACI was associated with the progression rate of GA and may be a useful measure for clinical trial eligibility. The association also suggests that enlargement of GA may be related to the extent of the junctional zone of damaged retinal pigment epithelium, which increases with noncircularity for a given GA area. (C) 2013 by the American Academy of Ophthalmology. C1 [Domalpally, Amitha; Danis, Ronald P.; White, James; Narkar, Ashwini] Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI USA. [Ferris, Fredrick; Chew, Emily] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Clemons, Traci] EMMES Corp, Rockville, MD USA. RP Danis, RP (reprint author), Fundus Photograph Reading Ctr, 8010 Excelsior Dr,Suite 100, Madison, WI 53717 USA. EM rdanis@rc.ophth.wisc.edu RI Domalpally, Amitha/B-2367-2015 NR 16 TC 9 Z9 9 U1 0 U2 12 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 DEC PY 2013 VL 120 IS 12 BP 2666 EP 2671 DI 10.1016/j.ophtha.2013.07.047 PG 6 WC Ophthalmology SC Ophthalmology GA 255OL UT WOS:000327249600053 PM 24206616 ER PT J AU Groninger, H AF Groninger, Hunter TI Regarding a definition of the palliative care patient SO PALLIATIVE MEDICINE LA English DT Letter ID PAIN C1 NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Groninger, H (reprint author), NIH, Pain & Palliat Care Serv, Ctr Clin, Room 2-1733, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-2163 EI 1477-030X J9 PALLIATIVE MED JI Palliat. Med. PD DEC PY 2013 VL 27 IS 10 BP 952 EP 953 DI 10.1177/0269216313493220 PG 2 WC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medicine, General & Internal SC Health Care Sciences & Services; Public, Environmental & Occupational Health; General & Internal Medicine GA 254FA UT WOS:000327148800009 PM 24259476 ER PT J AU Fox, MA Panessiti, MG Moya, PR Tolliver, TJ Chen, K Shih, JC Murphy, DL AF Fox, M. A. Panessiti, M. G. Moya, P. R. Tolliver, T. J. Chen, K. Shih, J. C. Murphy, D. L. TI Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans SO PHARMACOGENOMICS JOURNAL LA English DT Article DE 5-hydroxy-L-tryptophan (5-HTP); monoamine oxidase (MAO) A/B-knockout mice; serotonin syndrome; tramadol ID TRANSPORTER (SERT)-DEFICIENT MICE; KNOCK-OUT MICE; DEFICIENT MICE; FUNCTIONAL POLYMORPHISM; PROMOTER POLYMORPHISM; REUPTAKE INHIBITOR; BRAIN-SEROTONIN; POINT MUTATION; TRAMADOL; ASSOCIATION AB A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased similar to 2.6-3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased similar to 4.5-6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes. C1 [Fox, M. A.; Panessiti, M. G.; Moya, P. R.; Tolliver, T. J.; Murphy, D. L.] NIMH, LCS, NIH, Bethesda, MD 20892 USA. [Chen, K.; Shih, J. C.] Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA USA. [Shih, J. C.] Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90033 USA. RP Fox, MA (reprint author), NIMH, LCS, NIH, 10 Ctr Dr,Bldg 10-3D41,MSC 1264, Bethesda, MD 20892 USA. EM mfox@mail.nih.gov FU NIMH; NIH, NIMH [RO1-MH39085]; Boyd and Elsie Welin Professorship FX This research was supported by the NIMH Intramural Research Program and by NIH, NIMH RO1-MH39085 and the Boyd and Elsie Welin Professorship to JCS. NR 73 TC 2 Z9 2 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X EI 1473-1150 J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD DEC PY 2013 VL 13 IS 6 BP 551 EP 557 DI 10.1038/tpj.2012.35 PG 7 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 258HJ UT WOS:000327449700011 PM 22964922 ER PT J AU Rao, M AF Rao, Mahendra TI Anthony Atala (ed): Progenitor and Stem Cell Technologies and Therapies SO STEM CELL REVIEWS AND REPORTS LA English DT Editorial Material C1 NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Rao, M (reprint author), NIH, Ctr Regenerat Med, Bldg 10, Bethesda, MD 20892 USA. EM mahendra.rao@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 EI 1558-6804 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD DEC PY 2013 VL 9 IS 6 BP 873 EP 873 DI 10.1007/s12015-013-9471-2 PG 1 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 257LT UT WOS:000327386500012 ER PT J AU Alberts, MJ Wechsler, LR Jensen, MEL Latchaw, RE Crocco, TJ George, MG Baranski, J Bass, RR Ruff, RL Huang, J Mancini, B Gregory, T Gress, D Emr, M Warren, M Walker, MD AF Alberts, Mark J. Wechsler, Lawrence R. Jensen, Mary E. Lee Latchaw, Richard E. Crocco, Todd J. George, Mary G. Baranski, James Bass, Robert R. Ruff, Robert L. Huang, Judy Mancini, Barbara Gregory, Tammy Gress, Daryl Emr, Marian Warren, Margo Walker, Michael D. TI Formation and Function of Acute Stroke-Ready Hospitals Within a Stroke System of Care Recommendations From the Brain Attack Coalition SO STROKE LA English DT Article DE acute stroke; cerebrovascular disease; stroke ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; EMERGENCY MEDICAL-SERVICES; NORTH-CAROLINA STROKE; POLICY STATEMENT; GUIDELINES-STROKE; PILOT PROJECT; UNITED-STATES; ASSOCIATION; CENTERS AB Background and Purpose Many patients with an acute stroke live in areas without ready access to a Primary or Comprehensive Stroke Center. The formation of care facilities that meet the needs of these patients might improve their care and outcomes and guide them and emergency responders to such centers within a stroke system of care. Methods The Brain Attack Coalition conducted an electronic search of the English medical literature from January 2000 to December 2012 to identify care elements and processes shown to be beneficial for acute stroke care. We used evidence grading and consensus paradigms to synthesize recommendations for Acute Stroke-Ready Hospitals (ASRHs). Results Several key elements for an ASRH were identified, including acute stroke teams, written care protocols, involvement of emergency medical services and emergency department, and rapid laboratory and neuroimaging testing. Unique aspects include the use of telemedicine, hospital transfer protocols, and drip and ship therapies. Emergent therapies include the use of intravenous tissue-type plasminogen activator and the reversal of coagulopathies. Although many of the care elements are similar to those of a Primary Stroke Center, compliance rates of 67% are suggested in recognition of the staffing, logistical, and financial challenges faced by rural facilities. Conclusions ASRHs will form the foundation for acute stroke care in many settings. Recommended elements of an ASRH build on those proven to improve care and outcomes at Primary Stroke Centers. The ASRH will be a key component for patient care within an evolving stroke system of care. C1 [Alberts, Mark J.] Univ Texas Southwestern, Dept Neurol & Neurotherapeut, Dallas, TX USA. [Wechsler, Lawrence R.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Jensen, Mary E. Lee] Univ Virginia, Dept Radiol & Med Imaging, Charlottesville, VA USA. [Gress, Daryl] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Latchaw, Richard E.] UC Davis Med Ctr, Dept Radiol, Davis, CA USA. [Crocco, Todd J.] W Virginia Univ, Dept Emergency Med, Morgantown, WV 26506 USA. [George, Mary G.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Baranski, James] Natl Stroke Assoc, Englewood, CO USA. [Bass, Robert R.] Natl Assoc EMS Officials, Falls Church, VA USA. [Ruff, Robert L.] VA Med Ctr, Dept Neurol, Cleveland, OH USA. [Huang, Judy] Johns Hopkins Univ Hosp, Dept Neurosurg, Baltimore, MD 21287 USA. [Mancini, Barbara] Inova Inc, San Diego, CA USA. [Gregory, Tammy] Amer Heart Assoc, Dallas, TX USA. [Emr, Marian; Warren, Margo; Walker, Michael D.] NINDS, Bethesda, MD 20892 USA. RP Alberts, MJ (reprint author), Univ Texas SW Med Ctr Dallas, Dept Neurol & Neurotherapeut, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Mark.Alberts@UTSouthwestern.edu NR 58 TC 14 Z9 15 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2013 VL 44 IS 12 BP 3382 EP 3393 DI 10.1161/STROKEAHA.113.002285 PG 12 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 257LR UT WOS:000327386300309 PM 24222046 ER PT J AU Meltzer, JA Chu, R Braun, AR AF Meltzer, J. A. Chu, R. Braun, A. R. TI Detection and Quantification of Functional Lesions from Slowing in Resting-State MEG SO STROKE LA English DT Meeting Abstract CT Canadian Stroke Congress CY OCT 17-20, 2013 CL Montreal, CANADA C1 [Meltzer, J. A.] Baycrest, Rotman Res Inst, Toronto, ON, Canada. [Chu, R.] Univ Toronto, Toronto, ON, Canada. [Braun, A. R.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2013 VL 44 IS 12 BP E177 EP E178 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 257LR UT WOS:000327386300022 ER PT J AU Palesch, YY Martin, RH Hill, MD Tamariz, D Jauch, EC Weng, Y Speiser, JL Woolson, RF Barsan, WG Moy, CS Ginsberg, MD AF Palesch, Y. Y. Martin, R. H. Hill, M. D. Tamariz, D. Jauch, E. C. Weng, Y. Speiser, J. L. Woolson, R. F. Barsan, W. G. Moy, C. S. Ginsberg, M. D. TI Meta-analysis of Albumin in Acute Stroke (ALIAS) Parts 1 and 2 Trials SO STROKE LA English DT Meeting Abstract CT Canadian Stroke Congress CY OCT 17-20, 2013 CL Montreal, CANADA C1 [Palesch, Y. Y.; Martin, R. H.; Jauch, E. C.; Weng, Y.; Speiser, J. L.; Woolson, R. F.] Med Univ S Carolina, Charleston, SC 29425 USA. [Hill, M. D.] Univ Calgary, Calgary, AB, Canada. [Tamariz, D.; Ginsberg, M. D.] Univ Miami, Miami, FL USA. [Barsan, W. G.] Univ Michigan, Ann Arbor, MI 48109 USA. [Moy, C. S.] NINDS, Bethesda, MD 20892 USA. RI Hill, Michael/C-9073-2012 OI Hill, Michael/0000-0002-6269-1543 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2013 VL 44 IS 12 BP E209 EP E209 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 257LR UT WOS:000327386300185 ER PT J AU Castaneto, MS Barnes, AJ Scheidweiler, KB Schaffer, M Rogers, KK Stewart, D Huestis, MA AF Castaneto, Marisol S. Barnes, Allan J. Scheidweiler, Karl B. Schaffer, Michael Rogers, Kristen K. Stewart, Deborah Huestis, Marilyn A. TI Identifying Methamphetamine Exposure in Children SO THERAPEUTIC DRUG MONITORING LA English DT Article DE hair; urine; oral fluid; drug-exposed children; methamphetamine ID ORAL FLUID; MENTAL-HEALTH; HAIR SAMPLES; LABORATORIES; MANUFACTURE; COCAINE; URINE; ABUSE; MDMA; AMPHETAMINE AB Objective:Methamphetamine (MAMP) use, distribution, and manufacture remain a serious public health and safety problem in the United States, and children environmentally exposed to MAMP face a myriad of developmental, social, and health risks, including severe abuse and neglect necessitating child protection involvement. It is recommended that drug-endangered children receive medical evaluation and care with documentation of overall physical and mental conditions and have urine drug testing. The primary aim of this study was to determine the best biological matrix to detect MAMP, amphetamine (AMP), methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA), and 3,4-methylenedioxyethylamphetamine (MDEA) in environmentally exposed children.Methods:Ninety-one children, environmentally exposed to household MAMP intake, were medically evaluated at the Child and Adolescent Abuse Resource and Evaluation Diagnostic and Treatment Center at the University of California, Davis Children's Hospital. MAMP, AMP, MDMA, MDA, and MDEA were quantified in urine and oral fluid (OF) by gas chromatography mass spectrometry and in hair by liquid chromatography tandem mass spectrometry.Results:Overall drug detection rates in OF, urine, and hair were 6.9%, 22.1%, and 77.8%, respectively. Seventy children (79%) tested positive for 1 or more drugs in 1 or more matrices. MAMP was the primary analyte detected in all 3 biological matrices. All positive OF (n = 5), and 18 of 19 positive urine specimens also had a positive hair test.Conclusions:Hair analysis offered a more sensitive tool for identifying MAMP, AMP, and MDMA environmental exposure in children than urine or OF testing. A negative urine or hair test does not exclude the possibility of drug exposure, but hair testing provided the greatest sensitivity for identifying drug-exposed children. C1 [Castaneto, Marisol S.; Barnes, Allan J.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, IRP, NIH, Baltimore, MD 21224 USA. [Schaffer, Michael] Psychemed Corp, Culver City, CA USA. [Rogers, Kristen K.] Calif Dept Publ Hlth, Data Benchmark & Evaluat Sect, Maternal Child & Adolescent Hlth Div, Sacramento, CA USA. [Stewart, Deborah] Calif State Univ Chico, Student Hlth Serv, Chico, CA 95929 USA. RP Huestis, MA (reprint author), NIDA, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@nida.nih.gov FU National Institutes on Drug Abuse FX Supported by the Intramural Research Program, National Institutes on Drug Abuse and National Institutes of Health, University of California, Davis, Psychemedics, Corporation (hair testing and results). NR 39 TC 3 Z9 3 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD DEC PY 2013 VL 35 IS 6 BP 823 EP 830 DI 10.1097/FTD.0b013e31829685b2 PG 8 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 256LQ UT WOS:000327312200012 PM 24263642 ER PT J AU Gonzales, JM Law, SHW AF Gonzales, John M., Jr. Law, Sheran Hiu Wan TI Feed and Feeding Regime Affect Growth Rate and Gonadosomatic Index of Adult Zebrafish (Danio Rerio) SO ZEBRAFISH LA English DT Article ID TILAPIA OREOCHROMIS-NILOTICUS; BASS DICENTRARCHUS-LABRAX; VARYING DIETARY-PROTEIN; FATTY-ACID-COMPOSITION; REPRODUCTIVE-PERFORMANCE; CLARIAS-GARIEPINUS; NILE TILAPIA; BROODSTOCK NUTRITION; HAMILTON-BUCHANAN; FEMALE ZEBRAFISH AB A 5-week study was conducted to evaluate commercially available Artemia, Ziegler zebrafish diet, and Calamac diet fed in five different feeding regimes on the growth and reproductive development of 7-month-old zebrafish. Zebrafish were fed to satiation three times daily during the normal work week and twice daily during the weekend and holidays. Zebrafish in dietary groups CCC (Calamac three times daily) and CCA (Calamac twice daily, Artemia once daily) had a significantly (p<0.05) greater weight gain and specific growth rate as compared to all other dietary groups. Male zebrafish in dietary group 5 had significantly larger gonadosomatic index (GSI) values than all other groups, while female zebrafish in dietary group CCC had significantly larger GSI values than all other groups. No differences in the fatty acid content of female gonads were detected. Zebrafish fed solely Artemia had the greatest weight loss and lowest GSI values. Preliminary evidence of protein sparing in zebrafish is reported. Collectively, this study sheds more light into the effects of the use of commercially available feeds and feeding regime on the rearing of zebrafish. C1 [Gonzales, John M., Jr.; Law, Sheran Hiu Wan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Gonzales, JM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. EM gonzaljo@mail.nih.gov FU American Association for the Laboratory Animal Science; Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We would like to thank Dr. Igor Dawid for the use of fish, laboratory space, manuscript review, and other resources made available during the course of this study. We would also like to thank the Charles River aquatics husbandry staff at the NICHD for their involvement with this study. We would like to thank Mr. Dennis Barnard for his input and review of the manuscript. We also appreciate all the comments provided by the reviewers in completing this manuscript. This work was supported by grants for Laboratory Animal Science (GLAS) from the American Association for the Laboratory Animal Science. This research was party supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 62 TC 4 Z9 4 U1 1 U2 23 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 EI 1557-8542 J9 ZEBRAFISH JI Zebrafish PD DEC 1 PY 2013 VL 10 IS 4 BP 532 EP 540 DI 10.1089/zeb.2013.0891 PG 9 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA 255DH UT WOS:000327219100011 PM 23902461 ER PT J AU Choi, SE Fu, T Seok, S Kim, DH Yu, E Lee, KW Kang, Y Li, XL Kemper, B Kemper, JK AF Choi, Sung-E Fu, Ting Seok, Sunmi Kim, Dong-Hyun Yu, Eunkyung Lee, Kwan-Woo Kang, Yup Li, Xiaoling Kemper, Byron Kemper, Jongsook K. TI Elevated microRNA-34a in obesity reduces NAD(+) levels and SIRT1 activity by directly targeting NAMPT SO AGING CELL LA English DT Article DE deacetylation; diabetes; miR-34a; resveratrol; sirtuins; steatosis ID METABOLIC DISEASE; RESVERATROL; SIRTUINS; DIET; PROTECTS; BIOSYNTHESIS; INHIBITION; ACTIVATION; EXPRESSION; PATHWAY AB SIRT1 is an NAD(+)-dependent deacetylase that is implicated in prevention of many age-related diseases including metabolic disorders. As SIRT1 deacetylase activity is dependent on NAD(+) levels and the development of compounds that directly activate SIRT1 has been controversial, indirectly activating SIRT1 through enhancing NAD(+) bioavailability has received increasing attention. NAD(+) levels are reduced in obesity and the aged, but the underlying mechanisms remain unclear. We recently showed that hepatic microRNA-34a (miR-34a), which is elevated in obesity, directly targets and decreases SIRT1 expression. Here, we further show that miR-34a reduces NAD(+) levels and SIRT1 activity by targeting NAMPT, the rate-limiting enzyme for NAD(+) biosynthesis. A functional binding site for miR-34a is present in the 3 UTR of NAMPT mRNA. Hepatic overexpression of miR-34a reduced NAMPT/NAD(+) levels, increased acetylation of the SIRT1 target transcriptional regulators, PGC-1, SREBP-1c, FXR, and NF-B, and resulted in obesity-mimetic outcomes. The decreased NAMPT/NAD(+) levels were independent of miR-34a effects on SIRT1 levels as they were also observed in SIRT1 liver-specific knockout mice. Further, the miR-34a-mediated decreases were reversed by treatment with the NAD(+) intermediate, nicotinamide mononucleotide. Conversely, antagonism of miR-34a in diet-induced obese mice restored NAMPT/NAD(+) levels and alleviated steatosis, inflammation, and glucose intolerance. Anti-miR-34a-mediated increases in NAD(+) levels were attenuated when NAMPT was downregulated. Our findings reveal a novel function of miR-34a in reducing both SIRT1 expression and activity in obesity. The miR-34a/NAMPT axis presents a potential target for treating obesity- and aging-related diseases involving SIRT1 dysfunction like steatosis and type 2 diabetes. C1 [Choi, Sung-E; Fu, Ting; Seok, Sunmi; Kim, Dong-Hyun; Yu, Eunkyung; Kemper, Byron; Kemper, Jongsook K.] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Lee, Kwan-Woo] Ajou Univ, Sch Med, Dept Endocrinol & Metab, Suwon 442749, South Korea. [Kang, Yup] Ajou Univ, Sch Med, Inst Med Sci, Suwon 442749, South Korea. [Li, Xiaoling] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Kemper, JK (reprint author), Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. EM jongsook@illinois.edu FU Korean Health 21 R&D Project, Ministry of Health and Welfare [A102065]; MRC [2012-051426]; National Institutes of Health [DK62777, DK95842]; American Diabetes Association FX This study was supported by a grant from the Korean Health 21 R&D Project, Ministry of Health and Welfare (A102065) to K. W. Lee and a grant from MRC 2012-051426 to Y. Kang, and grants from National Institutes of Health (DK62777 and DK95842) and a Basic Science Award from the American Diabetes Association to J. K. Kemper. NR 42 TC 54 Z9 56 U1 1 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD DEC PY 2013 VL 12 IS 6 BP 1062 EP 1072 DI 10.1111/acel.12135 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 255AN UT WOS:000327211700013 PM 23834033 ER PT J AU Tembhare, PR Marti, G Wiestner, A Degheidy, H Farooqui, M Kreitman, RJ Jasper, GA Yuan, CM Liewehr, D Venzon, D Stetler-Stevenson, M AF Tembhare, Prashant R. Marti, Gerald Wiestner, Adrian Degheidy, Heba Farooqui, Mohammed Kreitman, Robert J. Jasper, Gregory A. Yuan, Constance M. Liewehr, David Venzon, David Stetler-Stevenson, Maryalice TI Quantification of Expression of Antigens Targeted by Antibody-Based Therapy in Chronic Lymphocytic Leukemia SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Chronic lymphocytic leukemia; Antibody therapy; Rituximab; Alemtuzumab; Quantitative flow cytometry ID QUANTITATIVE FLOW-CYTOMETRY; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; B-CELL LEUKEMIAS; PHASE-I TRIAL; CD20 EXPRESSION; LYMPHOPROLIFERATIVE DISORDERS; ALEMTUZUMAB CAMPATH-1H; RESIDUAL DISEASE; RITUXIMAB; FLUDARABINE AB Objectives: Anti-CD20 (rituximab), anti-CD52 (alemtuzumab), anti-CD22 (BL22, HA22), and anti-CD25 (Oncotac) are therapeutic options that are the mainstay or in preclinical development for the treatment of chronic lymphocytic leukemia (CLL). Studies suggest that levels of surface antigen expression may affect response to monoclonal antibody-based therapy. Methods: Using the flow cytometric Quantibrite method (BD Biosciences, San Jose, CA) to determine antibodies bound per cell, we quantified the levels of surface expression of CD20, CD22, CD25, and CD52 in CLL cells from 28 untreated patients. Results: The CLL cells in all cases expressed CD20, CD22, and CD52 but 4 (14%) cases were negative for CD25. Although the ranking of levels of expression from highest to lowest was CD52, CD20, CD22, and CD25, the level of antigen expression on any specific case could not be accurately predicted. Conclusions: Quantification of antigens might be useful in evaluating new antigens to target for therapy and may provide a systematic approach to selecting individualized therapy in CLL. (C) American Society for Clinical Pathology C1 [Tembhare, Prashant R.; Jasper, Gregory A.; Yuan, Constance M.; Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kreitman, Robert J.] NCI, Lab Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liewehr, David; Venzon, David] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Marti, Gerald; Degheidy, Heba] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Wiestner, Adrian; Farooqui, Mohammed] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM stetler@mail.nih.gov FU Intramural NIH HHS [Z01 BC011104-01] NR 31 TC 6 Z9 7 U1 0 U2 6 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2013 VL 140 IS 6 BP 813 EP 818 DI 10.1309/AJCPYFQ4XMGJD6TI PG 6 WC Pathology SC Pathology GA 255ZX UT WOS:000327280400007 PM 24225748 ER PT J AU Godfrey, CC Michelow, PM Godard, M Sahasrabuddhe, VV Darden, J Firnhaber, CS Wetherall, NT Bremer, J Coombs, RW Wilkin, T AF Godfrey, Catherine C. Michelow, Pamela M. Godard, Mandana Sahasrabuddhe, Vikrant V. Darden, Janice Firnhaber, Cynthia S. Wetherall, Neal T. Bremer, James Coombs, Robert W. Wilkin, Timothy CA A5282 Study Team TI Improving Diagnostic Capability for HPV Disease Internationally Within the NIH-NIAID Division of AIDS Clinical Trial Networks SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE External quality assurance; EQA; HPV; Cervical pathology; Cervical cytology; Histopathology; HPV DNA testing ID SQUAMOUS INTRAEPITHELIAL LESIONS; EXTERNAL QUALITY-ASSURANCE; CERVICAL-CANCER PREVENTION; HIV-INFECTED WOMEN; DEVELOPING-COUNTRIES; POSITIVE WOMEN; MORTALITY; CYTOLOGY; RISK; INDIA AB Objectives: To evaluate an external quality assurance (EQA) program for the laboratory diagnosis of human papillomavirus (HPV) disease that was established to improve international research capability within the Division of AIDS at the National Institute of Allergy and Infectious Disease supported Adult AIDS Clinical Trials Group network. Methods: A three-component EQA scheme was devised comprising assessments of diagnostic accuracy of cytotechnologists and pathologists using available EQA panels, review of quality and accuracy of clinical slides from local sites by an outside expert, and HPV DNA detection using a commercially available HPV test kit. Results: Seven laboratories and 17 pathologists in Africa, India, and South America participated EQA scores were suboptimal for EQA proficiency testing panels in three of seven laboratories. There was good agreement between the local laboratory and the central reader 70% of the time (90% confidence interval, 42%-98%). Performance on the College of American Pathologists' HPV DNA testing panel was successful in all laboratories tested Conclusions: The prequalifying EQA round identified correctable issues that will improve the laboratory diagnosis of HPV-related cervical disease at the participating international study sites and will provide a mechanism for ongoing education and continuous quality improvement. American Society for Clinical Pathology C1 [Godfrey, Catherine C.] NIAID, NIH, Bethesda, MD 20892 USA. [Michelow, Pamela M.] Univ Witwatersrand, Fac Hlth Sci, Cytol Unit, Johannesburg, South Africa. [Michelow, Pamela M.] Natl Hlth Lab Serv, Johannesburg, South Africa. [Godard, Mandana] Johns Hopkins Univ, Patient Safety Monitoring Int Labs SMILE, Baltimore, MD USA. [Sahasrabuddhe, Vikrant V.] Vanderbilt Univ, Vanderbilt Inst Global Hlth, Nashville, TN 37235 USA. [Sahasrabuddhe, Vikrant V.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Darden, Janice] Social & Sci Syst, Silver Spring, MD USA. [Firnhaber, Cynthia S.] Univ Witwatersrand, Fac Hlth Sci, Dept Internal Med, Clin HIV Res Unit, Johannesburg, South Africa. [Firnhaber, Cynthia S.] Right Care, Johannesburg, South Africa. [Wetherall, Neal T.] HJF DAIDS, Bethesda, MD USA. [Bremer, James] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Coombs, Robert W.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Coombs, Robert W.] Univ Washington, Dept Med, Seattle, WA USA. [Wilkin, Timothy] Weill Cornell Med Coll, Div Infect Dis, New York, NY USA. RP Godfrey, CC (reprint author), NIAID, NIH, 6700 B Rockledge Dr, Bethesda, MD 20892 USA. EM Cgodfrey@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases [UM1 AI068636, UM1 AI069463-07, AI38858] FX The project described was supported by award numbers UM1 AI068636 (C.S.F., R.W.C., and T. W.), UM1 AI069463-07 (C.S.F.), AI38858 (C.S.F., R.W.C., and T.W), AI27757 (R.W.C.) from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health and National Institute of Dental and Craniofacial Research. This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract numbers HHSN2722008000I4C (NT. W), HHSN272201300004C (MG.), and HHSN272201200023C (J.B). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. NR 31 TC 3 Z9 3 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2013 VL 140 IS 6 BP 881 EP 889 DI 10.1309/AJCPIBIS19QIYHJY PG 9 WC Pathology SC Pathology GA 255ZX UT WOS:000327280400016 PM 24225757 ER PT J AU Shah, MT Zonderman, AB Waldstein, SR AF Shah, Mauli T. Zonderman, Alan B. Waldstein, Shari R. TI Sex and Age Differences in the Relation of Depressive Symptoms With Blood Pressure SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE age factors; blood pressure; depressive symptoms; hypertension; longitudinal studies; older adults; repeated measures; sex factors; women ID CARDIOVASCULAR-DISEASE; RISK-FACTORS; HEART-DISEASE; LATE-LIFE; CES-D; HYPERTENSION; ANXIETY; WOMEN; METAANALYSIS; MODELS AB BACKGROUND Longitudinal associations between depressive symptoms and blood pressure have been inconsistent. Most studies have examined incident hypertension as an outcome, and few have examined effect modification. METHODS This study examined moderating influences of sex and age on coincident trajectories of depressive symptoms and blood pressure among 2,087 participants from the Baltimore Longitudinal Study of Aging (aged 19-97 years; 53% men; 74% white). Participants underwent clinical blood pressure measurement and completed the Center for Epidemiological Studies-Depression (CES-D) scale on up to 14 occasions (mean = 3.8; SD = 2.6) over up to 29 years (mean = 7.8; SD = 6.4). CES-D was log-transformed (CES-D(log)) for analyses. RESULTS Mixed-effects regression revealed that prospective relations of CESD(log) to diastolic blood pressure differed by age in women (b = 0.095; P = 0.001) but not men; greater CES-D(log) attenuated the expected age-related decline in diastolic blood pressure. Across all testing sessions, greater CES-D(log) was associated significantly with higher average systolic blood pressure for women (b = 2.238; P = 0.006) but not men. Age-stratified analyses showed that greater CES-D(log) was associated significantly with higher average systolic (b = 3.348; P = 0.02) and diastolic (b = 1.730; P < 0.03) blood pressure for older adults (>= 58.8 years at first visit). In the younger age cohort, sex moderated the relation of CES-D(log) to systolic blood pressure (b = -3.563; P = 0.007); greater CES-D(log) in women, but lesser CES-D(log) in men, was associated with higher systolic blood pressure. CONCLUSIONS Results demonstrate sex and age differences in the relation between depressive symptoms and blood pressure. Findings suggest the potential importance of preventing, detecting, and lowering depressive symptoms to prevent hypertension among women and older adults. C1 [Shah, Mauli T.; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. [Shah, Mauli T.; Zonderman, Alan B.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Waldstein, Shari R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. RP Shah, MT (reprint author), Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. EM maulishah@umbc.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS NR 40 TC 7 Z9 8 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD DEC PY 2013 VL 26 IS 12 BP 1413 EP 1420 DI 10.1093/ajh/hpt135 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 251IW UT WOS:000326922700008 PM 23959543 ER PT J AU George, MD Wine, RN Lackford, B Kissling, GE Akiyama, SK Olden, K Roberts, JD AF George, Margaret D. Wine, Robert N. Lackford, Brad Kissling, Grace E. Akiyama, Steven K. Olden, Kenneth Roberts, John D. TI p38 mitogen-activated protein kinase interacts with vinculin at focal adhesions during fatty acid-stimulated cell adhesion SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article DE p38 MAP kinase; vinculin; signal transduction; arachidonic acid; cell adhesion ID BREAST-CARCINOMA CELLS; HEAT-SHOCK PROTEINS; COLLAGEN TYPE-IV; ARACHIDONIC-ACID; MAP KINASE; TYROSINE PHOSPHORYLATION; TUMOR MICROENVIRONMENT; INTEGRIN ACTIVATION; MATRIX ADHESION; CANCER-CELLS AB Arachidonic acid stimulates cell adhesion by activating alpha 2 beta 1 integrins in a process that depends on protein kinases, including p38 mitogen activated protein kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules that contribute to the spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. Arachidonic acid-treated cells showed increased attachment and spreading on collagen type IV, as measured by electric cell-substrate impedance sensing. Fatty acid-treated cells displayed short cortical actin filaments associated with an increased number of beta 1 integrin-containing pseudopodia, whereas untreated cells displayed elongated stress fibers and fewer clusters of beta 1 integrins. Confocal microscopy of arachidonic acid-treated cells showed that vinculin and phospho-p38 both appeared enriched in pseudopodia and at the tips of actin filaments, and fluorescence ratio imaging indicated the increase was specific for the phospho-(active) form of p38. Immunoprecipitates of phospho-p38 from extracts of arachidonic acid-treated cells contained vinculin, and GST-vinculin fusion proteins carrying the central region of vinculin bound phospho-p38, whereas fusion proteins expressing the terminal portions of vinculin did not. These data suggest that phospho-p38 associates with particular domains on critical focal adhesion proteins that are involved in tumor cell adhesion and spreading, and that this association can be regulated by factors in the tumor microenvironment. C1 [George, Margaret D.; Wine, Robert N.; Lackford, Brad; Kissling, Grace E.; Akiyama, Steven K.; Olden, Kenneth; Roberts, John D.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Roberts, JD (reprint author), NIEHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM roberts1@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX We thank Dr. Kris DeMali of the University of Iowa and Dr. Keith Burridge of the University of North Carolina at Chapel Hill for providing the GST-vinculin DNA constructs. We thank Drs. Alex Merrick and David Miller of NIEHS for providing critical advice on the manuscript. We are grateful to Jeff Reece, Jeff Tucker, and Agnes Janoshazi for help with the confocal microscopy and to Toni Smith for carrying out initial spreading assays. This research was supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 102 TC 1 Z9 1 U1 0 U2 9 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 0829-8211 EI 1208-6002 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD DEC PY 2013 VL 91 IS 6 BP 404 EP 418 DI 10.1139/bcb-2013-0013 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 254DC UT WOS:000327142700013 PM 24219282 ER PT J AU Avigan, D Hari, P Battiwalla, M Bishop, MR Giralt, SA Hardy, NM Kroger, N Wayne, AS Hsu, KC AF Avigan, David Hari, Parameswaran Battiwalla, Minoo Bishop, Michael R. Giralt, Sergio A. Hardy, Nancy M. Kroeger, Nicolaus Wayne, Alan S. Hsu, Katharine C. TI Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part II. Autologous Transplantation-Novel Agents and Immunomodulatory Strategies SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Relapse; Hematopoietic stem cell transplantation; Autologous; Allogeneic; Multiple myeloma ID ACUTE MYELOID-LEUKEMIA; NATURAL-KILLER-CELLS; MINIMAL RESIDUAL DISEASE; WT1 PEPTIDE VACCINATION; ACUTE MYELOGENOUS LEUKEMIA; EARLY LYMPHOCYTE RECOVERY; CYTOTOXIC T-LYMPHOCYTES; NEWLY-DIAGNOSED MYELOMA; MULTIPLE-MYELOMA; DENDRITIC CELLS AB In the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on Autologous Transplantation addressed the role of novel agents and immunomodulatory strategies in management of relapse after autologous hematopoietic stem cell transplantation (AHSCT). Concepts were illustrated through in-depth discussion of multiple myeloma, with broader discussion of areas relevant for relapse of other malignancies as well as in the setting of allogeneic transplantation. Dr. Hari provided an overview of the epidemiology of relapse after AHSCT in multiple myeloma, addressing clinical patterns, management implications, and treatment options at relapse, highlighting the implications of novel therapeutic agents in initial, maintenance, and relapse treatment. Dr. Avigan discussed current concepts in tumor vaccine design, including whole cell and antigen-specific strategies, use of an AHSCT platform to reverse tumor-associated immunosuppression and tolerance, and combining vaccines with immunomodulatory agents to promote establishment of durable antitumor immunity. Dr. Hsu reviewed the immunogenetics of natural killer (NK) cells and general NK biology, the clinical importance of autologous NK activity (eg, lymphoma and neuroblastoma), the impact of existing therapies on promotion of NK cell activity (eg, immunomodulatory drugs, monoclonal antibodies), and strategies for enhancing autologous and allogeneic NK cell effects through NK cell gene profiling. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Avigan, David] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Hematol Malignancies Bone Marrow Transplant Progr, Boston, MA 02215 USA. [Hari, Parameswaran] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bishop, Michael R.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Giralt, Sergio A.; Hsu, Katharine C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Hardy, Nancy M.] NCI, Expt Transplantat Immunol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Kroeger, Nicolaus] Univ Med Ctr Hamburg Eppendorf, Dept Stem Cell Transplantat, Hamburg, Germany. [Wayne, Alan S.] NCI, Pediat Oncol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Wayne, Alan S.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Current Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90033 USA. RP Hardy, NM (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Hatfield Clin Res Ctr, 10 Ctr Dr,Room 3E-3330, Bethesda, MD 20892 USA. EM hardyn@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute, Center for Cancer Research; National Heart, Lung and Blood Institute FX Financial disclosure: Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and National Heart, Lung and Blood Institute. NR 97 TC 4 Z9 4 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2013 VL 19 IS 12 BP 1661 EP 1669 DI 10.1016/j.bbmt.2013.08.011 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 257CL UT WOS:000327361100003 PM 24018393 ER PT J AU Pedone, C Scarlata, S Napoli, N Lauretani, F Bandinelli, S Ferrucci, L Incalzi, RA AF Pedone, Claudio Scarlata, Simone Napoli, Nicola Lauretani, Fulvio Bandinelli, Stefania Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Relationship Between Bone Cross-Sectional Area and Indices of Peripheral Artery Disease SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE Bone cross-sectional area; Peripheral artery disease; Osteoporosis; Atherosclerosis; Women; Elderly ID MINERAL DENSITY; VITAMIN-D; POSTMENOPAUSAL WOMEN; CORONARY-ARTERY; CARDIOVASCULAR-DISEASE; AORTIC CALCIUM; FRACTURE RISK; ATHEROSCLEROSIS; CALCIFICATION; OSTEOPOROSIS AB Most studies on the relationship between bone mineral density and atherosclerosis have used dual-energy X-ray absorptiometry, but this method is relatively insensitive to bone geometry. The aim of this study was to investigate the relationship between bone area and indices of carotid and peripheral atherosclerosis. We studied 841 persons aged 65 years or older (women = 444, mean age 73.8 years; men = 397, mean age = 75.3 years) enrolled in the InCHIANTI study and free from active malignancies, chronic use of bisphosphonates or steroids, and estrogen replacement therapy. The tibial cortical and total cross-sectional area (CSA) were measured by peripheral quantitative computed tomography and their ratio was calculated (cortical/total cross-sectional area ratio, cCSA/tCSA); carotid plaques were screened by echography, and peripheral artery disease (PAD) was defined as an ankle/brachial index < 0.9 or presence of intermittent claudication. No association between cCSA/tCSA and atherosclerosis was observed in men. In women, lower cCSA/tCSA was associated with both carotid plaques [odds ratio (OR) for lowest vs. best quartile = 2.09, 95 % confidence interval (CI) 1.2-3.68] and PAD (OR = 3.43, 95 % CI 1.58-8.12). After correction for potential confounders (age since menopause, body mass index, Parathyroid hormone, vitamin D, leptin, DHEA-S, testosterone, physical activity, chronic obstructive pulmonary disease, and reduced renal function), the association was not confirmed. According to partial logistic regression, the carotid plaque-cCSA/tCSA association, but not the PAD-cCSA/tCSA association, was mostly dependent on years since menopause. In women the association between osteoporosis and carotid plaques likely reflects hormonal deprivation, whereas that between osteoporosis and PAD seems multifactorial in origin. C1 [Pedone, Claudio; Scarlata, Simone; Incalzi, Raffaele Antonelli] Campus Biomed Univ & Teaching Hosp, Area Geriatr, I-00128 Rome, Italy. [Napoli, Nicola] Campus Biomed Univ & Teaching Hosp, Div Endocrinol, I-00128 Rome, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr & Rehabil Dept, Geriatr Unit, Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr & Rehabil Dept, Lab Movement Anal, Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Study Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Incalzi, Raffaele Antonelli] San Raffaele Cittadella Carita Fdn, Taranto, Italy. RP Pedone, C (reprint author), Campus Biomed Univ & Teaching Hosp, Area Geriatr, Via Alvaro Portillo 200, I-00128 Rome, Italy. EM c.pedone@unicampus.it RI Scarlata, Simone/G-6490-2010; Lauretani, Fulvio/K-5115-2016 OI Scarlata, Simone/0000-0002-2704-2708; Napoli, Nicola/0000-0002-3091-8205; Pedone, Claudio/0000-0003-1847-9032; Lauretani, Fulvio/0000-0002-5287-9972 NR 36 TC 2 Z9 2 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X EI 1432-0827 J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD DEC PY 2013 VL 93 IS 6 BP 508 EP 516 DI 10.1007/s00223-013-9782-y PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 253HH UT WOS:000327074400004 PM 23995829 ER PT J AU Caliendo, AM Gilbert, DN Ginocchio, CC Hanson, KE May, L Quinn, TC Tenover, FC Alland, D Blaschke, AJ Bonomo, RA Carroll, KC Ferraro, MJ Hirschhorn, LR Joseph, WP Karchmer, T MacIntyre, AT Reller, LB Jackson, AF AF Caliendo, Angela M. Gilbert, David N. Ginocchio, Christine C. Hanson, Kimberly E. May, Larissa Quinn, Thomas C. Tenover, Fred C. Alland, David Blaschke, Anne J. Bonomo, Robert A. Carroll, Karen C. Ferraro, Mary Jane Hirschhorn, Lisa R. Joseph, W. Patrick Karchmer, Tobi MacIntyre, Ann T. Reller, L. Barth Jackson, Audrey F. CA IDSA TI Better Tests, Better Care: Improved Diagnostics for Infectious Diseases SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE diagnostics; rapid diagnostics; point-of-care testing; molecular diagnostics; clinical microbiology; infectious diseases ID DESORPTION IONIZATION-TIME; POLYMERASE-CHAIN-REACTION; FLIGHT MASS-SPECTROMETRY; VENTILATOR-ASSOCIATED PNEUMONIA; BLOOD-STREAM INFECTIONS; PEDIATRIC EMERGENCY-DEPARTMENT; RESPIRATORY-TRACT INFECTIONS; HUMAN SEPTIC SHOCK; CHLAMYDIA-TRACHOMATIS; PATIENT-MANAGEMENT AB In this IDSA policy paper, we review the current diagnostic landscape, including unmet needs and emerging technologies, and assess the challenges to the development and clinical integration of improved tests. To fulfill the promise of emerging diagnostics, IDSA presents recommendations that address a host of identified barriers. Achieving these goals will require the engagement and coordination of a number of stakeholders, including Congress, funding and regulatory bodies, public health agencies, the diagnostics industry, healthcare systems, professional societies, and individual clinicians. C1 [Caliendo, Angela M.] Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. [Gilbert, David N.] Providence Portland Med Ctr, Div Infect Dis, Portland, OR USA. [Gilbert, David N.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Ginocchio, Christine C.] North Shore LIJ Labs, Div Infect Dis Diagnost, Lake Success, NY USA. [Ginocchio, Christine C.] Hofstra North Shore LIJ Sch Med, Dept Pathol & Lab Med, Hempstead, NY USA. [Ginocchio, Christine C.] Hofstra North Shore LIJ Sch Med, Dept Mol Med, Hempstead, NY USA. [Hanson, Kimberly E.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. [Hanson, Kimberly E.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [May, Larissa] George Washington Univ, Dept Emergency Med, Washington, DC USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Quinn, Thomas C.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Tenover, Fred C.] Cepheid, Sunnyvale, CA USA. [Alland, David] Rutgers State Univ, Rutgers New Jersey Med Sch, Dept Med, Ctr Emerging Pathogens, Newark, NJ USA. [Blaschke, Anne J.] Univ Utah, Sch Med, Dept Pediat, Div Pediat Infect Dis, Salt Lake City, UT USA. [Bonomo, Robert A.] Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Bonomo, Robert A.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. [Bonomo, Robert A.] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. [Bonomo, Robert A.] Case Western Reserve Univ, Sch Med, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA. [Carroll, Karen C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Med Microbiol, Baltimore, MD 21205 USA. [Carroll, Karen C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Ferraro, Mary Jane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ferraro, Mary Jane] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirschhorn, Lisa R.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Hirschhorn, Lisa R.] JSI Res & Training Inst, Boston, MA USA. [Joseph, W. Patrick] Siemens Clin Lab, Berkeley, CA USA. [Joseph, W. Patrick] Genom Hlth, Redwood City, CA USA. [Joseph, W. Patrick] XDx Lab, San Francisco, CA USA. [Joseph, W. Patrick] Tethys Biosci, Emeryville, CA USA. [Karchmer, Tobi] Becton Dickinson & Co, Sparks, MD USA. [MacIntyre, Ann T.] Nova SE Univ, Dept Internal Med, Ft Lauderdale, FL 33314 USA. [Reller, L. Barth] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Reller, L. Barth] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27706 USA. [Jackson, Audrey F.] Infect Dis Soc Amer, Arlington, VA 22209 USA. RP Jackson, AF (reprint author), Infect Dis Soc Amer, 1300 Wilson Blvd,Ste 300, Arlington, VA 22209 USA. EM ajackson@idsociety.org FU IDSA FX This supplement is sponsored by IDSA. The policy paper was developed by IDSA's Diagnostics Task Force through discussion and deliberation over several months, and the authors thank all who provided input and interesting discussion during that time. The authors extend special thanks to Drs Johan S. Bakken and Janet Nicholson for careful review of the manuscript. NR 82 TC 103 Z9 104 U1 2 U2 27 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 DEC 1 PY 2013 VL 57 SU 3 BP S139 EP S170 DI 10.1093/cid/cit578 PG 32 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 251XB UT WOS:000326965600001 PM 24200831 ER PT J AU Krause, BR Remaley, AT AF Krause, Brian R. Remaley, Alan T. TI Reconstituted HDL for the acute treatment of acute coronary syndrome SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE acute coronary syndrome; apoA-I; cholesterol; high density lipoprotein; reverse cholesterol transport ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; LECITHIN-CHOLESTEROL ACYLTRANSFERASE; RANDOMIZED CONTROLLED-TRIAL; LANDSCHUTZ ASCITES-CELLS; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC LESIONS; PLAQUE STABILIZATION; ENDOTHELIAL FUNCTION; PLASMA-LIPOPROTEINS AB Purpose of reviewNew therapeutic strategies are needed for the rapid stabilization of acute coronary syndrome (ACS) patients by treating nonculprit lesions. Reconstituted HDL (rHDL), which is apoA-I combined with phospholipids, is currently being tested in clinical trials for this purpose and is the subject of this review.Recent findingsAt least four different formulations (SRC-rHDL, CSL-111, CSL-112 and ETC-216) have been tested in clinical trials. The various rHDL preparations have been shown to be effective in the rapid mobilization of excess cholesterol from cells and in regressing atherosclerotic plaques in animal models. Two of the rHDL agents, namely ETC-216 and CSL-111, have been shown to be effective after only a few treatments in reducing plaque volume in ACS patients, as assessed by intravascular ultrasound, but no clinical trials assessing clinical endpoints have yet been completed.SummaryrHDL is a promising new potential therapy for ACS patients, but much work remains to be done, and there are many unresolved questions. Progress in developing rHDL into a therapy will depend on improving our understanding of their mechanism of action, determining the optimum formulation and delivery and how to monitor rHDL therapy. C1 [Krause, Brian R.] AlphaCore Pharma, Ann Arbor, MI USA. [Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Bldg 10,Rm 2C-433, Bethesda, MD USA. EM aremaley1@cc.nih.gov FU intramural National Heart, Lung, and Blood Institute of the NIH, Bethesda, MD FX Research support for one of the authors (A. R.) comes from the intramural National Heart, Lung, and Blood Institute of the NIH, Bethesda, MD. NR 92 TC 24 Z9 25 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0957-9672 EI 1473-6535 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD DEC PY 2013 VL 24 IS 6 BP 480 EP 486 DI 10.1097/MOL.0000000000000020 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 251VJ UT WOS:000326959100004 PM 24184938 ER PT J AU Howard, BV Rossouw, JE AF Howard, Barbara V. Rossouw, Jacques E. TI Estrogens and cardiovascular disease risk revisited: the Women's Health Initiative SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE cardiovascular disease; CVD risk factors; hormone therapy; Women's Health Initiative ID CORONARY-HEART-DISEASE; POSTMENOPAUSAL HORMONE-THERAPY; CONJUGATED EQUINE ESTROGENS; RANDOMIZED CONTROLLED-TRIAL; PERIPHERAL ARTERIAL-DISEASE; PLUS PROGESTIN; REPLACEMENT THERAPY; VENOUS THROMBOSIS; EVENTS; ATHEROSCLEROSIS AB Purpose of reviewIn 2002 and 2004, the Women's Health Initiative found no evidence that hormone therapy with estrogen or estrogen with progestin (E+P) protected against cardiovascular disease (CVD). Since then, further analyses have been performed. This review summarizes current analyses on the effects of hormone therapy on CVD and CVD risk factors.Recent findingsThe negative effects of hormone therapy vary by the type of CVD event. Estrogen alone and E+P show consistent effects on CVD, but E+P has more impact on coronary heart disease (CHD) and venous thromboembolism. Women of all ethnicities, including those who are obese, have diabetes, or are taking daily aspirin or statins remain at risk for adverse effects from hormone therapy. Although younger women or more recently menopausal women taking hormone therapy may be at relatively lower risk for CHD and myocardial infarction, they remain at risk for stroke, venous thromboembolism and peripheral artery disease. Adverse effects are enhanced in older women with menopausal symptoms. Although hormone therapy lowers LDL cholesterol and lipoprotein (a) and raises high-density lipoprotein cholesterol, it has adverse effects on triglyceride, lipoprotein composition, and inflammatory and hemostatic markers. Baseline metabolic syndrome and high LDL cholesterol increase the CHD risk with hormone therapy. Analyses of discontinuation data in the estrogen-alone and E+P trials suggest that the adverse effects of hormone therapy on CVD are reversible.SummaryRecent analyses do not justify postmenopausal hormone therapy for CVD prevention. Further research on the role of hormone therapy-induced changes in CVD risk factors along with genetic studies may increase understanding and aid in developing safer therapies for menopausal symptoms. C1 [Howard, Barbara V.] MedStar Hlth Res Inst, Hyattsville, MD 20782 USA. [Howard, Barbara V.] Georgetown Howard Univ Ctr Clin & Translat Sci, Washington, DC USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. RP Howard, BV (reprint author), MedStar Hlth Res Inst, 6525 Belcrest Rd,Suite 700, Hyattsville, MD 20782 USA. EM Barbara.V.Howard@MedStar.net FU National Heart, Lung, and Blood Institute, National Institutes of Health; U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX This research was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. We thank Rachel Schaperow, MedStar Health Research Institute, for editing the manuscript.; The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 35 TC 16 Z9 18 U1 1 U2 49 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 EI 1473-6535 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD DEC PY 2013 VL 24 IS 6 BP 493 EP 499 DI 10.1097/MOL.0000000000000022 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 251VJ UT WOS:000326959100006 PM 24184944 ER PT J AU Lo Surdo, JL Millis, BA Bauer, SR AF Lo Surdo, Jessica L. Millis, Bryan A. Bauer, Steven R. TI Automated microscopy as a quantitative method to measure differences in adipogenic differentiation in preparations of human mesenchymal stromal cells SO CYTOTHERAPY LA English DT Article DE adipogenesis; bone marrow stromal cell; mesenchymal stromal cell; microscopy ID HUMAN BONE-MARROW; ADULT STEM-CELLS; IN-VITRO; OSTEOGENIC DIFFERENTIATION; ADIPOSE-TISSUE; PROGENITOR CELLS; EXPANSION; POPULATIONS; PRECURSORS; CULTURES AB Background aims. Multipotent stromal cells, also called mesenchymal stromal cells (MSCs), are potentially valuable as a cellular therapy because of their differentiation and immunosuppressive properties. As the result of extensive heterogeneity of MSCs, quantitative approaches to measure differentiation capacity between donors and passages on a per-cell basis are needed. Methods. Human bone marrow-derived MSCs were expanded to passages P3, P5 and P7 from eight different donors and were analyzed for colony-forming unit capacity (CPU), cell size, surface marker expression and forward/side-scatter analysis by flow cytometry. Adipogenic differentiation potential was quantified with the use of automated microscopy. Percentage of adipogenesis was determined by quantifying nuclei and Nile red positive adipocytes after automated image acquisition. Results. MSCs varied in expansion capacity and increased in average cell diameter with passage. CFU capacity decreased with passage and varied among cell lines within the same passage. The number of adipogenic precursors varied between cell lines, ranging from 0.5% to 13.6% differentiation at P3. Adipogenic capacity decreased significantly with increasing passage. MSC cell surface marker analysis revealed no changes caused by passaging or donor differences. Conclusions. We measured adipogenic differentiation on a per-cell basis with high precision and accuracy with the use of automated fluorescence microscopy. We correlated these findings with other quantitative bioassays to better understand the role of donor variability and passaging on CPU, cell size and adipogenic differentiation capacity in vitro. These quantitative approaches provide valuable tools to measure MSC quality and measure functional biological differences between donors and cell passages that are not revealed by conventional MSC cell surface marker analysis. C1 [Lo Surdo, Jessica L.; Bauer, Steven R.] Off Cellular Tissue & Gene Therapies, Div Cellular & Gene Therapies, FDA Ctr Biol Evaluat & Res, Bethesda, MD USA. [Millis, Bryan A.] NIDCD, NIH, Sect Struct Cell Biol, Bethesda, MD USA. RP Bauer, SR (reprint author), US FDA, Ctr Biol Evaluat & Res, NIH Bldg 29B HFM 740,Room 2NN10, Bethesda, MD 20892 USA. EM steven.bauer@fda.hhs.gov OI Bauer, Steven/0000-0003-2831-846X FU Jessica Lo Surdo's appointment to the Research Participation Program at the Center for Biologics Evaluation and Research; US Food and Drug Administration; Food and Drug Administration Modernizing Science grant program; Biomedical Advanced Research and Development Authority grant; Medical Countermeasures Initiative; Division of Cell and Gene Therapies FX The authors would like to acknowledge Eva Rudikoff for her assistance in growing the MSCs and Drs Brenton McCright, Deborah Hursh and Patrick Lynch for reviewing the manuscript. This project was supported in part by Jessica Lo Surdo's appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through US Department of Education and US Food and Drug Administration. This work was also supported in part by the Food and Drug Administration Modernizing Science grant program, a Biomedical Advanced Research and Development Authority grant, a grant from the Medical Countermeasures Initiative and research funds from the Division of Cell and Gene Therapies. NR 62 TC 16 Z9 17 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD DEC PY 2013 VL 15 IS 12 BP 1527 EP 1540 DI 10.1016/j.jcyt.2013.04.010 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 254ME UT WOS:000327169000010 PM 23992827 ER PT J AU Yamben, IF Rachel, RA Shatadal, S Copeland, NG Jenkins, NA Warming, S Griep, AE AF Yamben, Idella F. Rachel, Rivka A. Shatadal, Shalini Copeland, Neal G. Jenkins, Nancy A. Warming, Soren Griep, Anne E. TI Scrib is required for epithelial cell identity and prevents epithelial to mesenchymal transition in the mouse SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Scrib; PDZ proteins; Lens development; Epithelial to mesenchymal transition; Cell adhesion; Cell polarity ID GROWTH-FACTOR-BETA; PROLIFERATION CONTROL; SUBCAPSULAR CATARACT; TUMOR SUPPRESSORS; POLARITY MODULE; E-CADHERIN; TGF-BETA; LENS; CANCER; EXPRESSION AB The integrity and function of epithelial tissues depend on the establishment and maintenance of defining characteristics of epithelial cells, cell-cell adhesion and cell polarity. Disruption of these characteristics can lead to the loss of epithelial identity through a process called epithelial to mesenchymal transition (EMT), which can contribute to pathological conditions such as tissue fibrosis and invasive cancer. In invertebrates, the epithelial polarity gene scrib plays a critical role in establishing and maintaining cell adhesion and polarity. In this study we asked if the mouse homolog, Scrib, is required for establishment and/or maintenance of epithelial identity in vivo. To do so, we conditionally deleted Scrib in the head ectoderm tissue that gives rise to both the ocular lens and the corneal epithelium. Deletion of Scrib in the lens resulted in a change in epithelial cell shape from cuboidal to flattened and elongated. Early in the process, the cell adhesion protein, E-cadherin, and apical polarity protein, ZO-1, were downregulated and the myofibroblast protein, alpha SMA, was upregulated, suggesting EMT was occurring in the Scrib deficient lenses. Correlating temporally with the upregulation of alpha SMA, Smad3 and Smad4, TGF beta signaling intermediates, accumulated in the nucleus and Snail, a TGF beta target and transcriptional repressor of the gene encoding E-cadherin, was upregulated. Pax6, a lens epithelial transcription factor required to maintain lens epithelial cell identity also was downregulated. Loss of Scrib in the corneal epithelium also led to molecular changes consistent with EMT, suggesting that the effect of Scrib deficiency was not unique to the lens. Together, these data indicate that mammalian Scrib is required to maintain epithelial identity and that loss of Scrib can culminate in EMT, mediated, at least in part, through TCF beta signaling. (C) 2013 Elsevier Inc. All rights reserved. C1 [Yamben, Idella F.; Shatadal, Shalini; Griep, Anne E.] Univ Wisconsin, Dept Cell & Regenerat Biol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Rachel, Rivka A.; Copeland, Neal G.; Jenkins, Nancy A.; Warming, Soren] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Griep, AE (reprint author), Univ Wisconsin, Dept Cell & Regenerat Biol, Sch Med & Publ Hlth, Madison, WI 53706 USA. EM aegriep@wisc.edu FU NIH [GM07215, EY09091, CA98428, CA14520, EY016665] FX The authors thank Ruth Ashery-Padan for generously providing the LeCre mice. The authors also thank Lance Roderick of the Keck Imaging Facility, Toshi Kinoshita of the Pathology Department Histology Core, the McArdle Laboratories Histology Core and Denis Lee and Susan Moran of the McArdle Laboratories. The authors thank Angela Verdoni and Aki Ikeda for guidance with the cornea experiments. The authors thank Paul Lambert for helpful discussions and his critical reading of the manuscript I.F.Y. was supported by the NIH training Grant GM07215. This work was supported by NIH Grants EY09091, CA98428, CA14520, and EY016665. NR 66 TC 14 Z9 14 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD DEC 1 PY 2013 VL 384 IS 1 BP 41 EP 52 DI 10.1016/j.ydbio.2013.09.027 PG 12 WC Developmental Biology SC Developmental Biology GA 251AV UT WOS:000326901100004 PM 24095903 ER PT J AU Chin, LMK Heigenhauser, GJF Paterson, DH Kowalchuk, JM AF Chin, Lisa M. K. Heigenhauser, George J. F. Paterson, Donald H. Kowalchuk, John M. TI Effect of voluntary hyperventilation with supplemental CO2 on pulmonary O-2 uptake and leg blood flow kinetics during moderate-intensity exercise SO EXPERIMENTAL PHYSIOLOGY LA English DT Article ID RESPIRATORY MUSCLE WORK; INDUCED HYPOCAPNIC ALKALOSIS; NEAR-INFRARED SPECTROSCOPY; OXYGEN-UPTAKE KINETICS; PRIOR HEAVY EXERCISE; FEMORAL-ARTERY; PHOSPHOCREATINE KINETICS; SUBMAXIMAL EXERCISE; MAXIMAL EXERCISE; GAS-EXCHANGE AB New findings center dot What is the central question of this study? Voluntary hyperventilation that induces hypocapnic alkalosis (HYPO) is associated with slowed adaptation of O-2 uptake and leg blood flow during moderate exercise; however, it is unknown whether hypocapnia, alkalosis and/or the hyperventilation manoeuvre is related to these observations. center dot What is the main finding and its importance? We included a condition with the same work of breathing as HYPO, but the fall in CO2 was prevented by the addition of higher CO2 to the inspirate (normocapnia). This condition demonstrated that hypocapnia/alkalosis was responsible for the slower leg blood flow response; however, the act of hyperventilation itself also had a role to play in the slower O-2 uptake kinetics. Pulmonary O-2 uptake ((V) over dot(O2P)) and leg blood flow (LBF) kinetics were examined at the onset of moderate-intensity exercise, during hyperventilation with and without associated hypocapnic alkalosis. Seven male subjects (25 +/- 6 years old; mean +/- SD) performed alternate-leg kneeextension exercise from baseline to moderate-intensity exercise (80% of estimated lactate threshold) and completed four to six repetitions for each of the following three conditions: (i) control [CON; end-tidal partial pressure of CO2 (P-ET,(CO2)) similar to 40 mmHg], i. e. normal breathing with normal inspired CO2 (0.03%); (ii) hypocapnia (HYPO; P-ET,P-CO2 similar to 20 mmHg), i. e. sustained hyperventilation with normal inspired CO2 (0.03%); and (iii) normocapnia (NORMO; P-ET,P-CO2 similar to 40 mmHg), i.e. sustained hyperventilation with elevated inspired CO2 (similar to 5%). The. (V)over dot(O2P) was measured breath by breath usingmass spectrometry and a volume turbine. Femoral artery mean blood velocity was measured by Doppler ultrasound, and LBF was calculated from femoral artery diameter and mean blood velocity. Phase 2 (V)over dot(O2P) kinetics (tau(V)over dot(O2P)) was different (P < 0.05) amongst all three conditions (CON, 19 +/- 7 s; HYPO, 43 +/- 17 s; and NORMO, 30 +/- 8 s), while LBF kinetics (tLBF) was slower (P < 0.05) in HYPO (31 +/- 9s) compared with both CON (19 +/- 3 s) and NORMO (20 +/- 6 s). Similar to previous findings, HYPO was associated with slower. (V) over dot(O2P) and LBF kinetics compared with CON. In the present study, preventing the fall in end-tidal P-CO2 (NORMO) restored LBF kinetics, but not. (V) over dot(O2P) kinetics, which remained ` slowed' relative to CON. These data suggest that the hyperventilation manoeuvre itself (i.e. independent of induced hypocapnic alkalosis) may contribute to the slower. (V) over dot(O2P) kinetics observed during HYPO. C1 [Chin, Lisa M. K.; Paterson, Donald H.; Kowalchuk, John M.] Univ Western Ontario, Sch Kinesiol, London, ON N6A 5B9, Canada. [Kowalchuk, John M.] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5B9, Canada. [Chin, Lisa M. K.] George Mason Univ, Dept Rehabil Sci, Fairfax, VA 22030 USA. [Chin, Lisa M. K.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Heigenhauser, George J. F.] McMaster Univ, Dept Med, Hamilton, ON, Canada. RP Kowalchuk, JM (reprint author), Univ Western Ontario, Sch Kinesiol, Canadian Ctr Act & Aging, Arthur & Sonia Labatt Hlth Sci Bldg,Room 411C, London, ON N6A 5B9, Canada. EM jkowalch@uwo.ca RI Chin, Lisa/O-4706-2014 OI Chin, Lisa/0000-0002-0178-739X FU Natural Sciences and Engineering Research Council of Canada (NSERC); Western's Graduate Thesis Research Fund; National Institutes of Health FX This study was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) grants. Additional support was provided to L. M. K. C. by Western's Graduate Thesis Research Fund and by intramural funds from the National Institutes of Health. NR 32 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0958-0670 EI 1469-445X J9 EXP PHYSIOL JI Exp. Physiol. PD DEC 1 PY 2013 VL 98 IS 12 BP 1668 EP 1682 DI 10.1113/expphysiol.2013.074021 PG 15 WC Physiology SC Physiology GA 254KF UT WOS:000327163100004 PM 23975901 ER PT J AU Singh, TP Lee, CH Farber, JM AF Singh, Tej Pratap Lee, Chang Hoon Farber, Joshua M. TI Chemokine receptors in psoriasis SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE chemokine receptors; cytokines; inflammation; psoriasis ID REGULATORY T-CELLS; PLASMACYTOID DENDRITIC CELLS; INFLAMMATORY PROTEIN 3-ALPHA; EXTRACELLULAR TRAP FORMATION; MESSENGER-RNA EXPRESSION; NECROSIS-FACTOR-ALPHA; DRAINING LYMPH-NODES; HUMAN TH17 CELLS; SKIN INFLAMMATION; ATOPIC-DERMATITIS AB Introduction: Psoriasis is a prevalent immune-mediated disease involving primarily the skin. Infiltrating leukocytes play key roles in driving the disease. Along with an array of adhesion proteins, leukocyte trafficking into tissue is controlled by chemoattractants, including chemokines, and their receptors. This review summarizes the data on roles for the chemokine system in psoriasis in order to highlight opportunities for inhibiting this system for therapeutic benefit. Areas covered: The review covers the roles of various leukocyte subsets in psoriasis, focusing on the chemokine receptors that are thought to be responsible for the trafficking of these cells into tissue. The review also discusses in some detail the significance of the IL-23/IL-17/IL-22 cytokine axis in disease. Expert opinion: Many of the new therapies developed for psoriasis are antibodies to neutralize cytokines that have pleiotropic functions in host defense. Inhibiting chemokine receptors can be accomplished using small molecules, and would be expected to block inflammation while resulting in more limited immunosuppression. There has been limited success to date in treating inflammatory disease with chemokine receptor antagonists, which has often been ascribed to the system's redundancy. Other factors may also be important, however, including sub-optimal choices of targets based on incomplete understandings of disease pathogenesis. C1 [Singh, Tej Pratap; Lee, Chang Hoon; Farber, Joshua M.] NIAID, NIH, Lab Mol Immunol, Inflammat Biol Sect, Bethesda, MD 20892 USA. RP Farber, JM (reprint author), NIAID, NIH, Lab Mol Immunol, Inflammat Biol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov FU Intramural Research Program of the DIR, NIAID, NIH FX The authors have no relevant financial interests. This work was supported by the Intramural Research Program of the DIR, NIAID, NIH. NR 223 TC 7 Z9 8 U1 1 U2 19 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 EI 1744-7631 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD DEC PY 2013 VL 17 IS 12 BP 1405 EP 1422 DI 10.1517/14728222.2013.838220 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 255QT UT WOS:000327255600003 PM 24070343 ER PT J AU Corona, A Masaoka, T Tocco, G Tramontano, E Le Grice, SFJ AF Corona, Angela Masaoka, Takashi Tocco, Graziella Tramontano, Enzo Le Grice, Stuart F. J. TI Active site and allosteric inhibitors of the ribonuclease H activity of HIV reverse transcriptase SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID SMALL-MOLECULE INHIBITORS; CELL-BASED ASSAYS; RNASE-H; DNA-POLYMERASE; DUAL INHIBITORS; INTEGRASE INHIBITORS; STRAND TRANSFER; STRUCTURAL BASIS; DIKETO ACID; VIRUS AB Despite the wealth of information available for the reverse transcriptase (RT)-associated ribonuclease H (RNaseH) domain of lentiviruses, gammaretroviruses and long terminal repeat containing retrotransposons, exploiting this information in the form of an RNaseH inhibitor with high specificity and low cellular toxicity has been disappointing. However, it is now becoming increasingly evident that the two-subunit HIV-1 RT is a highly versatile enzyme, undergoing major structural alterations in order to interact with, position and ultimately hydrolyze the RNA component of an RNA/DNA hybrid. Thus, in addition to targeting the RNaseH active site, identifying small molecules that bind elsewhere and disrupt catalysis allosterically by impairing conformational flexibility is gaining increased attention. This review summarizes current progress towards development of both active site and allosteric RNaseH inhibitors. C1 [Corona, Angela; Tramontano, Enzo] Univ Cagliari, Dept Life & Environm Sci, Unit Biomed, I-09124 Cagliari, Italy. [Masaoka, Takashi; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Tocco, Graziella] Univ Cagliari, Dept Life & Environm Sci, Unit Drug Sci, I-09124 Cagliari, Italy. RP Le Grice, SFJ (reprint author), NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM legrices@mail.nih.gov RI Tramontano, Enzo/B-4919-2012; Corona, Angela/G-7327-2014 OI Tramontano, Enzo/0000-0002-4849-0980; Corona, Angela/0000-0002-6630-8636 FU RAS [LR 7/2007 CRP-24915]; MIUR PRIN; Ministero dell 'Universita, dell' Istruzione e della Ricerca MIUR - PRIN; Fondazione Banco di Sardegna; Intramural Research Program of the National Cancer Institute, NIH, Department of Health and Human Services, USA FX A Corona and E Tramontano were supported by RAS grant LR 7/2007 CRP-24915 and MIUR PRIN 2012, G Tocco by Ministero dell 'Universita, dell' Istruzione e della Ricerca MIUR - PRIN 2008 and Fondazione Banco di Sardegna, and T Masaoka and SFJ Le Grice by the Intramural Research Program of the National Cancer Institute, NIH, Department of Health and Human Services, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NR 62 TC 16 Z9 16 U1 0 U2 22 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 EI 1756-8927 J9 FUTURE MED CHEM JI Future Med. Chem. PD DEC PY 2013 VL 5 IS 18 BP 2127 EP 2139 DI 10.4155/fmc.13.178 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 255EO UT WOS:000327222400007 PM 24261890 ER PT J AU Wu, JC Pfeiffer, RM Gail, MH AF Wu, Jincao Pfeiffer, Ruth M. Gail, Mitchell H. TI Strategies for Developing Prediction Models From Genome-Wide Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE GWAS; risk prediction; discriminatory accuracy; ROC curve; AUC; probability of correct classification ID SINGLE-NUCLEOTIDE POLYMORPHISMS; COMPLEX DISEASES; RISK PREDICTION; WINNERS CURSE; GENETIC RISK; CANCER-RISK; ODDS RATIOS; SUSCEPTIBILITY; PROSTATE AB Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with complex human diseases. However, risk prediction models based on them have limited discriminatory accuracy. It has been suggested that including many such SNPs can improve predictive performance. Here, we studied various aspects of model building to improve discriminatory accuracy, as measured by the area under the receiver operating characteristic curve (AUC), including: (1) How well does a one-phase procedure that selects SNPs and estimates odds ratios on the same data perform? (2) How should training data be allocated between SNP selection (Phase 1) and estimation (Phase 2) in a two-phase procedure? (3) Should SNP selection be based on P-value thresholding or ranking P-values? (4) How many SNPs should be selected? and (5) Is multivariate estimation preferred to univariate estimation in the presence of linkage disequilibrium (LD)? We used realistic estimates of the distributions of genetic effect sizes, allele frequencies, and LD patterns based on GWAS data for Crohn's disease and prostate cancer. Theory and simulations were used to estimate AUC. Empirical risk models based on 10,000 cases and controls had considerably lower AUC than theoretically achievable. The most critical aspect of prediction model building was initial SNP selection. The single-phase procedure achieved higher AUC than the two-phase procedure. Multivariate estimation did not perform as well as univariate (marginal) estimation. For complex diseases and samples of 10,000 or fewer cases and controls, one should limit the number of SNPs to tens or hundreds. C1 [Wu, Jincao; Pfeiffer, Ruth M.; Gail, Mitchell H.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20850 USA. RP Wu, JC (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM jincao.wu@nih.gov FU National Cancer Institute, Division of Cancer Epidemiology, and Genetics FX This work was supported by the intramural research program of the National Cancer Institute, Division of Cancer Epidemiology, and Genetics. We thank Drs. Ju-Hyun Park and Nilanjan Chatterjee for providing the formulas for the conditional densities of log odds ratios per allele given minor allele frequency, leading to the distributions in Supplementary Fig. S1. We thank Dr. Charles Kooperberg for providing the Crohn's disease data with imputed genotypes from Kooperberg et al. [2010] and the Welcome Trust Case Control Consortium for access to the data. We thank the reviewers for helpful comments that improved the paper. NR 27 TC 7 Z9 8 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2013 VL 37 IS 8 BP 768 EP 777 DI 10.1002/gepi.21762 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 251ZZ UT WOS:000326975300002 PM 24166696 ER PT J AU Chen, HS Pfeiffer, RM Zhang, SP AF Chen, Huann-Sheng Pfeiffer, Ruth M. Zhang, Shunpu TI A Powerful Method for Combining P-Values in Genomic Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE association study; gene set; permutation test; Simes test ID TRUNCATED PRODUCT; MULTIPLE; VARIANTS; CANCER AB After genetic regions have been identified in genomewide association studies (GWAS), investigators often follow up with more targeted investigations of specific regions. These investigations typically are based on single nucleotide polymorphisms (SNPs) with dense coverage of a region. Methods are thus needed to test the hypothesis of any association in given genetic regions. Several approaches for combining P-values obtained from testing individual SNP hypothesis tests are available. We recently proposed a sequential procedure for testing the global null hypothesis of no association in a region. When this global null hypothesis is rejected, this method provides a list of significant hypotheses and has weak control of the family-wise error rate. In this paper, we devise a permutation-based version of the test that accounts for correlations of tests based on SNPs in the same genetic region. Based on simulated data, the method has correct control of the type I error rate and higher or comparable power to other tests. C1 [Chen, Huann-Sheng] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zhang, Shunpu] Univ Nebraska, Dept Stat, Lincoln, NE USA. RP Chen, HS (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 9609 Med Ctr Dr,Room 4E348,MSC 9765, Bethesda, MD 20892 USA. EM chenh6@mail.nih.gov NR 18 TC 3 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2013 VL 37 IS 8 BP 814 EP 819 DI 10.1002/gepi.21755 PG 6 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 251ZZ UT WOS:000326975300006 PM 23959976 ER PT J AU Yu, B Zheng, Y Alexander, D Manolio, TA Alonso, A Nettleton, JA Boerwinkle, E AF Yu, Bing Zheng, Yan Alexander, Danny Manolio, Teri A. Alonso, Alvaro Nettleton, Jennifer A. Boerwinkle, Eric TI Genome-Wide Association Study of a Heart Failure Related Metabolomic Profile Among African Americans in the Atherosclerosis Risk in Communities (ARIC) Study SO GENETIC EPIDEMIOLOGY LA English DT Article DE African Americans; heart failure; genome-wide association; metabolomics ID CHRONIC KIDNEY-DISEASE; OXIDATIVE STRESS; CARDIOVASCULAR-DISEASE; EPIDEMIOLOGY; SYSTEMS; ADULTS AB Both the prevalence and incidence of heart failure (HF) are increasing, especially among African Americans, but no large-scale, genome-wide association study (GWAS) of HF-related metabolites has been reported. We sought to identify novel genetic variants that are associated with metabolites previously reported to relate to HF incidence. GWASs of three metabolites identified previously as risk factors for incident HF (pyroglutamine, dihydroxy docosatrienoic acid, and X-11787, being either hydroxy-leucine or hydroxy-isoleucine) were performed in 1,260 African Americans free of HF at the baseline examination of the Atherosclerosis Risk in Communities (ARIC) study. A significant association on chromosome 5q33 (rs10463316, MAF = 0.358, P-value = 1.92 x 10(-10)) was identified for pyroglutamine. One region on chromosome 2p13 contained a nonsynonymous substitution in N-acetyltransferase 8 (NAT8) was associated with X-11787 (rs13538, MAF = 0.481, P-value = 1.71 x 10(-23)). The smallest P-value for dihydroxy docosatrienoic acid was rs4006531 on chromosome 8q24 (MAF = 0.400, P-value = 6.98 x 10(-7)). None of the above SNPs were individually associated with incident HF, but a genetic risk score (GRS) created by summing the most significant risk alleles from each metabolite detected 11% greater risk of HF per allele. In summary, we identified three loci associated with previously reported HF-related metabolites. Further use of metabolomics technology will facilitate replication of these findings in independent samples. C1 [Yu, Bing; Zheng, Yan; Nettleton, Jennifer A.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Alexander, Danny] Metabolon Inc, Durham, NC USA. [Manolio, Teri A.] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Boerwinkle, E (reprint author), Univ Texas Houston, Ctr Human Genet, Sch Publ Hlth, 1200 Herman Pressler E-447, Houston, TX 77030 USA. EM Eric.Boerwinkle@uth.tmc.edu RI Alonso, Alvaro/A-4917-2010 OI Alonso, Alvaro/0000-0002-2225-8323 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005] FX The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute grant U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. NR 37 TC 11 Z9 11 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2013 VL 37 IS 8 BP 840 EP 845 DI 10.1002/gepi.21752 PG 6 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 251ZZ UT WOS:000326975300009 PM 23934736 ER PT J AU Stephens, SH Hartz, SM Hoft, NR Saccone, NL Corley, RC Hewitt, JK Hopfer, CJ Breslau, N Coon, H Chen, XN Ducci, F Dueker, N Franceschini, N Frank, J Han, YH Hansel, NN Jiang, CH Korhonen, T Lind, PA Liu, J Lyytikainen, LP Michel, M Shaffer, JR Short, SE Sun, JZ Teumer, A Thompson, JR Vogelzangs, N Vink, JM Wenzlaff, A Wheeler, W Yang, BZ Aggen, SH Balmforth, AJ Baumeister, SE Beaty, TH Benjamin, DJ Bergen, AW Broms, U Cesarini, D Chatterjee, N Chen, JC Cheng, YC Cichon, S Couper, D Cucca, F Dick, D Foroud, T Furberg, H Giegling, I Gillespie, NA Gu, FY Hall, AS Haellfors, J Han, S Hartmann, AM Heikkilae, K Hickie, IB Hottenga, JJ Jousilahti, P Kaakinen, M Kaehoenen, M Koellinger, PD Kittner, S Konte, B Landi, MT Laatikainen, T Leppert, M Levy, SM Mathias, RA McNeil, DW Medland, SE Montgomery, GW Murray, T Nauck, M North, KE Pare, PD Pergadia, M Ruczinski, I Salomaa, V Viikari, J Willemsen, G Barnes, KC Boerwinkle, E Boomsma, DI Caporaso, N Edenberg, HJ Francks, C Gelernter, J Grabe, HJ Hops, H Jarvelin, MR Johannesson, M Kendler, KS Lehtimaeki, T Magnusson, PKE Marazita, ML Marchini, J Mitchell, BD Noethen, MM Penninx, BW Raitakari, O Rietschel, M Rujescu, D Samani, NJ Schwartz, AG Shete, S Spitz, M Swan, GE Volzke, H Veijola, J Wei, QY Amos, C Cannon, DS Grucza, R Hatsukami, D Heath, A Johnson, EO Kaprio, J Madden, P Martin, NG Stevens, VL Weiss, RB Kraft, P Bierut, LJ Ehringer, MA AF Stephens, Sarah H. Hartz, Sarah M. Hoft, Nicole R. Saccone, Nancy L. Corley, Robin C. Hewitt, John K. Hopfer, Christian J. Breslau, Naomi Coon, Hilary Chen, Xiangning Ducci, Francesca Dueker, Nicole Franceschini, Nora Frank, Josef Han, Younghun Hansel, Nadia N. Jiang, Chenhui Korhonen, Tellervo Lind, Penelope A. Liu, Jason Lyytikaeinen, Leo-Pekka Michel, Martha Shaffer, John R. Short, Susan E. Sun, Juzhong Teumer, Alexander Thompson, John R. Vogelzangs, Nicole Vink, Jacqueline M. Wenzlaff, Angela Wheeler, William Yang, Bao-Zhu Aggen, Steven H. Balmforth, Anthony J. Baumeister, Sebastian E. Beaty, Terri H. Benjamin, Daniel J. Bergen, Andrew W. Broms, Ulla Cesarini, David Chatterjee, Nilanjan Chen, Jingchun Cheng, Yu-Ching Cichon, Sven Couper, David Cucca, Francesco Dick, Danielle Foroud, Tatiana Furberg, Helena Giegling, Ina Gillespie, Nathan A. Gu, Fangyi Hall, Alistair S. Haellfors, Jenni Han, Shizhong Hartmann, Annette M. Heikkilae, Kauko Hickie, Ian B. Hottenga, Jouke Jan Jousilahti, Pekka Kaakinen, Marika Kaehoenen, Mika Koellinger, Philipp D. Kittner, Stephen Konte, Bettina Landi, Maria-Teresa Laatikainen, Tiina Leppert, Mark Levy, Steven M. Mathias, Rasika A. McNeil, Daniel W. Medland, Sarah E. Montgomery, Grant W. Murray, Tanda Nauck, Matthias North, Kari E. Pare, Peter D. Pergadia, Michele Ruczinski, Ingo Salomaa, Veikko Viikari, Jorma Willemsen, Gonneke Barnes, Kathleen C. Boerwinkle, Eric Boomsma, Dorret I. Caporaso, Neil Edenberg, Howard J. Francks, Clyde Gelernter, Joel Grabe, Hans Joergen Hops, Hyman Jarvelin, Marjo-Riitta Johannesson, Magnus Kendler, Kenneth S. Lehtimaeki, Terho Magnusson, Patrik K. E. Marazita, Mary L. Marchini, Jonathan Mitchell, Braxton D. Noethen, Markus M. Penninx, Brenda W. Raitakari, Olli Rietschel, Marcella Rujescu, Dan Samani, Nilesh J. Schwartz, Ann G. Shete, Sanjay Spitz, Margaret Swan, Gary E. Voelzke, Henry Veijola, Juha Wei, Qingyi Amos, Chris Cannon, Dale S. Grucza, Richard Hatsukami, Dorothy Heath, Andrew Johnson, Eric O. Kaprio, Jaakko Madden, Pamela Martin, Nicholas G. Stevens, Victoria L. Weiss, Robert B. Kraft, Peter Bierut, Laura J. Ehringer, Marissa A. TI Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking SO GENETIC EPIDEMIOLOGY LA English DT Article DE CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke ID SUBSTANCE-USE DISORDERS; HIGH-SCHOOL-STUDENTS; NICOTINE DEPENDENCE; LUNG-CANCER; CIGARETTE-SMOKING; YOUNG-ADULTS; EARLY AGE; ENVIRONMENTAL-INFLUENCES; SUSCEPTIBILITY LOCUS; QUANTITATIVE TRAITS AB Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype. C1 [Stephens, Sarah H.; Dueker, Nicole; Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Hartz, Sarah M.; Saccone, Nancy L.; Pergadia, Michele; Grucza, Richard; Heath, Andrew; Madden, Pamela; Bierut, Laura J.] Washington Univ Sch Med, Dept Psychiat, St Louis, MO USA. [Hoft, Nicole R.; Corley, Robin C.; Hewitt, John K.; Hopfer, Christian J.; Ehringer, Marissa A.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Breslau, Naomi] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Coon, Hilary; Leppert, Mark; Cannon, Dale S.; Weiss, Robert B.] Univ Utah Sch Med, Dept Psychiat, Salt Lake City, UT USA. [Chen, Xiangning; Aggen, Steven H.; Chen, Jingchun; Dick, Danielle; Gillespie, Nathan A.; Kendler, Kenneth S.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Ducci, Francesca] Univ London, Kings Coll London, Inst Psychiat, London SW3 6LX, England. [Ducci, Francesca] St Georges Univ, Dept Mental Hlth, London, England. [Ducci, Francesca; Couper, David] Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, Pisa, Italy. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Frank, Josef; Rietschel, Marcella] Heidelberg Univ, Clin Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Han, Younghun; Shete, Sanjay; Spitz, Margaret; Wei, Qingyi; Amos, Chris] MD Anderson, Dept Epidemiol, Houston, TX USA. [Hansel, Nadia N.; Beaty, Terri H.; Mathias, Rasika A.; Murray, Tanda; Ruczinski, Ingo; Barnes, Kathleen C.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Jiang, Chenhui; Yang, Bao-Zhu; Han, Shizhong; Gelernter, Joel] Yale Univ Sch Med, Dept Psychiat, New Haven, CT USA. [Korhonen, Tellervo; Broms, Ulla; Haellfors, Jenni; Heikkilae, Kauko; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Lind, Penelope A.; Medland, Sarah E.; Montgomery, Grant W.; Martin, Nicholas G.] Queensland Inst Med Res, Dept Epidemiol, Brisbane, Qld 4006, Australia. [Liu, Jason; Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Lyytikaeinen, Leo-Pekka; Lehtimaeki, Terho] Tampere Univ Hosp, Dept Clin Chem, Fimlab Labs, FIN-33521 Tampere, Finland. [Lyytikaeinen, Leo-Pekka; Lehtimaeki, Terho] Univ Tampere Sch Med, Tampere, Finland. [Michel, Martha; Bergen, Andrew W.; Swan, Gary E.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Shaffer, John R.; Marazita, Mary L.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Short, Susan E.] Brown Univ, Dept Sociol, Providence, RI 02912 USA. [Sun, Juzhong; Stevens, Victoria L.] Amer Canc Soc, Dept Epidemiol Res, Atlanta, GA 30329 USA. [Teumer, Alexander; Baumeister, Sebastian E.; Nauck, Matthias; Grabe, Hans Joergen; Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Univ Med Greifswald, Greifswald, Germany. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Vogelzangs, Nicole; Penninx, Brenda W.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Vink, Jacqueline M.; Hottenga, Jouke Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Wenzlaff, Angela; Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Wheeler, William] NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Balmforth, Anthony J.; Hall, Alistair S.] Univ Leeds, Fac Med & Hlth, LIGHT Res Inst, Leeds, W Yorkshire, England. [Benjamin, Daniel J.] Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. [Cesarini, David] NYU, Dept Econ, New York, NY 10003 USA. [Chatterjee, Nilanjan; Gu, Fangyi] NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cichon, Sven] Res Ctr Juelich, Life & Brain Ctr, Dept Genom, Inst Neurosci & Med Struct & Funct Org Brain Geno, Julich, Germany. [Cichon, Sven] Univ Bonn, Life & Brain Ctr, Bonn, Germany. [Cichon, Sven] Univ Bonn, Inst Human Genet, Bonn, Germany. [Cucca, Francesco] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Foroud, Tatiana; Edenberg, Howard J.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Furberg, Helena] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Giegling, Ina; Hartmann, Annette M.; Konte, Bettina; Rujescu, Dan] Univ Munich LMU, Dept Psychiat, Munich, Germany. [Hickie, Ian B.] Univ Sydney, Brain & Mind Res Inst, Sydney, NSW 2006, Australia. [Jousilahti, Pekka; Laatikainen, Tiina; Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Kaakinen, Marika; Veijola, Juha] Univ Oulu, Inst Hlth Sci, SF-90100 Oulu, Finland. [Kaakinen, Marika; Veijola, Juha] Univ Oulu, Bioctr Oulu, SF-90100 Oulu, Finland. [Kaehoenen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kaehoenen, Mika] Univ Tampere Sch Med, Tampere, Finland. [Koellinger, Philipp D.] Erasmus Univ, Dept Appl Econ, Rotterdam, Netherlands. [Kittner, Stephen] Univ Maryland Sch Med, Baltimore Vet Affairs Med Ctr, Dept Neurol, Baltimore, MD USA. [Landi, Maria-Teresa; Caporaso, Neil] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Levy, Steven M.] Univ Iowa, Dept Prevent & Community Dent, Iowa City, IA USA. [Levy, Steven M.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [McNeil, Daniel W.] W Virginia Univ, Dept Psychol & Dent Practice & Rural Hlth, Morgantown, WV 26506 USA. [Pare, Peter D.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Viikari, Jorma] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA. [Francks, Clyde] Max Planck Inst Psycholinguist, Dept MPI Psycholinguist, Nijmegen, Netherlands. [Hops, Hyman] Oregon Res Inst, Eugene, OR 97403 USA. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, MRC Hlth Protect Agcy HPA Ctr Environm & Hlth, Sch Publ Hlth, London SW7 2AZ, England. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, SF-90100 Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, SF-90100 Oulu, Finland. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children & Young People & Families, Oulu, Finland. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, S-11383 Stockholm, Sweden. [Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Noethen, Markus M.] Univ Bonn, Inst Human Genet, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester, Leics, England. [Hatsukami, Dorothy] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Johnson, Eric O.] RTI Int, Dept Behav Hlth Epidemiol, Res Triangle Pk, NC USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Ehringer, MA (reprint author), 1480 30th St, Boulder, CO 80303 USA. EM Marissa.Ehringer@colorado.edu RI Cichon, Sven/B-9618-2014; Johannesson, Magnus/E-9680-2011; Gu, Fangyi/I-5957-2014; Medland, Sarah/C-7630-2013; Montgomery, Grant/B-7148-2008; Cichon, Sven/H-8803-2013; Lyytikainen, Leo-Pekka/C-8544-2016; Magnusson, Patrik/C-4458-2017; OI Lind, Penelope/0000-0002-3887-2598; Grucza, Richard/0000-0002-8191-6875; Bergen, Andrew/0000-0002-1237-7644; Korhonen, Tellervo/0000-0003-2838-3085; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Nothen, Markus/0000-0002-8770-2464; Hartz, Sarah/0000-0002-5429-3799; Edenberg, Howard/0000-0003-0344-9690; Mitchell, Braxton/0000-0003-4920-4744; Kaprio, Jaakko/0000-0002-3716-2455; Martin, Nicholas/0000-0003-4069-8020; Cichon, Sven/0000-0002-9475-086X; Johannesson, Magnus/0000-0001-8759-6393; Medland, Sarah/0000-0003-1382-380X; Montgomery, Grant/0000-0002-4140-8139; Cichon, Sven/0000-0002-9475-086X; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Kaakinen, Marika/0000-0002-9228-0462; Koellinger, Philipp/0000-0001-7413-0412; Cesarini, David/0000-0002-0043-009X FU NIH [R01 DA12690, R01 DA12849, K01 DA24758, R01 AA11330, R01 AA017535, R01 AA07535, R01 AA07728, R01 AA13320, R01AA13321, R01 AA14041, R01 AA11998, R01 AA17688, R01DA012854, K02DA021237, UL1RR024992, R01 DA021913, P60 DA011015, K01 DA19498, R21 DA027070, K02 AA018755, U01 DA020830, R01HL089651-01, N01-AG1-2109, K07 CA118412, R01 DA03706, U01 HG004436]; Australian National Health and Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 464914, 496739, 552485, 552498]; Australian Research Council [A7960034, A79906588, A79801419, APP1009839, DP0770096, DP0212016, DP0343921, FT110100548]; Germany Federal Ministry for Education and Research [BMBF NGNF-2, BMBF IG MooDS 01GS08144, 01GS08147]; Alfried Krupp von Bohlen und Halbach-Stiftung; 5th Framework Programme (FP-5); GenomEUtwin Project [QLG2-CT-2002-01254]; University of California Tobacco-Related Disease Research Program [7PT2000-2004]; Academy of Finland [134309, 126925, 121584, 124282, 129378, 117787, 129494, 41071]; Center of Excellence in Complex Diseases); University Hospital Oulu (Oulu, Finland); Tampere and Turku University Hospital Medical Funds [9M048, 9N035]; Juho Vainio Foundation; Finnish Foundation for Cardiovascular Diseases; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Social Insurance Institution of Finland; NARSAD Young Investigator Award; Welcome Trust; British Heart Foundation; National Institute for Health Research; Academy of Finland Center of Excellence in Complex Disease Genetics; Global Research Awards for Nicotine Dependence (GRAND); SALVE Program; NIHR Academic Clinical Fellowship at the Division of Mental Health, StGeorge's, University of London, UK; Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; European Commission; Genome EU twin Project under the European Commission Programme Quality of Life and Management of the Living Resources of Fifth Framework Programme; Swedish Research Council; Swedish Council for Working Life and Social Research; Swedish Foundation for Strategic Research; Swedish Heart and Lung Foundation; Ragnar Soderberg Foundation; Jan Wallander and Tom Hedelius Foundation; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Netherlands Organization for Scientific Research (NWO); CMSB: Center for Medical Systems Biology (NWO Genomics); Spinozapremie [SPI 56-464-14192]; VU University Centre for Neurogenomics and Cognitive Research (CNCR); Genomewide analyses of European twin and population cohorts [EU/QLRT-2001-01254]; European Research Council: Genetics of Mental Illness [ERC 230374]; Beyond the Genetics of Addiction [ERC 284167]; Mary Beryl Patch Turnbull Scholar Program; N.I.H [R01 NS45012, U01 NS069208, P01 CA089392, R01 DA12854, R01 CA060691, N01-PC35146, R01 CA87895, P01 AG005842, T32 AG000186, K99R00 DA023549, R01 DA026911, KL2 RR024994, K08 DA032680, P30 DK-072488, U01 HG004738, R01 DE12101] FX NIH Grants R01 DA12690, R01 DA12849, K01 DA24758, R01 AA11330, R01 AA017535, R01 AA07535, R01 AA07728, R01 AA13320, R01AA13321, R01 AA14041, R01 AA11998, R01 AA17688, R01DA012854, K02DA021237, UL1RR024992, R01 DA021913, P60 DA011015, K01 DA19498, R21 DA027070, K02 AA018755, U01 DA020830, R01HL089651-01, N01-AG1- 2109, K07 CA118412, R01 DA03706, U01 HG004436, R01 NS45012, U01 NS069208, P01 CA089392, R01 DA12854, R01 CA060691, N01-PC35146, R01 CA87895, P01 AG005842, T32 AG000186, K99R00 DA023549, R01 DA026911, KL2 RR024994, K08 DA032680, P30 DK-072488, U01 HG004738, R01 DE12101; Australian National Health and Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 464914, 496739, 552485, 552498); Australian Research Council (A7960034, A79906588, A79801419, APP1009839, DP0770096, DP0212016, DP0343921, and FT110100548); Germany Federal Ministry for Education and Research (project grants BMBF NGNF-2; BMBF NGFNplus; BMBF IG MooDS 01GS08144 and 01GS08147); Alfried Krupp von Bohlen und Halbach-Stiftung; 5th Framework Programme (FP-5); GenomEUtwin Project (QLG2-CT-2002-01254); 7PT2000-2004, from the University of California Tobacco-Related Disease Research Program; Academy of Finland (project grants 134309, 126925, 121584, 124282, 129378, 117787, 129494, 41071 and The Center of Excellence in Complex Diseases); University Hospital Oulu (Oulu, Finland); Tampere and Turku University Hospital Medical Funds (project grants 9M048 and 9N035); Juho Vainio Foundation; Finnish Foundation for Cardiovascular Diseases; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (T. L.); Social Insurance Institution of Finland; NARSAD Young Investigator Award; Welcome Trust; British Heart Foundation; National Institute for Health Research; Academy of Finland Center of Excellence in Complex Disease Genetics; Global Research Awards for Nicotine Dependence (GRAND); SALVE Program; NIHR Academic Clinical Fellowship at the Division of Mental Health, StGeorge's, University of London, UK; Medical Research Service and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; The European Commission; Genome EU twin Project under the European Commission Programme Quality of Life and Management of the Living Resources of Fifth Framework Programme; the Swedish Research Council; the Swedish Council for Working Life and Social Research; the Swedish Foundation for Strategic Research; the Swedish Heart and Lung Foundation; the Ragnar Soderberg Foundation; the Jan Wallander and Tom Hedelius Foundation; Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103, 01ZZ0403, and 03ZIK012); The Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. For the NTR study (www.tweelingregister.org) funding was obtained from the Netherlands Organization for Scientific Research (NWO); CMSB: Center for Medical Systems Biology (NWO Genomics); Spinozapremie (SPI 56-464-14192); the VU University Centre for Neurogenomics and Cognitive Research (CNCR); Genomewide analyses of European twin and population cohorts (EU/QLRT-2001-01254); the European Research Council: Genetics of Mental Illness (ERC 230374) and Beyond the Genetics of Addiction (ERC 284167). KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. NR 78 TC 14 Z9 14 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2013 VL 37 IS 8 BP 846 EP 859 DI 10.1002/gepi.21760 PG 14 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 251ZZ UT WOS:000326975300010 PM 24186853 ER PT J AU Kubo, A Cook, MB Shaheen, NJ Vaughan, TL Whiteman, DC Murray, L Corley, DA AF Kubo, Ai Cook, Michael Blaise Shaheen, Nicholas J. Vaughan, Thomas L. Whiteman, David C. Murray, Liam Corley, Douglas A. TI Sex-specific associations between body mass index, waist circumference and the risk of Barrett's oesophagus: a pooled analysis from the international BEACON consortium SO GUT LA English DT Article DE Barrett's Oesophagus; Obesity; Gastroesophageal Reflux Disease; Nutrition ID GASTROESOPHAGEAL-REFLUX DISEASE; GROWTH-FACTOR-I; METABOLIC SYNDROME; ABDOMINAL OBESITY; GASTRIC CARDIA; ESOPHAGOGASTRIC JUNCTION; BREAST-CANCER; ADENOCARCINOMA; METAANALYSIS; HYPERINSULINEMIA AB Objective Barrett's oesophagus is a precursor lesion of oesophageal adenocarcinoma, a cancer that, in the USA, has increased in incidence over 600% during the past 40years. Barrett's oesophagus and oesophageal adenocarcinoma are much more common among men than among women; this finding is unexplained and most earlier studies lacked sufficient numbers of women to evaluate sex-specific risk factors. We leveraged the power of an international consortium to assess sex-specific relationships between body mass index (BMI), abdominal circumference and Barrett's oesophagus. Design Four case-control studies provided a total of 1102 cases (316 women, 786 men) and 1400 population controls (436 women, 964 men) for analysis. Study-specific estimates, generated using individual participant data, were combined using random effects meta-analysis. Results Waist circumference was significantly associated with Barrett's oesophagus, even after adjustment for BMI; persons in the highest versus the lowest quartiles of waist circumference had approximately 125% and 275% increases in the odds of Barrett's oesophagus among men and women, respectively (OR 2.24, 95% CI 1.08 to 4.65, I-2=57; OR 3.75, 95% CI 1.47 to 9.56, I-2=0). In contrast, there was no evidence of a significant association between BMI and the risk of Barrett's oesophagus, with or without adjustment for waist circumference. Conclusions Waist circumference, independent of BMI, was found to be a risk factor for Barrett's oesophagus among both men and women. Future studies examining the biological mechanisms of this association will extend our knowledge regarding the pathogenesis of Barrett's oesophagus. C1 [Kubo, Ai; Corley, Douglas A.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Cook, Michael Blaise] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shaheen, Nicholas J.] Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Dept Epidemiol, Seattle, WA 98104 USA. [Whiteman, David C.] Queensland Inst Med Res, Dept Populat & Canc Studies, Brisbane, Qld 4006, Australia. [Murray, Liam] Sch Med, Belfast, Antrim, North Ireland. RP Kubo, A (reprint author), Kaiser Permanente, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM ai.kubo@kp.org RI Cook, Michael/A-5641-2009; Whiteman, David/P-2728-2014 OI Cook, Michael/0000-0002-0533-7302; Whiteman, David/0000-0003-2563-9559 FU National Institutes of Health [RO1 DK63616, 1R21DK077742, K23DK59311, R03DK75842]; intramural program of the National Institutes of Health; Ireland-Northern Ireland cooperation research project; Northern Ireland Research and Development Office; Health Research Board, Ireland (FINBAR) [RES/1699/01N/S]; Study of Digestive Health [NCI RO1 CA 001833]; Study of Reflux Disease [NCI R01 CA72866]; Established Investigator Award in Cancer Prevention and Control [K05 CA124911, KR021183] FX This work was supported by the National Institutes of Health RO1 DK63616 (AK and DAC); 1R21DK077742 (AK, NJS and DAC); K23DK59311 and R03DK75842 (NJS); the intramural program of the National Institutes of Health (MBC); an Ireland-Northern Ireland cooperation research project grant sponsored by the Northern Ireland Research and Development Office and the Health Research Board, Ireland (FINBAR) (LM: RES/1699/01N/S); the Study of Digestive Health, NCI RO1 CA 001833 (DCW); the Study of Reflux Disease, NCI R01 CA72866 (TLV) and the Established Investigator Award in Cancer Prevention and Control, K05 CA124911 (TLV, Kaiser Permanente Community Benefit Grant (KR021183)). NR 47 TC 51 Z9 51 U1 0 U2 5 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 DEC PY 2013 VL 62 IS 12 BP 1684 EP 1691 DI 10.1136/gutjnl-2012-303753 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 250TH UT WOS:000326877200005 PM 23355549 ER PT J AU Xin, HW Ambe, CM Hari, DM Wiegand, GW Miller, TC Chen, JQ Anderson, AJ Ray, S Mullinax, JE Koizumi, T Langan, RC Burka, D Herrmann, MA Goldsmith, PK Stojadinovic, A Rudloff, U Thorgeirsson, SS Avital, I AF Xin, Hong-Wu Ambe, Chenwi M. Hari, Danielle M. Wiegand, Gordon W. Miller, Tyler C. Chen, Jin-Qiu Anderson, Andrew J. Ray, Satyajit Mullinax, John E. Koizumi, Tomotake Langan, Russell C. Burka, Douglas Herrmann, Michelle A. Goldsmith, Paul K. Stojadinovic, Alexander Rudloff, Udo Thorgeirsson, Snorri S. Avital, Itzhak TI Label-retaining liver cancer cells are relatively resistant to sorafenib SO GUT LA English DT Article DE Cancer; Cell Proliferation; Drug Resistance; Hepatocellular Carcinoma; Stem Cells ID ADVANCED HEPATOCELLULAR-CARCINOMA; MULTIKINASE INHIBITOR; MYELOID-LEUKEMIA; STEM-CELLS; PROLIFERATION; APOPTOSIS; DIVISION AB Objective The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. Methods We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. Results LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. Conclusions Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC. C1 [Xin, Hong-Wu; Ambe, Chenwi M.; Hari, Danielle M.; Wiegand, Gordon W.; Miller, Tyler C.; Anderson, Andrew J.; Ray, Satyajit; Mullinax, John E.; Koizumi, Tomotake; Langan, Russell C.; Burka, Douglas; Rudloff, Udo; Avital, Itzhak] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Jin-Qiu; Herrmann, Michelle A.; Goldsmith, Paul K.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stojadinovic, Alexander] Walter Reed Natl Mil Med Ctr, Div Surg Oncol, Dept Surg, Bethesda, MD USA. [Stojadinovic, Alexander; Avital, Itzhak] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Avital, Itzhak] Bon Secours Canc Inst, Richmond, VA 23230 USA. RP Thorgeirsson, SS (reprint author), NCI, Ctr Excellence Integrat Canc Biol & Genom, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, 37 Convent Dr MSC 4262,Bldg 37,Room 4146A, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov; itzhak.avital@gmail.com RI Mullinax, John/L-2509-2014 FU NIH/National Cancer Institute, NCI [1ZIABC011005] FX The NIH/National Cancer Institute, NCI intramural grant 1ZIABC011005. NR 22 TC 21 Z9 21 U1 1 U2 8 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 DEC PY 2013 VL 62 IS 12 BP 1777 EP 1786 DI 10.1136/gutjnl-2012-303261 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 250TH UT WOS:000326877200016 PM 23411027 ER PT J AU Liu, QY Pittaluga, S Davies-Hill, T Raffeld, M Xi, LQ Jaffe, ES AF Liu, Qingyan Pittaluga, Stefania Davies-Hill, Theresa Raffeld, Mark Xi, Liqiang Jaffe, Elaine S. TI Increased CD5-positive polyclonal B cells in Castleman disease: a diagnostic pitfall SO HISTOPATHOLOGY LA English DT Letter C1 [Liu, Qingyan; Pittaluga, Stefania; Davies-Hill, Theresa; Raffeld, Mark; Xi, Liqiang; Jaffe, Elaine S.] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Liu, QY (reprint author), NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. OI Jaffe, Elaine/0000-0003-4632-0301 FU Intramural NIH HHS [ZIA BC011070-05] NR 8 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD DEC PY 2013 VL 63 IS 6 BP 877 EP 880 DI 10.1111/his.12213 PG 4 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 252PB UT WOS:000327018300015 PM 24033372 ER PT J AU Leoyklang, P Suphapeetiporn, K Srichomthong, C Tongkobpetch, S Fietze, S Dorward, H Cullinane, AR Gahl, WA Huizing, M Shotelersuk, V AF Leoyklang, Petcharat Suphapeetiporn, Kanya Srichomthong, Chalurmpon Tongkobpetch, Siraprapa Fietze, Stefanie Dorward, Heidi Cullinane, Andrew R. Gahl, William A. Huizing, Marjan Shotelersuk, Vorasuk TI Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene SO HUMAN GENETICS LA English DT Article ID CLEFT-PALATE; MESSENGER-RNA; MENTAL-RETARDATION; PROTEIN; EXPRESSION; MUTATIONS; COMPLEX; NUCLEUS; DECAY; DIFFERENTIATION AB Two syndromic cognitive impairment disorders have very similar craniofacial dysmorphisms. One is caused by mutations of SATB2, a transcription regulator and the other by heterozygous mutations leading to premature stop codons in UPF3B, encoding a member of the nonsense-mediated mRNA decay complex. Here we demonstrate that the products of these two causative genes function in the same pathway. We show that the SATB2 nonsense mutation in our patient leads to a truncated protein that localizes to the nucleus, forms a dimer with wild-type SATB2 and interferes with its normal activity. This suggests that the SATB2 nonsense mutation has a dominant negative effect. The patient's leukocytes had significantly decreased UPF3B mRNA compared to controls. This effect was replicated both in vitro, where siRNA knockdown of SATB2 in HEK293 cells resulted in decreased UPF3B expression, and in vivo, where embryonic tissue of Satb2 knockout mice showed significantly decreased Upf3b expression. Furthermore, chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter. These findings indicate that SATB2 activates UPF3B expression through binding to its promoter. This study emphasizes the value of recognizing disorders with similar clinical phenotypes to explore underlying mechanisms of genetic interaction. C1 [Leoyklang, Petcharat] Chulalongkorn Univ, Program Biomed Sci, Fac Grad Sch, Bangkok, Thailand. [Leoyklang, Petcharat; Suphapeetiporn, Kanya; Srichomthong, Chalurmpon; Tongkobpetch, Siraprapa; Shotelersuk, Vorasuk] Chulalongkorn Univ, Fac Med, Dept Pediat, Ctr Excellence Med Genet, Bangkok 10330, Thailand. [Leoyklang, Petcharat; Suphapeetiporn, Kanya; Srichomthong, Chalurmpon; Tongkobpetch, Siraprapa; Shotelersuk, Vorasuk] King Chulalongkorn Mem Hosp, Thai Red Cross Soc, Excellence Ctr Med Genet, Bangkok, Thailand. [Leoyklang, Petcharat; Dorward, Heidi; Cullinane, Andrew R.; Gahl, William A.; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Suphapeetiporn, Kanya] King Chulalongkorn Mem Hosp, Dept Pediat, Div Med Genet & Metab, Bangkok 10330, Thailand. [Fietze, Stefanie] Max Planck Inst Immunobiol & Epigenet, Dept Cellular & Mol Immunol, D-79108 Freiburg, Germany. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. EM kanya.su@chula.ac.th; mhuizing@mail.nih.gov FU Royal Golden Jubilee Ph.D. Program [PHD/0026/2549]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Thailand Research Fund; Ratchadapiseksomphot Fund [RES560530177-HR]; Chulalongkorn University Centenary Academic Development Project [CU56-HR05]; Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission [HR1163A] FX We like to thank Drs. Gergana Dobreva and Rudolph Grosschedl (Max Planck Institution for Immunobiology and Epigenetics, Freiburg, Germany) for kindly providing the pfos-luc-Wt SATB2 plasmid and Satb2 knockout mice. This study was supported by the Royal Golden Jubilee Ph.D. Program to PL (Grant No PHD/0026/2549); the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; The Thailand Research Fund; Ratchadapiseksomphot Fund (RES560530177-HR), Chulalongkorn University Centenary Academic Development Project (CU56-HR05), and the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission (HR1163A). NR 35 TC 9 Z9 9 U1 3 U2 9 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 DEC PY 2013 VL 132 IS 12 BP 1383 EP 1393 DI 10.1007/s00439-013-1345-9 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 251LE UT WOS:000326929500006 PM 23925499 ER PT J AU Dumitrescu, L Carty, CL Franceschini, N Hindorff, LA Cole, SA Buzkova, P Schumacher, FR Eaton, CB Goodloe, RJ Duggan, DJ Haessler, J Cochran, B Henderson, BE Cheng, I Johnson, KC Carlson, CS Love, SA Brown-Gentry, K Nato, AQ Quibrera, M Shohet, RV Ambite, JL Wilkens, LR Le Marchand, L Haiman, CA Buyske, S Kooperberg, C North, KE Fornage, M Crawford, DC AF Dumitrescu, Logan Carty, Cara L. Franceschini, Nora Hindorff, Lucia A. Cole, Shelley A. Buzkova, Petra Schumacher, Fredrick R. Eaton, Charles B. Goodloe, Robert J. Duggan, David J. Haessler, Jeff Cochran, Barbara Henderson, Brian E. Cheng, Iona Johnson, Karen C. Carlson, Chris S. Love, Shelly-Anne Brown-Gentry, Kristin Nato, Alejandro Q. Quibrera, Miguel Shohet, Ralph V. Ambite, Jose Luis Wilkens, Lynne R. Le Marchand, Loic Haiman, Christopher A. Buyske, Steven Kooperberg, Charles North, Kari E. Fornage, Myriam Crawford, Dana C. TI No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population SO HUMAN GENETICS LA English DT Article AB Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP x smoking interactions. C1 [Dumitrescu, Logan; Goodloe, Robert J.; Brown-Gentry, Kristin; Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA. [Carty, Cara L.; Haessler, Jeff; Carlson, Chris S.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Franceschini, Nora; Love, Shelly-Anne; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Cole, Shelley A.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Schumacher, Fredrick R.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Eaton, Charles B.] Brown Univ, Dept Family Med, Warren Alpert Med Sch, Providence, RI 02912 USA. [Duggan, David J.] Translat Genom Sci Inst, Phoenix, AZ USA. [Cochran, Barbara] Baylor Coll Med, Houston, TX 77030 USA. [Cheng, Iona; Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Nato, Alejandro Q.; Buyske, Steven] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Quibrera, Miguel] Univ N Carolina, Gillings Sch Publ Hlth, Chapel Hill, NC USA. [Shohet, Ralph V.] Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Sch Publ Hlth, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. RP Crawford, DC (reprint author), Vanderbilt Univ, Ctr Human Genet Res, 2215 Garland Ave,515B Light Hall, Nashville, TN 37232 USA. EM logan.dumitrescu@chgr.mc.vanderbilt.edu; crawford@chgr.mc.vanderbilt.edu RI Nato, Alejandro/J-3880-2016; OI Nato, Alejandro/0000-0002-8745-9046; Buyske, Steven/0000-0001-8539-5416 FU National Human Genome Research Institute (NHGRI); CALiCo [U01HG004803]; EAGLE [U01HG004798]; MEC [U01HG004802]; WHI [U01HG004790]; Coordinating Center [U01HG004801]; NHGRI ARRA; NHGRI PAGE [U01HG004803, U01HG004798, U01HG004802, U01HG004790]; NHLBI [N01-HV-48195, U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521]; Centers for Disease Control and Prevention; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; National Heart, Lung, and Blood Institute; NIH; U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN 268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institutes of Health, National Heart, Lung and Blood Institute [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295]; National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058] FX The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org. The "Epidemiologic Architecture for Genes Linked to Environment (EAGLE)" is funded through the NHGRI PAGE program (U01HG004798 and its NHGRI ARRA supplement). Genotyping services for select NHANES III SNPs presented here were also provided by the Johns Hopkins University under federal contract number (N01-HV-48195) from NHLBI. The study participants were derived from the National Health and Nutrition Examination Surveys (NHANES), and these studies are supported by the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI PAGE program (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). Funding support for the "Epidemiology of putative genetic variants: The Women's Health Initiative" study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf. Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program was provided through the NHGRI PAGE program (U01HG004803 and its NHGRI ARRA supplement). The following studies contributed to this manuscript and are funded by the following agencies: The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN 268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. The Coronary Artery Risk Development in Young Adults (CARDIA) study is supported by the following National Institutes of Health, National Heart, Lung and Blood Institute contracts: N01-HC-95095; N01-HC-48047; N01-HC-48048; N01-HC-48049; N01-HC-48050; N01-HC-45134; N01-HC-05187; and N01-HC-45205. The Cardiovascular Health Study (CHS) is supported by contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS).; Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging (NIA). The Strong Heart Study (SHS) is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service. Assistance with phenotype harmonization, SNP selection and annotation, data cleaning, data management, integration and dissemination, and general study coordination were provided by the PAGE Coordinating Center (U01HG004801 and its NHGRI ARRA supplement). The National Institutes of Mental Health also contributes to the support for the Coordinating Center. The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. NR 7 TC 1 Z9 1 U1 0 U2 2 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 DEC PY 2013 VL 132 IS 12 BP 1427 EP 1431 DI 10.1007/s00439-013-1375-3 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 251LE UT WOS:000326929500010 PM 24100633 ER PT J AU Sergeev, YV Vitale, S Sieving, PA Vincent, A Robson, AG Moore, AT Webster, AR Holder, GE AF Sergeev, Yuri V. Vitale, Susan Sieving, Paul A. Vincent, Ajoy Robson, Anthony G. Moore, Anthony T. Webster, Andrew R. Holder, Graham E. TI Molecular modeling indicates distinct classes of missense variants with mild and severe XLRS phenotypes SO HUMAN MOLECULAR GENETICS LA English DT Article ID X-LINKED RETINOSCHISIS; PROTEIN DISULFIDE-ISOMERASE; JUVENILE RETINOSCHISIS; B-WAVE; ENDOPLASMIC-RETICULUM; GENE-THERAPY; A-WAVE; MUTATIONS; DOMAIN; ELECTRORETINOGRAM AB X-linked retinoschisis (XLRS) is a vitreo-retinal degeneration caused by mutations in the RS1 gene which encodes the protein retinoschisin (RS1), required for the structural and functional integrity of the retina. Data are presented from a group of 38 XLRS patients from Moorfields Eye Hospital (London, UK) who had one of 18 missense mutations in RS1. Patients were grouped based on mutation severity predicted by molecular modeling: mild (class I), moderate (intermediate) and severe (class II). Most patients had an electronegative scotopic bright flash electroretinogram (ERG) (reduced b/a-wave ratio) in keeping with predominant inner retinal dysfunction. An association between the type of structural RS1 alterations and the severity of b/a-wave reduction was found in all but the oldest group of patients, significant in patients aged 15-30 years. Severe RS1 missense changes were associated with a lower ERG b/a ratio than were mild changes, suggesting that the extent of inner retinal dysfunction is influenced by the effect of the mutations on protein structure. The majority of class I mutations showed no changes involving cysteine residues. Class II mutations caused severe perturbations due to the removal or insertion of cysteine residues or due to changes in the hydrophobic core. The ERG b/a ratio in intermediate cases was abnormal but showed significant variability, possibly related to the role of praline or arginine residues. We also conducted a second study, using a completely independent cohort, to indicate a genotype-ERG phenotype correlation. C1 [Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. [Vincent, Ajoy; Robson, Anthony G.; Holder, Graham E.] Moorfields Eye Hosp, Dept Electrophysiol, London, England. [Robson, Anthony G.; Moore, Anthony T.; Webster, Andrew R.; Holder, Graham E.] UCL, Inst Ophthalmol, London, England. RP Sergeev, YV (reprint author), NEI, OGVFB, Bldg 10,Rm 5B47,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sergeevy@nei.nih.gov OI Vincent, Ajoy/0000-0001-6446-3846 FU National Institutes of Health [Z01-EY000476-01, Z01-DC000065-08]; Foundation Fighting Blindness (USA); National Institute for Health Research UK (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust; UCL Institute of Ophthalmology FX This work was supported by National Institutes of Health (Z01-EY000476-01 to Y.V.S., and Z01-DC000065-08 to P.A.S.) and Foundation Fighting Blindness (USA), and was partly funded by the National Institute for Health Research UK (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. NR 60 TC 6 Z9 7 U1 1 U2 4 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 DEC 1 PY 2013 VL 22 IS 23 BP 4756 EP 4767 DI 10.1093/hmg/ddt329 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 251ZD UT WOS:000326973000010 PM 23847049 ER PT J AU Miura, K Takashima, E Deng, BB Tullo, G Diouf, A Moretz, SE Nikolaeva, D Diakite, M Fairhurst, RM Fay, MP Long, CA Tsuboi, T AF Miura, Kazutoyo Takashima, Eizo Deng, Bingbing Tullo, Gregory Diouf, Ababacar Moretz, Samuel E. Nikolaeva, Daria Diakite, Mahamadou Fairhurst, Rick M. Fay, Michael P. Long, Carole A. Tsuboi, Takafumi TI Functional Comparison of Plasmodium falciparum Transmission-Blocking Vaccine Candidates by the Standard Membrane-Feeding Assay SO INFECTION AND IMMUNITY LA English DT Article ID CELL-FREE SYSTEM; MALARIA; ANTIBODIES; ANTIGEN; DISCOVERY; PROTEINS; PFS230; TRIAL; STAGE AB Recently, there has been a renewed interest in the development of transmission-blocking vaccines (TBV) against Plasmodium falciparum malaria. While several candidate TBVs have been reported, studies directly comparing them in functional assays are limited. To this end, recombinant proteins of TBV candidates Pfs25, Pfs230, and PfHAP2 were expressed in the wheat germ cell-free expression system. Outbred CD-1 mice were immunized twice with the antigens. Two weeks after the second immunization, IgG levels were measured by enzyme-linked immunosorbent assay (ELISA), and IgG functionality was assessed by the standard membrane-feeding assay (SMFA) using cultured P. falciparum NF54 gametocytes and Anopheles stephensi mosquitoes. All three recombinant proteins elicited similar levels of antigen-specific IgG judged by ELISA. When IgGs purified from pools of immune serum were tested at 0.75 mg/ml in the SMFA, all three IgGs showed 97 to 100% inhibition in oocyst intensity compared to control IgG. In two additional independent SMFA evaluations, anti-Pfs25, anti-Pfs230, and anti-PfHAP2 IgGs inhibited oocyst intensity in a dose-dependent manner. When all three data sets were analyzed, anti-Pfs25 antibody showed significantly higher inhibition than the other two antibodies (P < 0.001 for both), while there was no significant difference between the other two (P = 0.15). A proportion of plasma samples collected from adults living in an area of malaria endemicity in Mali recognized Pfs230 and PfHAP2. This is the first study showing that the HAP2 protein of P. falciparum can induce transmission-blocking antibody. The current study supports the possibility of using this system for a comparative study with multiple TBV candidates. C1 [Miura, Kazutoyo; Deng, Bingbing; Tullo, Gregory; Diouf, Ababacar; Moretz, Samuel E.; Nikolaeva, Daria; Fairhurst, Rick M.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Takashima, Eizo; Tsuboi, Takafumi] Ehime Univ, Div Malaria Res, Proteosci Ctr, Matsuyama, Ehime, Japan. [Diakite, Mahamadou] Univ Bamako, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Tsuboi, Takafumi] Ehime Univ, Venture Business Lab, Matsuyama, Ehime, Japan. RP Tsuboi, T (reprint author), Ehime Univ, Div Malaria Res, Proteosci Ctr, Matsuyama, Ehime, Japan. EM clong@niaid.nih.gov; tsuboi@ccr.ehime-u.ac.jp OI Fay, Michael P./0000-0002-8643-9625 FU National Institute of Allergy and Infectious Diseases, NIH; PATH Malaria Vaccine Initiative; MEXT KAKENHI [23117008]; JSPS KAKENHI in Japan [23406007] FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, the PATH Malaria Vaccine Initiative, and MEXT KAKENHI (23117008) and JSPS KAKENHI (23406007) in Japan. NR 22 TC 26 Z9 27 U1 3 U2 15 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 DEC PY 2013 VL 81 IS 12 BP 4377 EP 4382 DI 10.1128/IAI.01056-13 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 253EU UT WOS:000327066100005 PM 24042109 ER PT J AU Tremblay, JM Mukherjee, J Leysath, CE Debatis, M Ofori, K Baldwin, K Boucher, C Peters, R Beamer, G Sheoran, A Bedenice, D Tzipori, S Shoemaker, CB AF Tremblay, Jacqueline M. Mukherjee, Jean Leysath, Clinton E. Debatis, Michelle Ofori, Kwasi Baldwin, Karen Boucher, Courtney Peters, Rachel Beamer, Gillian Sheoran, Abhineet Bedenice, Daniela Tzipori, Saul Shoemaker, Charles B. TI A Single VHH-Based Toxin-Neutralizing Agent and an Effector Antibody Protect Mice against Challenge with Shiga Toxins 1 and 2 SO INFECTION AND IMMUNITY LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; ESCHERICHIA-COLI; MONOCLONAL-ANTIBODIES; SYSTEMIC COMPLICATIONS; ENDOTHELIAL-CELLS; IMMUNE-COMPLEXES; BINDING-AGENTS; INFECTION; RECEPTOR; ASSOCIATION AB Shiga toxin-producing Escherichia coli (STEC) is a major cause of severe food-borne disease worldwide, and two Shiga toxins, Stx1 and Stx2, are primarily responsible for the serious disease consequence, hemolytic-uremic syndrome (HUS). Here we report identification of a panel of heavy-chain-only antibody (Ab) VH (VHH) domains that neutralize Stx1 and/or Stx2 in cell-based assays. VHH heterodimer toxin-neutralizing agents containing two linked Stx1-neutralizing VHHs or two Stx2-neutralizing VHHs were generally much more potent at Stx neutralization than a pool of the two-component monomers tested in cell-based assays and in vivo mouse models. We recently reported that clearance of toxins can be promoted by coadministering a VHH-based toxin-neutralizing agent with an antitag monoclonal antibody (MAb), called the "effector Ab," that indirectly decorates each toxin molecule with four Ab molecules. Decoration occurs because the Ab binds to a common epitopic tag present at two sites on each of the two VHH heterodimer molecules that bind to each toxin molecule. Here we show that coadministration of effector Ab substantially improved the efficacy of Stx toxin-neutralizing agents to prevent death or kidney damage in mice following challenge with Stx1 or Stx2. A single toxin-neutralizing agent consisting of a double-tagged VHH heterotrimer-one Stx1-specific VHH, one Stx2-specific VHH, and one Stx1/Stx2 cross-specific VHH-was effective in preventing all symptoms of intoxication from Stx1 and Stx2 when coadministered with effector Ab. Overall, the availability of simple, defined, recombinant proteins that provide cost-effective protection against HUS opens up new therapeutic approaches to managing disease. C1 [Tremblay, Jacqueline M.; Mukherjee, Jean; Debatis, Michelle; Ofori, Kwasi; Baldwin, Karen; Boucher, Courtney; Peters, Rachel; Beamer, Gillian; Sheoran, Abhineet; Bedenice, Daniela; Tzipori, Saul; Shoemaker, Charles B.] Tufts Cummings Sch Vet Med, Dept Infect Dis & Global Hlth, North Grafton, MA 01536 USA. [Leysath, Clinton E.] NIAID, NIH, Bethesda, MD 20892 USA. RP Shoemaker, CB (reprint author), Tufts Cummings Sch Vet Med, Dept Infect Dis & Global Hlth, North Grafton, MA 01536 USA. EM charles.shoemaker@tufts.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [N01-AI-30050, U54 AI057159] FX This project has been supported in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number N01-AI-30050 and award number U54 AI057159. NR 40 TC 22 Z9 22 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2013 VL 81 IS 12 BP 4592 EP 4603 DI 10.1128/IAI.01033-13 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 253EU UT WOS:000327066100028 PM 24082082 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Fridkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, DR Hill, NS Horan, T Kollef, M Levy, M Septimus, E VanAntwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Fridkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean R. Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward VanAntwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a New, National Approach to Surveillance for Ventilator-Associated Events: Executive Summary SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article C1 [Magill, Shelley S.; Fridkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30329 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Univ, Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Balk, Robert; Burns, Suzanne M.; Deutschman, Clifford S.; Gutterman, David; Hammer, Beth; Hill, Nicholas S.; Kollef, Marin; Levy, Mitchell; Lipsett, Pamela] Amer Thorac Soc, Soc Crit Care Med, Amer Coll Chest Phys, Crit Care Soc Collaborat Amer Assoc Crit Care Nur, Philadelphia, PA USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Carver Coll Med, Div Infect Dis, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Surveillance Working Grp, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Profess Infect Control & Epidemiol, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Zablocki VA Med Ctr, Dept Cardiol, Milwaukee, WI USA. [Henderson, David] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean R.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Hess, Dean R.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Hess, Dean R.] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Warren Alpert Med Sch, Rhode Isl Hosp, Div Pulm Crit Care & Sleep, Providence, RI 02912 USA. [Septimus, Edward] Texas A&M Hlth Sci Ctr, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [VanAntwerpen, Carole] New York State Dept Hlth, Bur Healthcare Assoc Infect, Albany, NY USA. [VanAntwerpen, Carole] Council State & Terr Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept HHS, Off Dis Prevent & Hlth Promot, Washington, DC 20201 USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd,MS A-24, Atlanta, GA 30329 USA. EM smagill@cdc.gov FU Centers for Disease Control and Prevention (CDC) FX Financial support. The work described herein was supported by the Centers for Disease Control and Prevention (CDC). NR 2 TC 4 Z9 5 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD DEC 1 PY 2013 VL 34 IS 12 BP 1239 EP 1243 DI 10.1086/673463 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 252AJ UT WOS:000326976300001 PM 24225607 ER PT J AU Kim, H Crago, E Kim, M Sherwood, P Conley, Y Poloyac, S Kerr, M AF Kim, Hyungsuk Crago, Elizabeth Kim, Mirim Sherwood, Paula Conley, Yvette Poloyac, Samuel Kerr, Mary TI Cerebral vasospasm after sub-arachnoid hemorrhage as a clinical predictor and phenotype for genetic association study SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE brain; genetic disorders; hemorrhage; ischaemic stroke; risk factors; sub-arachnoid hemorrhage ID INTRACRANIAL ANEURYSMS; POLYMORPHISM; RISK; DEFINITION; INFARCTION; RELATIVES; MUTATION; REGION; PAIN AB BackgroundA typology of cerebral vasospasm has been proposed based on distinct clinical manifestations: delayed cerebral ischemia, symptomatic vasospasm', angiographic vasospasm, and transcranial Doppler vasospasm. We examined each distinct clinical manifestation in a nonparametric genetic association study. AimsThe purpose of this study was to examine and compare each four distinct acute clinical manifestations and test its perspectives in genetic association studies. MethodsTwo hundred forty-five Caucasian patients with sub-arachnoid hemorrhage were evaluated for these four distinct clinical manifestations along with 906600 single-nucleotide polymorphisms across the human genome. ResultsThe four clinical manifestations were significantly associated with each other as P-values ranged from 331x10(-4) to 810x10(-15). Transcranial Doppler vasospasm showed significant genetic association with single nucleotide polymorphism (SNP) (rs999662, P=339x10(-8)). Statistical P-value of rs999662 in association with delayed cerebral ischemia, symptomatic vasospasm', and angiographic vasospasm was 00017, 00017, and 019, respectively. ConclusionsDespite different criteria for each of the four clinical manifestations, they are significantly associated with each other. Our results suggest transcranial Doppler vasospasm may be an appropriate intermediate but still clinically relevant phenotype for genetic association studies. Association with SNP rs999662 indicates a potential role for the region containing the solute carrier family 12 member 3 (SLC12A3) gene in transcranial Doppler vasospasm following sub-arachnoid hemorrhage. C1 [Kim, Hyungsuk; Kim, Mirim; Kerr, Mary] NINR, NIH, Bethesda, MD 20892 USA. [Crago, Elizabeth; Sherwood, Paula; Conley, Yvette; Poloyac, Samuel] Univ Pittsburgh, Sch Nursing, Dept Hlth Promot & Dev, Pittsburgh, PA 15261 USA. [Crago, Elizabeth; Sherwood, Paula; Conley, Yvette; Poloyac, Samuel] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. RP Kim, H (reprint author), NIH, 9 Mem Dr B9 Rm 1W121, Bethesda, MD 20892 USA. EM kimhy@mail.nih.gov FU National Institutes of Health FX This research was funded by National Institutes of Health. NR 27 TC 4 Z9 4 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD DEC PY 2013 VL 8 IS 8 BP 620 EP 625 DI 10.1111/j.1747-4949.2012.00823.x PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 255RN UT WOS:000327257600009 PM 22568564 ER PT J AU Leviton, A Allred, EN Dammann, O Engelke, S Fichorova, RN Hirtz, D Kuban, KCK Ment, LR O'shea, TM Paneth, N Shah, B Schreiber, MD AF Leviton, Alan Allred, Elizabeth N. Dammann, Olaf Engelke, Stephen Fichorova, Raina N. Hirtz, Deborah Kuban, Karl C. K. Ment, Laura R. O'shea, T. Michael Paneth, Nigel Shah, Bhavesh Schreiber, Michael D. CA ELGAN Study Investigators TI Systemic Inflammation, Intraventricular Hemorrhage, and White Matter Injury SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE premature; hemorrhage; brain injuries; acute; inflammation; white matter ID LOW-BIRTH-WEIGHT; LOW GESTATIONAL-AGE; BLOOD PROTEIN CONCENTRATIONS; CRANIAL ULTRASOUND LESIONS; EXTREMELY PRETERM INFANTS; BRAIN-DAMAGE; HISTOLOGIC CHARACTERISTICS; MAGNETIC-RESONANCE; PREMATURE-INFANTS; PLACENTA AB To see if the systemic inflammation profile of 123 infants born before the 28th week of gestation who had intraventricular hemorrhage without white matter injury differed from that of 68 peers who had both lesions, we compared both groups to 677 peers who had neither. Cranial ultrasound scans were read independently by multiple readers until concordance. The concentrations of 25 proteins were measured with multiplex arrays using an electrochemiluminescence system. Infants who had both hemorrhage and white matter injury were more likely than others to have elevated concentrations of C-reactive protein and interleukin 8 on days 1, 7, and 14, and elevated concentrations of serum amyloid A and tumor necrosis factor- on 2 of these days. Intraventricular hemorrhage should probably be viewed as 2 entities: hemorrhage alone and hemorrhage with white matter injury. Each entity is associated with inflammation, but the combination has a stronger inflammatory signal than hemorrhage alone. C1 [Leviton, Alan; Allred, Elizabeth N.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Leviton, Alan; Allred, Elizabeth N.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Allred, Elizabeth N.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Dammann, Olaf] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Engelke, Stephen] E Carolina Univ, Brody Sch Med, Dept Pediat, Greenville, NC USA. [Fichorova, Raina N.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Fichorova, Raina N.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Hirtz, Deborah] NINDS, Off Clin Res, Bethesda, MD 20892 USA. [Kuban, Karl C. K.] Boston Med Ctr, Dept Pediat, Boston, MA USA. [Kuban, Karl C. K.] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Kuban, Karl C. K.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Ment, Laura R.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. [Ment, Laura R.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA. [O'shea, T. Michael] Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27103 USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Paneth, Nigel] Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. [Shah, Bhavesh] Baystate Med Ctr, Div Newborn Med, Springfield, MA USA. [Schreiber, Michael D.] Univ Chicago, Comer Childrens Hosp, Dept Pediat, Chicago, IL 60637 USA. RP Leviton, A (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM alan.leviton@childrens.harvard.edu RI Fichorova, Raina/G-9969-2014 FU National Institute of Neurological Disorders and Stroke [5U01NS040069-05]; National Institute of Child Health and Human Development [5P30HD018655-28] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a cooperative agreement with the National Institute of Neurological Disorders and Stroke (5U01NS040069-05) and a center grant award from the National Institute of Child Health and Human Development (5P30HD018655-28). NR 42 TC 9 Z9 10 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD DEC PY 2013 VL 28 IS 12 BP 1637 EP 1645 DI 10.1177/0883073812463068 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 250NQ UT WOS:000326859900012 PM 23112243 ER PT J AU Mariotto, AB Wang, ZQ Klabunde, CN Cho, H Das, B Feuer, EJ AF Mariotto, Angela B. Wang, Zhuoqiao Klabunde, Carrie N. Cho, Hyunsoon Das, Barnali Feuer, Eric J. TI Life tables adjusted for comorbidity more accurately estimate noncancer survival for recently diagnosed cancer patients SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Life expectancy; Comorbidity; Cancer; Health-adjusted age; Survival; Life tables; SEER-Medicare ID PROSTATE-CANCER; RADICAL PROSTATECTOMY; BREAST-CANCER; CANDIDATES; RADIOTHERAPY; PREDICTION; MORTALITY; MODELS AB Objectives: To provide cancer patients and clinicians with more accurate estimates of a patient's life expectancy with respect to noncancer mortality, we estimated comorbidity-adjusted life tables and health-adjusted age. Study Design and Setting: Using data from the Surveillance Epidemiology and End Results Medicare database, we estimated comorbidity scores that reflect the health status of people who are 66 years of age and older in the year before cancer diagnosis. Noncancer survival by comorbidity score was estimated for each age, race, and sex. Health-adjusted age was estimated by systematically comparing the noncancer survival models with US life tables. Results: Comorbidity, cancer status, sex, and race are all important predictors of noncancer survival; however, their relative impact on noncancer survival decreases as age increases. Survival models by comorbidity better predicted noncancer survival than the US life tables. The health-adjusted age and national life tables can be consulted to provide an approximate estimate of a person's life expectancy, for example, the health-adjusted age of a black man aged 75 years with no comorbidities is 67 years, giving him a life expectancy of 13 years. Conclusion: The health-adjusted age and the life tables adjusted by age, race, sex, and comorbidity can provide important information to facilitate decision making about treatment for cancer and other conditions. Published by Elsevier Inc. C1 [Mariotto, Angela B.; Klabunde, Carrie N.; Cho, Hyunsoon; Das, Barnali; Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Wang, Zhuoqiao] Informat Management Serv Inc, Beltsville, MD 20705 USA. [Das, Barnali] Westat Corp, Rockville, MD 20850 USA. RP Mariotto, AB (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr 4E602, Bethesda, MD 20892 USA. EM mariotta@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 12 Z9 14 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 EI 1878-5921 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD DEC PY 2013 VL 66 IS 12 BP 1376 EP 1385 DI 10.1016/j.jclinepi.2013.07.002 PG 10 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 250MP UT WOS:000326857200010 PM 24035494 ER PT J AU Shenai, S Amisano, D Ronacher, K Kriel, M Banada, PP Song, T Lee, M Joh, JS Winter, J Thayer, R Via, LE Kim, S Barry, CE Walzl, G Alland, D AF Shenai, Shubhada Amisano, Danielle Ronacher, Katharina Kriel, Magdalena Banada, Padmapriya P. Song, Taeksun Lee, Myungsun Joh, Joon Sung Winter, Jill Thayer, Rich Via, Laura E. Kim, Soyeon Barry, Clifton E., III Walzl, Gerhard Alland, David TI Exploring Alternative Biomaterials for Diagnosis of Pulmonary Tuberculosis in HIV-Negative Patients by Use of the GeneXpert MTB/RIF Assay SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION; EXHALED BREATH CONDENSATE; MYCOBACTERIUM-TUBERCULOSIS; XPERT MTB/RIF; PERIPHERAL-BLOOD; RIFAMPICIN RESISTANCE; PCR ASSAY; URINE; DNA; SALIVA AB The utility of the GeneXpert MTB/RIF (Xpert) assay for detection of Mycobacterium tuberculosis in sputum samples has been extensively studied. However, the performance of the Xpert assay as applied to other readily accessible body fluids such as exhaled breath condensate (EBC), saliva, urine, and blood has not been established. We used the Xpert assay to test EBC, saliva, urine, and blood samples from HIV-negative, smear-and culture-positive pulmonary tuberculosis (TB) patients for the presence of M. tuberculosis. To compare the ability of the assay to perform bacterial load measurements on sputum samples with versus without sample processing, the assay was also performed on paired direct and processed sputum samples from each patient. The Xpert assay detected M. tuberculosis in none of the 26 EBC samples (sensitivity, 0.0%; 95% confidence interval [ 95% CI], 0.0%, 12.9%), 10 of the 26 saliva samples (sensitivity, 38.5%; 95% CI, 22.4%, 57.5%), 1 of 26 urine samples (sensitivity, 3.8%; 95% CI, 0.7%, 18.9%), and 2 of 24 blood samples (sensitivity, 8.3%; 95% CI, 2.3%, 25.8%). For bacterial load measurements in the different types of sputum samples, the cycle thresholds of the two M. tuberculosis-positive sputum types were well correlated (Spearman correlation of 0.834). This study demonstrates that the Xpert assay should not be routinely used to detect M. tuberculosis in EBC, saliva, urine, or blood samples from HIV-negative patients suspected of having pulmonary tuberculosis. As a test of bacterial load, the assay produced similar results when used to test direct versus processed sputum samples. Sputum remains the optimal sample type for diagnosing pulmonary tuberculosis in HIV-negative patients with the Xpert assay. C1 [Shenai, Shubhada; Amisano, Danielle; Banada, Padmapriya P.; Alland, David] Rutgers Biomed & Hlth Sci, New Jersey Med Sch, Ctr Infect Dis, Newark, NJ 07103 USA. [Ronacher, Katharina; Kriel, Magdalena; Walzl, Gerhard] Univ Stellenbosch, Fac Med & Hlth Sci, DST NRF Ctr Excellence Biomed TB Res, Cape Town, South Africa. [Ronacher, Katharina; Kriel, Magdalena; Walzl, Gerhard] Univ Stellenbosch, Fac Med & Hlth Sci, MRC Ctr Mol & Cellular Biol, Div Mol Biol & Human Genet,Dept Biomed Sci, Cape Town, South Africa. [Song, Taeksun; Lee, Myungsun] Int TB Res Ctr, Chang Won, South Korea. [Joh, Joon Sung] Natl Med Ctr, Seoul, South Korea. [Winter, Jill; Thayer, Rich] Catalysis Fdn Hlth, Emeryville, CA USA. [Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Kim, Soyeon] Rutgers Biomed & Hlth Sci, New Jersey Med Sch, Dept Prevent Med & Community Hlth, Newark, NJ USA. RP Alland, D (reprint author), Rutgers Biomed & Hlth Sci, New Jersey Med Sch, Ctr Infect Dis, Newark, NJ 07103 USA. EM allandda@njms.rutgers.edu RI Barry, III, Clifton/H-3839-2012; Ronacher, Katharina/N-9603-2016; OI Ronacher, Katharina/0000-0002-6371-1462; Via, Laura/0000-0001-6074-9521; banada, padmapriya/0000-0002-5217-6142; Walzl, Gerhard/0000-0003-2487-125X FU Bill and Melinda Gates Foundation; Intramural Research Program of the NIAID, NIH FX This work was supported in part by the Bill and Melinda Gates Foundation through a grant to the Catalysis Foundation for Health and in part by the Intramural Research Program of the NIAID, NIH (C. E. Barry). NR 42 TC 10 Z9 10 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2013 VL 51 IS 12 BP 4161 EP 4166 DI 10.1128/JCM.01743-13 PG 6 WC Microbiology SC Microbiology GA 254EL UT WOS:000327147100043 PM 24108610 ER PT J AU Ritzwoller, DP Glasgow, RE Sukhanova, AY Bennett, GG Warner, ET Greaney, ML Askew, S Goldman, J Emmons, KM Colditz, GA AF Ritzwoller, Debra P. Glasgow, Russell E. Sukhanova, Anna Y. Bennett, Gary G. Warner, Erica T. Greaney, Mary L. Askew, Sandy Goldman, Julie Emmons, Karen M. Colditz, Graham A. CA Be Fit Be Well Study Investigators TI Economic Analyses of the Be Fit Be Well Program: A Weight Loss Program for Community Health Centers SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE weight loss; RCT; pragmatic trial; cost; cost-effectiveness; health disparities ID UNITED-STATES; CARDIOVASCULAR RISK; ETHNIC DISPARITIES; CLINICAL-TRIALS; OBESE-PATIENTS; PRIMARY-CARE; MANAGEMENT; ADULTS; INTERVENTIONS; PATTERNS AB BACKGROUND: The U.S. Preventive Services Task Force has released new guidelines on obesity, urging primary care physicians to provide obese patients with intensive, multi-component behavioral interventions. However, there are few studies of weight loss in real world nonacademic primary care, and even fewer in largely racial/ethnic minority, low-income samples. To evaluate the recruitment, intervention and replications costs of a 2-year, moderate intensity weight loss and blood pressure control intervention. A comprehensive cost analysis was conducted, associated with a weight loss and hypertension management program delivered in three community health centers as part of a pragmatic randomized trial. Three hundred and sixty-five high risk, low-income, inner city, minority (71 % were Black/African American and 13 % were Hispanic) patients who were both hypertensive and obese. Measures included total recruitment costs and intervention costs, cost per participant, and incremental costs per unit reduction in weight and blood pressure. Recruitment and intervention costs were estimated $2,359 per participant for the 2-year program. Compared to the control intervention, the cost per additional kilogram lost was $2,204 /kg, and for blood pressure, $621 /mmHg. Sensitivity analyses suggest that if the program was offered to a larger sample and minor modifications were made, the cost per participant could be reduced to the levels of many commercially available products. The costs associated with the Be Fit Be Well program were found to be significantly more expensive than many commercially available products, and much higher than the amount that the Centers for Medicare and Medicaid reimburse physicians for obesity counseling. However, given the serious and costly health consequences associated with obesity in high risk, multimorbid and socioeconomically disadvantaged patients, the resources needed to provide interventions like those described here may still prove to be cost-effective with respect to producing long-term behavior change. C1 [Ritzwoller, Debra P.; Sukhanova, Anna Y.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO 80237 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Bennett, Gary G.; Askew, Sandy] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Warner, Erica T.; Colditz, Graham A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Warner, Erica T.; Greaney, Mary L.; Goldman, Julie; Emmons, Karen M.] Dana Farber Canc Inst, Div Populat Sci, Ctr Community Based Res, Boston, MA 02115 USA. [Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci,Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. RP Ritzwoller, DP (reprint author), Kaiser Permanente Colorado, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. EM Debra.Ritzwoller@kp.org RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU National Heart Lung Blood Institute [UO1-HL087071]; Foundation for Barnes-Jewish Hospital; National Cancer Institute [5T32CA009001-36]; [K22CA126992]; [K05CA124415-04]; [P30CA091842] FX This work was supported in part by grant funding from the National Heart Lung Blood Institute (UO1-HL087071). G. Bennett was supported by K22CA126992.; K. Emmons was supported by K05CA124415-04. G. Colditz was supported in part by P30CA091842 and the Foundation for Barnes-Jewish Hospital. E. Warner was supported by grant 5T32CA009001-36 from the National Cancer Institute. NR 45 TC 7 Z9 7 U1 0 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2013 VL 28 IS 12 BP 1581 EP 1588 DI 10.1007/s11606-013-2492-3 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 253YY UT WOS:000327127700012 PM 23733374 ER PT J AU Maruthur, NM Ma, Y Delahanty, LM Nelson, JA Aroda, V White, NH Marrero, D Brancati, FL Clark, JM AF Maruthur, Nisa M. Ma, Yong Delahanty, Linda M. Nelson, Julie A. Aroda, Vanita White, Neil H. Marrero, David Brancati, Frederick L. Clark, Jeanne M. CA Diabet Prevention Program Res Grp TI Early Response to Preventive Strategies in the Diabetes Prevention Program SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE diabetes prevention; diabetes risk; type 2 diabetes ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; WEIGHT-LOSS; METFORMIN; MELLITUS; THERAPY; TRIAL AB BACKGROUND: Recommendations for diabetes prevention in patients with prediabetes include lifestyle modification and metformin. However, the significance of early weight loss and glucose measurements when monitoring response to these proven interventions is unknown. To quantify the relationship between early measures of weight and glucose and subsequent diabetes in patients undergoing diabetes prevention interventions. Analysis of results from a randomized controlled trial in 27 academic medical centers in the United States. 3,041 adults with hyperglycemia randomized to lifestyle (n = 1,018), metformin (n = 1,036), or placebo (n = 987) with complete follow-up in The Diabetes Prevention Program. Independent variables were weight loss at 6 and 12 months; fasting glucose (FG) at 6 months; hemoglobin A1c (HbA1c) at 6 months; and post-load glucose at 12 months. The main outcome was time to diabetes diagnosis. After 6 months, 604 participants developed diabetes in the lifestyle (n = 140), metformin (n = 206), and placebo (n = 258) arms over 2.7 years. In the lifestyle arm, 6-month weight loss predicted decreased diabetes risk in a graded fashion: adjusted HR (95 % CI) 0.65 (0.35-1.22), 0.62 (0.33-1.18), 0.46 (0.24-0.87), 0.34 (0.18-0.64), and 0.15 (0.07-0.30) for 0-< 3 %, 3-< 5 %, 5-< 7 %, 7-< 10 %, and a parts per thousand yen10 % weight loss, respectively (reference: weight gain). Attainment of optimal 6-month FG and HbA1c and 12-month post-load glucose predicted > 60 % lower diabetes risk across arms. We found a significant interaction between 6-month weight loss and FG in the lifestyle arm (P = 0.038). Weight and glucose at 6 and 12 months strongly predict lower subsequent diabetes risk with a lifestyle intervention; lower FG predicts lower risk even with substantial weight loss. Early reduction in glycemia is a stronger predictor of future diabetes risk than weight loss for metformin. We offer the first evidence to guide clinicians in making interval management decisions for high-risk patients undertaking measures to prevent diabetes. C1 [Maruthur, Nisa M.; Brancati, Frederick L.; Clark, Jeanne M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Maruthur, Nisa M.; Brancati, Frederick L.; Clark, Jeanne M.] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Ma, Yong] George Washington Univ, Rockville, MD 20852 USA. [Delahanty, Linda M.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Delahanty, Linda M.] Harvard Univ, Sch Med, Boston, MA USA. [Nelson, Julie A.] NIDDK, Southwest Amer Indian Ctr Arizona, Phoenix, AZ USA. [Aroda, Vanita] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [White, Neil H.] Washington Univ, Sch Med, St Louis, MO USA. [Marrero, David] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. [Marrero, David] Indiana Univ Sch Med, Diabet Translat Res Ctr, Indianapolis, IN 46202 USA. [Brancati, Frederick L.; Clark, Jeanne M.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Maruthur, NM (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu FU NIH/NCCR [1KL2RR025006-01] FX Dr. Maruthur was supported by NIH/NCCR grant 1KL2RR025006-01. NR 16 TC 10 Z9 11 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2013 VL 28 IS 12 BP 1629 EP 1636 DI 10.1007/s11606-013-2548-4 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 253YY UT WOS:000327127700018 PM 23860722 ER PT J AU Irvin, VL Nichols, JF Hofstetter, CR Ojeda, VD Song, YJ Kang, S Hovell, MF AF Irvin, Veronica L. Nichols, Jeanne F. Hofstetter, C. Richard Ojeda, Victoria D. Song, Yoon Ju Kang, Sunny Hovell, Melbourne F. TI Osteoporosis and Milk Intake Among Korean Women in California: Relationship with Acculturation to US Lifestyle SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Osteoporosis; Milk; Acculturation; Asian; Korean; Women's health ID AMERICAN; DESCENT AB The Korean population in the US increased by a third between 2000 and 2010. Korean women in the US report low calcium intake and relatively high rate of fractures. However, little is known about the prevalence of osteoporosis among Korean American women. This paper examined the relationship between prevalence of osteoporosis and milk consumption, and their relationship with acculturation among a representative sample of immigrant California women of Korean descent. Bilingual telephone surveys were conducted from a probability sample (N = 590) in 2007. Lower acculturation significantly related to lower milk consumption for women during the age periods of 12-18 and 19-34 years. Acculturation was related to higher prevalence of osteoporosis among post-menopausal, but not pre-menopausal Korean women in California. Future research should include larger cohorts, objective measures of osteoporosis, other sources of calcium specific to Korean cuisine, and assessment of bone-loading physical activity. C1 [Irvin, Veronica L.; Nichols, Jeanne F.; Hofstetter, C. Richard; Kang, Sunny; Hovell, Melbourne F.] San Diego State Univ, Ctr Behav Epidemiol & Community Hlth, Grad Sch Publ Hlth, San Diego, CA 92123 USA. [Irvin, Veronica L.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Irvin, Veronica L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Nichols, Jeanne F.] San Diego State Univ, Sch Exercise & Nutrit Sci, San Diego, CA 92183 USA. [Hofstetter, C. Richard] San Diego State Univ, Dept Polit Sci, San Diego, CA 92182 USA. [Ojeda, Victoria D.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Song, Yoon Ju] Catholic Univ Korea, Sch Human Ecol, Wonmi Gu 420743, Bucheon Si, South Korea. RP Irvin, VL (reprint author), San Diego State Univ, Ctr Behav Epidemiol & Community Hlth, Grad Sch Publ Hlth, 9245 Sky Pk Court,Suite 230, San Diego, CA 92123 USA. EM veronica.irvin@nih.gov; mhovell@cbeachsdsu.org FU Intramural NIH HHS; NCI NIH HHS [R01CA105199, R01 CA105199, R01CA138192]; NIDA NIH HHS [K01 DA025504, K01DA025504] NR 14 TC 1 Z9 1 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD DEC PY 2013 VL 15 IS 6 BP 1119 EP 1124 DI 10.1007/s10903-013-9774-z PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 250WT UT WOS:000326888100015 PM 23338905 ER PT J AU Cox, CJ Sharma, M Leckman, JF Zuccolo, J Zuccolo, A Kovoor, A Swedo, SE Cunningham, MW AF Cox, Carol J. Sharma, Meenakshi Leckman, James F. Zuccolo, Jonathan Zuccolo, Amir Kovoor, Abraham Swedo, Susan E. Cunningham, Madeleine W. TI Brain Human Monoclonal Autoantibody from Sydenham Chorea Targets Dopaminergic Neurons in Transgenic Mice and Signals Dopamine D2 Receptor: Implications in Human Disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS; OBSESSIVE-COMPULSIVE SYMPTOMS; BETA-D-GLUCOSAMINE; STREPTOCOCCAL-M-PROTEINS; GROUP-A STREPTOCOCCI; RHEUMATIC-FEVER; BASAL GANGLIA; CLINICAL DESCRIPTION; ANTIBODY-RESPONSE; TIC DISORDERS AB How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic manifestation of streptococcal-induced rheumatic fever. Previously, our novel SC-derived mAb 24.3.1 was found to recognize streptococcal and brain Ags. To investigate in vivo targets of human mAb 24.3.1, V-H/V-L genes were expressed in B cells of transgenic (Tg) mice as functional chimeric human V-H 24.3.1mouse C-region IgG1(a) autoantibody. Chimeric human-mouse IgG1 a autoantibody colocalized with tyrosine hydroxylase in the basal ganglia within dopaminergic neurons in vivo in V-H 24.3.1 Tg mice. Both human mAb 24.3.1 and IgG1(a) in Tg sera were found to react with human dopamine D2 receptor (D2R). Reactivity of chorea-derived mAb 24.3.1 or SC IgG with D2R was confirmed by dose-dependent inhibitory signaling of D2R as a potential consequence of targeting dopaminergic neurons, reaction with surface-exposed FLAG epitope-tagged D2R, and blocking of Ab reactivity by an extracellular D2R peptide. IgG from SC and a related subset of streptococcal-associated behavioral disorders called " pediatric autoimmune neuropsychiatric disorder associated with streptococci "(PANDAS) with small choreiform movements reacted in ELISA with D2R. Reaction with FLAG-tagged D2R distinguished SC from PANDAS, whereas sera from both SC and PANDAS induced inhibitory signaling of D2R on transfected cells comparably to dopamine. In this study, we define a mechanism by which the brain may be altered by Ab in movement and behavioral disorders. C1 [Cox, Carol J.; Zuccolo, Jonathan; Zuccolo, Amir; Cunningham, Madeleine W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Biomed Res Ctr, Oklahoma City, OK 73104 USA. [Sharma, Meenakshi; Kovoor, Abraham] Univ Rhode Isl, Dept Biomed & Pharmacol Sci, Coll Pharm, Kingston, RI 02881 USA. [Leckman, James F.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06519 USA. [Leckman, James F.; Swedo, Susan E.] Yale Univ, Dept Pediat, Sch Med, New Haven, CT 06519 USA. [Leckman, James F.] Yale Univ, Dept Psychiat, Sch Med, New Haven, CT 06519 USA. [Swedo, Susan E.] NIMH, Pediat & Dev Neurosci Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Cunningham, MW (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Biomed Res Ctr, Room 217,975 NE 10th St, Oklahoma City, OK 73104 USA. EM madeleine-cunningham@ouhsc.edu FU National Heart, Lung, and Blood Institute [HL35280, HL56267]; National Institute of Mental Health; Oklahoma Center for Advancement of Science and Technology FX This work was supported by Grants HL35280 and HL56267 from the National Heart, Lung, and Blood Institute, a supplement from the National Institute of Mental Health, and a grant from the Oklahoma Center for Advancement of Science and Technology. M.W.C. is the recipient of a National Institutes of Health Merit Award. J.F.L. receives grant support from Grifols and the National Institutes of Mental Health Intramural program for a randomized clinical trial of i.v. Ig treatment for children with pediatric autoimmune neuropsychiatric disorder associated with streptococci being conducted at the National Institutes of Health Clinical Center under the leadership of S.E.S NR 81 TC 26 Z9 26 U1 9 U2 14 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 DEC 1 PY 2013 VL 191 IS 11 BP 5524 EP 5541 DI 10.4049/jimmunol.1102592 PG 18 WC Immunology SC Immunology GA 254QO UT WOS:000327180600020 PM 24184556 ER PT J AU Wu, LT Blazer, DG Gersing, KR Burchett, B Swartz, MS Mannelli, P AF Wu, Li-Tzy Blazer, Dan G. Gersing, Kenneth R. Burchett, Bruce Swartz, Marvin S. Mannelli, Paolo CA NIDA AAPI Workgrp TI Comorbid substance use disorders with other Axis I and II mental disorders among treatment-seeking Asian Americans, Native Hawaiians/Pacific Islanders, and mixed-race people SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Asian Americans; Comorbidity; Mixed-race; Native Hawaiians; Pacific islanders; Substance use disorder ID NATIONAL EPIDEMIOLOGIC SURVEY; UNITED-STATES; DRUG-USE; PERSONALITY-DISORDERS; PSYCHIATRIC-DISORDERS; LIFETIME PREVALENCE; ETHNIC-DIFFERENCES; SURVEY REPLICATION; HEALTH-SERVICES; ALCOHOL AB Little is known about behavioral healthcare needs of Asian Americans (AAs), Native Hawaiians/Pacific Islanders (NHs/PIs), and mixed-race people (MRs) the fastest growing segments of the U.S. population. We examined substance use disorder (SUD) prevalences and comorbidities among AAs, NHs/PIs, and MRs (N = 4572) in a behavioral health electronic health record database. DSM-IV diagnoses among patients aged 1-90 years who accessed behavioral healthcare from 11 sites were systematically captured: SUD, anxiety, mood, personality, adjustment, childhood-onset, cognitive/dementia, dissociative, eating, factitious, impulse-control, psychotic/schizophrenic, sleep, and somatoform diagnoses. Of all patients, 15.0% had a SUD. Mood (60%), anxiety (312%), adjustment (30.9%), and disruptive (attention deficit-hyperactivity, conduct, oppositional defiant, disruptive behavior diagnosis, 22.7%) diagnoses were more common than others (psychotic 14.2%, personality 133%, other childhood-onset 11.4%, impulse-control 6.6%, cognitive 2.8%, eating 2.2%, iomatoform 2.1%). Less than 1% of children aged <12 years had SUD. Cannabis diagnosis was the primary SUD affecting adolescents aged 12-17. MRs aged 35-49 years had the highest prevalence of cocaine diagnosis. Controlling for age at first visit, sex, treatment setting, length of treatment, and number of comorbid diagnoses, NHs/Pls and MRs were about two times more likely than AAs to have >= 2 SUDs. Regardless of race/ethnicity, personality diagnosis was comorbid with SUD. NHs/Pls with a mood diagnosis had elevated odds of having SUD. Findings present the most comprehensive patterns of mental diagnoses available for treatment-seeking AAs, NHs/Pls, and MRs in the real-world medical setting. In-depth research is needed to elucidate intraracial and interracial differences in treatment needs. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Wu, Li-Tzy; Blazer, Dan G.; Gersing, Kenneth R.; Burchett, Bruce; Swartz, Marvin S.; Mannelli, Paolo] Duke Univ, Sch Med, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [NIDA AAPI Workgrp] Natl Inst Drug Abuse Asian Amer & Pacific Islande, Bethesda, MD USA. RP Wu, LT (reprint author), Duke Univ, Sch Med, Med Ctr, Dept Psychiat & Behav Sci, Box 3903, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU U.S. National Institute on Drug Abuse; National Institute on Minority Health and Health Disparities of the National Institutes of Health [R01MD007658, HHSN271200900499P, R01DA019623, R01DA019901, R33DA027503]; Duke University Department of Psychiatry and Behavioral Sciences FX This work was made possible by research support from the U.S. National Institute on Drug Abuse and National Institute on Minority Health and Health Disparities of the National Institutes of Health (R01MD007658, HHSN271200900499P, R01DA019623, R01DA019901, R33DA027503 to Li-Tzy Wu) and by Duke University Department of Psychiatry and Behavioral Sciences. The sponsoring agency had no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors. NR 53 TC 11 Z9 11 U1 4 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD DEC PY 2013 VL 47 IS 12 BP 1940 EP 1948 DI 10.1016/j.jpsychires.2013.08.022 PG 9 WC Psychiatry SC Psychiatry GA 253ST UT WOS:000327110300015 PM 24060266 ER PT J AU Lau, MWL Ferre-D'Amare, AR AF Lau, Matthew W. L. Ferre-D'Amare, Adrian R. TI An in vitro evolved glmS ribozyme has the wild-type fold but loses coenzyme dependence SO NATURE CHEMICAL BIOLOGY LA English DT Article ID SELF-CLEAVING RIBOZYMES; ACTIVE-SITE GUANINE; ACID-BASE CATALYSIS; HAIRPIN RIBOZYME; HAMMERHEAD RIBOZYME; STRUCTURAL BASIS; SMALL MOLECULES; RNA; RIBOSWITCH; BINDING AB Uniquely among known ribozymes, the glmS ribozyme-riboswitch requires a small-molecule coenzyme, glucosamine-6-phosphate (GlcN6P). Although consistent with its gene-regulatory function, the use of GlcN6P is unexpected because all of the other characterized self-cleaving ribozymes use RNA functional groups or divalent cations for catalysis. To determine what active site features make this ribozyme reliant on GlcN6P and to evaluate whether it might have evolved from a coenzyme-independent ancestor, we isolated a GlcN6P-independent variant through in vitro selection. Three active site mutations suffice to generate a highly reactive RNA that adopts the wild-type fold but uses divalent cations for catalysis and is insensitive to GlcN6P. Biochemical and crystallographic comparisons of wild-type and mutant ribozymes show that a handful of functional groups fine-tune the RNA to be either coenzyme or cation dependent. These results indicate that a few mutations can confer new biochemical activities on structured RNAs. Thus, families of structurally related ribozymes with divergent function may exist. C1 [Lau, Matthew W. L.; Ferre-D'Amare, Adrian R.] NHLBI, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU Croucher Foundation; US National Heart, Lung and Blood Institute-National Institutes of Health FX We thank the staff at beamlines 5.0.1 and 5.0.2 of the Advanced Light Source and of 12-ID (BESSRC CAT) of the Advanced Photon Source for crystallographic and SAXS data collection support, respectively; X. Fang and Y.-X. Wang for access to SAXS beam-time; D.-Y. Lee and R. Levine for access to MS; J. Sellers for access to a rapid quench apparatus; N. Baird for performing analysis of SAXS data; K. Deigan, J. Posakony and J. Zhang for discussions; and an anonymous referee for motivating the phosphorothioate interference analysis of glmSAAG and glmSUAG. M. W. L. L. was a recipient of the Croucher Foundation Fellowship. This work was supported in part by the intramural program of the US National Heart, Lung and Blood Institute-National Institutes of Health. NR 60 TC 11 Z9 11 U1 0 U2 15 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 DEC PY 2013 VL 9 IS 12 BP 805 EP + DI 10.1038/NCHEMBIO.1360 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 253ZR UT WOS:000327130000012 PM 24096303 ER PT J AU Jelicic, K Cimbro, R Nawaz, F Huang, DW Zheng, X Yang, J Lempicki, RA Pascuccio, M Van Ryk, D Schwing, C Hiatt, J Okwara, N Wei, DL Roby, G David, A Hwang, IY Kehrl, JH Arthos, J Cicala, C Fauci, AS AF Jelicic, Katija Cimbro, Raffaello Nawaz, Fatima Huang, Da Wei Zheng, Xin Yang, Jun Lempicki, Richard A. Pascuccio, Massimiliano Van Ryk, Donald Schwing, Catherine Hiatt, Joseph Okwara, Noreen Wei, Danlan Roby, Gregg David, Antonio Hwang, Il Young Kehrl, John H. Arthos, James Cicala, Claudia Fauci, Anthony S. TI The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-beta 1 production and FcRL4 expression SO NATURE IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; VIRUS TYPE-1 INFECTION; INTEGRIN ALPHA(4)BETA(7); HUMORAL IMMUNITY; DENDRITIC CELLS; IGA PRODUCTION; T-CELLS; RESPONSES; TISSUE; INDIVIDUALS AB The humoral immune response after acute infection with HIV-1 is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through integrin alpha(4)beta(7) on T cells. We found that gp120 also bound to and signaled through alpha(4)beta(7) on naive B cells, which resulted in an abortive proliferative response. In primary B cells, signaling by gp120 through alpha(4)beta(7) resulted in increased expression of the immunosuppressive cytokine TGF-beta 1 and FcRL4, an inhibitory receptor expressed on B cells. Coculture of B cells with HIV-1-infected autologous CD4(+) T cells also increased the expression of FcRL4 by B cells. Our findings indicated that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV-1-associated B cell dysfunction. Our studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response. C1 [Jelicic, Katija; Cimbro, Raffaello; Nawaz, Fatima; Pascuccio, Massimiliano; Van Ryk, Donald; Schwing, Catherine; Hiatt, Joseph; Okwara, Noreen; Wei, Danlan; Roby, Gregg; Hwang, Il Young; Kehrl, John H.; Arthos, James; Cicala, Claudia; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Cimbro, Raffaello; Zheng, Xin; Yang, Jun; Lempicki, Richard A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Nawaz, Fatima] NYU, Sch Med, Sackler Inst Grad Biomed Sci, New York, NY USA. [Huang, Da Wei] Sci Applicat Int Corp, Lab Immunopathogenesis & Bioinformat, Frederick, MD USA. [David, Antonio] Univ Messina, Dept Internal Med, Fac Med, Messina, Italy. RP Cicala, C (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ccicala@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Hiatt, Joseph/0000-0002-8015-9614 FU Intramural Research Program of the US National Institutes of Health (National Institute of Allergy and Infectious Diseases) FX We thank C. Derdeyn for HIV sequence information; A. Introini for suggestions; and J. Weddle and A. Weddle for assistance with figure preparation. Supported by the Intramural Research Program of the US National Institutes of Health (National Institute of Allergy and Infectious Diseases). NR 59 TC 29 Z9 30 U1 3 U2 20 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 DEC PY 2013 VL 14 IS 12 BP 1256 EP + DI 10.1038/ni.2746 PG 12 WC Immunology SC Immunology GA 254FG UT WOS:000327149400011 PM 24162774 ER PT J AU Huang, L Goldsmith, J Reiss, PT Reich, DS Crainiceanu, CM AF Huang, Lei Goldsmith, Jeff Reiss, Philip T. Reich, Daniel S. Crainiceanu, Ciprian M. TI Bayesian scalar-on-image regression with application to association between intracranial DTI and cognitive outcomes SO NEUROIMAGE LA English DT Article DE Multiple sclerosis; Diffusion tensor imaging; Ising prior; Binary Markov random field ID GENERALIZED LINEAR-MODELS; MULTIPLE-SCLEROSIS; FMRI DATA; FRACTIONAL ANISOTROPY; VARIABLE SELECTION; WHITE-MATTER; MEAN DIFFUSIVITY; QUANTITATIVE MRI; CORPUS-CALLOSUM; TRACTOGRAPHY AB Diffusion tensor imaging (DTI) measures water diffusion within white matter, allowing for in vivo quantification of brain pathways. These pathways often subserve specific functions, and impairment of those functions is often associated with imaging abnormalities. As a method for predicting clinical disability from DTI images, we propose a hierarchical Bayesian "scalar-on-image" regression procedure. Our procedure introduces a latent binary map that estimates the locations of predictive voxels and penalizes the magnitude of effect sizes in these voxels, thereby resolving the ill-posed nature of the problem. By inducing a spatial prior structure, the procedure yields a sparse association map that also maintains spatial continuity of predictive regions. The method is demonstrated on a simulation study and on a study of association between fractional anisotropy and cognitive disability in a cross-sectional sample of 135 multiple sclerosis patients. (C) 2013 Elsevier Inc. All rights reserved. C1 [Huang, Lei; Reich, Daniel S.; Crainiceanu, Ciprian M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Goldsmith, Jeff] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Reiss, Philip T.] NYU, Sch Med, Dept Child & Adolescent Psychiat, New York, NY USA. [Reiss, Philip T.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Reich, Daniel S.] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD USA. [Reich, Daniel S.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. RP Huang, L (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. EM lehuang@jhsph.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Reiss, Philip/0000-0002-8491-7080 FU National Institute of Neurological Disorders and Stroke; National Institutes of Health FX This work was partially supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 56 TC 6 Z9 6 U1 1 U2 7 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 DEC PY 2013 VL 83 BP 210 EP 223 DI 10.1016/j.neuroimage.2013.06.020 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 251TN UT WOS:000326953700020 PM 23792220 ER PT J AU Nasr, S Devaney, KJ Tootell, RBH AF Nasr, Shahin Devaney, Kathryn J. Tootell, Roger B. H. TI Spatial encoding and underlying circuitry in scene-selective cortex SO NEUROIMAGE LA English DT Article ID PARAHIPPOCAMPAL PLACE AREA; SHORT-TERM-MEMORY; PARIETAL CORTEX; VISUAL-CORTEX; RETROSPLENIAL CORTEX; PERCEPTUAL DECISION; CORTICAL REGIONS; GLOBAL SIGNAL; OBJECT; NAVIGATION AB Three cortical areas (Retro-Splenial Cortex (RSC), Transverse Occipital Sulcus (TOS) and Parahippocampal Place Area (PPA)) respond selectively to scenes. However, their wider role in spatial encoding and their functional connectivity remain unclear. Using fMRI, first we tested the responses of these areas during spatial comparison tasks using dot targets on white noise. Activity increased during task performance in both RSC and TOS, but not in PPA. However, the amplitude of task-driven activity and behavioral measures of task demand were correlated only in RSC. A control experiment showed that none of these areas were activated during a comparable shape comparison task. Secondly, we analyzed functional connectivity of these areas during the resting state. Results revealed a significant connection between RSC and frontal association areas (known to be involved in perceptual decision-making). In contrast, TOS showed functional connections dorsally with the Inferior Parietal Sulcus, and ventrally with the Lateral Occipital Complex - but not with RSC and/or frontal association areas. Moreover, RSC and TOS showed differentiable functional connections with the anterior-medial and posterior-lateral parts of PPA, respectively. These results suggest two parallel pathways for spatial encoding, including RSC and TOS respectively. Only the RSC network was involved in active spatial comparisons. (C) 2013 Elsevier Inc. All rights reserved. C1 [Nasr, Shahin; Devaney, Kathryn J.; Tootell, Roger B. H.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Tootell, Roger B. H.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Nasr, S (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM shahin@ranr.mgh.harvard.edu FU National Institutes of Health (NIH) [R01 MH67529, R01 EY017081]; Martinos Center for Biomedical Imaging; NCRR; MIND Institute; NIMH Intramural Research Program FX We thank Drs. A. Afraz, R Rajimehr and M. Vaziri for review and suggestions on the manuscript This study was supported by National Institutes of Health (NIH Grants R01 MH67529 and R01 EY017081 to RBHT), the Martinos Center for Biomedical Imaging, the NCRR, the MIND Institute, and the NIMH Intramural Research Program. NR 61 TC 16 Z9 16 U1 1 U2 14 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 DEC PY 2013 VL 83 BP 892 EP 900 DI 10.1016/j.neuroimage.2013.07.030 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 251TN UT WOS:000326953700082 PM 23872156 ER PT J AU Raznahan, A Probst, F Palmert, MR Giedd, JN Lerch, JP AF Raznahan, Armin Probst, Frank Palmert, Mark R. Giedd, Jay N. Lerch, Jason P. TI High resolution whole brain imaging of anatomical variation in XO, XX, and XY mice SO NEUROIMAGE LA English DT Article DE Sex chromosomes; Aneuploidy; Sex differences; Brain development ID ORIGIN ALLELIC EXPRESSION; MUS-MUSCULUS L; TURNER-SYNDROME; MOUSE-BRAIN; COGNITIVE FUNCTION; SEX-DIFFERENCES; CHROMOSOME; GENE; MRI; TESTOSTERONE AB The capacity of sex to modify behavior in health and illness may stem from biological differences between males and females. One such difference - fundamental to the biological definition of sex - is inequality of X chromosome dosage. Studies of Turner Syndrome (TS) suggest that X-monosomy profoundly alters mammalian brain development. However, use of TS as a model for X chromosome haploinsufficiency is complicated by karyotypic mosaicism, background genetic heterogeneity and ovarian dysgenesis. Therefore, to better isolate X chromosome effects on brain development and identify how these overlap with normative sex differences, we used wholebrain structural imaging to study X-monosomic mice (free of mosaicism and ovarian dysgenesis) alongside their karyotypical normal male and female littermates. We demonstrate that murine X-monosomy (XO) causes (i) accentuation of XX vs XY differences in a set of sexually dimorphic structures including classical foci of sexhormone action, such as the bed nucleus of the stria terminal and medial amygdala, (ii) parietal and striatal abnormalities that recapitulate those reported TS, and (iii) abnormal development of brain systems relevant for domains of altered cognition and emotion in both murine and human X-monosomy. Our findings suggest an unexpected role frit X-linked genes in shaping sexually dimorphic brain development, and an evolutionarily conserved influence of X-linked genes on both cortical and subcortical development in mammals. Furthermore, our murine findings highlight the bed nucleus of the stria terminalis and periaqueductal gray matter as novel neuroanatomical candidates for closer study in TS. Integration of these data with existing genomic knowledge generates a set of novel, testable hypotheses regarding candidate mechanisms for each observed pattern of anatomical variation across XO,)0( and XY groups.. Published by Elsevier Inc. C1 [Raznahan, Armin; Giedd, Jay N.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Probst, Frank] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Palmert, Mark R.] Hosp Sick Children, Div Endocrinol, Toronto, ON M5G 1X8, Canada. [Palmert, Mark R.] Univ Toronto, Dept Pediat, Toronto, ON, Canada. [Palmert, Mark R.] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Lerch, Jason P.] Hosp Sick Children Hosp, Mouse Imaging Ctr, Toronto, ON, Canada. [Lerch, Jason P.] Hosp Sick Children Hosp, Program Neurosci & Mental, Toronto, ON, Canada. [Lerch, Jason P.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. RP Raznahan, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-2002-8978 FU National Institutes of Health; Institute of Health Research; Burroughs Wellcome Fund FX This study was funded through the National Institutes of Health, Institute of Health Research. FJP holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. We thank Monica J Justice for the use of laboratory space and reagents; and Christine Laliberte, Shoshana Spring and Dr. Miriam Friedel for their assistance with data acquisition and processing. NR 47 TC 12 Z9 12 U1 1 U2 10 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 DEC PY 2013 VL 83 BP 962 EP 968 DI 10.1016/j.neuroimage.2013.07.052 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 251TN UT WOS:000326953700088 PM 23891883 ER PT J AU Chen, M Carass, A Oh, J Nair, G Pham, DL Reich, DS Prince, JL AF Chen, Min Carass, Aaron Oh, Jiwon Nair, Govind Pham, Dzung L. Reich, Daniel S. Prince, Jerry L. TI Automatic magnetic resonance spinal cord segmentation with topology constraints for variable fields of view SO NEUROIMAGE LA English DT Article DE Atlas construction; Topology-preserving segmentation; Digital homeomorphism; Spinal cord segmentation; Magnetic resonance imaging ID GRADIENT VECTOR FLOW; MULTIPLE-SCLEROSIS; CT IMAGES; MR-IMAGES; SEMIAUTOMATIC SEGMENTATION; DISEASE PROGRESSION; ATROPHY; ARTIFACTS; DISABILITY; REGISTRATION AB Spinal cord segmentation is an important step in the analysis of neurological diseases such as multiple sclerosis. Several studies have shown correlations between disease progression and metrics relating to spinal cord atrophy and shape changes. Current practices primarily involve segmenting the spinal cord manually or semiautomatically, which can be inconsistent and time-consuming for large datasets. An automatic method that segments the spinal cord and cerebrospinal fluid from magnetic resonance images is presented. The method uses a deformable atlas and topology constraints to produce results that are robust to noise and artifacts. The method is designed to be easily extended to new data with different modalities, resolutions, and fields of view. Validation was performed on two distinct datasets. The first consists of magnetization transfer-prepared T2*-weighted gradient-echo MRI centered only on the cervical vertebrae (CI-CS). The second consists of TI-weighted MRI that covers both the cervical and portions of the thoracic vertebrae (C1-T4). Results were found to be highly accurate in comparison to manual segmentations. A pilot study was carried out to demonstrate the potential utility of this new method for research and clinical studies of multiple sclerosis. (C) 2013 Elsevier Inc. All rights reserved. C1 [Chen, Min; Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Oh, Jiwon; Reich, Daniel S.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Chen, Min; Nair, Govind; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. [Pham, Dzung L.] Ctr Neurosci & Regenerat Med, Image Proc Core, Bethesda, MD USA. RP Chen, M (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, 105 Barton Hall,3400 N Charles St, Baltimore, MD 21218 USA. EM mchen55@jhu.edu; aaron_carass@jhu.edu; jioh@jhsph.edu; govindnib@gmail.com; dzung.pham@nih.gov; reichds@ninds.nih.gov; prince@jhu.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Carass, Aaron/0000-0003-4939-5085 FU NIH/NINDS [R01-N5070906]; Intramural Research Program of NINDS; National MS Society (NMSS) FX Funding for this work was supported in part by NIH/NINDS grant R01-N5070906, the Intramural Research Program of NINDS, and the National MS Society (NMSS). NR 48 TC 21 Z9 21 U1 0 U2 7 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 DEC PY 2013 VL 83 BP 1051 EP 1062 DI 10.1016/j.neuroimage.2013.07.060 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 251TN UT WOS:000326953700097 PM 23927903 ER PT J AU Feligioni, M Mattson, M Nistico, R AF Feligioni, Marco Mattson, Mark P. Nistico, Robert TI SUMOylation in Neuroplasticity and Neurological Disorders SO NEUROMOLECULAR MEDICINE LA English DT Editorial Material C1 [Feligioni, Marco] European Brain Res Inst, Rome, Italy. [Mattson, Mark P.] NIA, Natl Inst Hlth, Intramural Res Program, Bethesda, MD 20892 USA. [Nistico, Robert] IRCSS Santa Lucia Fdn, Rome, Italy. [Nistico, Robert] Sapienza Univ Rome, Rome, Italy. RP Feligioni, M (reprint author), European Brain Res Inst, Rome, Italy. EM m.feligioni@ebri.it OI Nistico, Robert/0000-0003-3433-9232 NR 9 TC 0 Z9 0 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD DEC PY 2013 VL 15 IS 4 BP 637 EP 638 DI 10.1007/s12017-013-8267-5 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 250XV UT WOS:000326891000001 PM 24354012 ER PT J AU Lee, YJ Hallenbeck, JM AF Lee, Yang-ja Hallenbeck, John M. TI SUMO and Ischemic Tolerance SO NEUROMOLECULAR MEDICINE LA English DT Review DE SUMO; Ischemia; Hibernation; ULMs; miR-200; miR-182; Hypothermia ID ARCTIC GROUND-SQUIRRELS; FOCAL CEREBRAL-ISCHEMIA; UBIQUITIN-LIKE PROTEIN; SUMO2/3-CONJUGATED PROTEINS; MAMMALIAN HIBERNATION; MODIFIER CONJUGATION; NUCLEAR ACCUMULATION; GLUCOSE DEPRIVATION; IN-VITRO; SUMOYLATION AB Hibernating squirrels slow blood flow to a crawl, but sustain no damage to brain or other tissues. This phenomenon provides an excellent model of natural tolerance to ischemia. Small ubiquitin-like modifier (SUMO) is a 100-residue peptide that modifies other proteins by being attached to the epsilon amino group of specific lysine residues. The discovery of massive SUMOylation (by both SUMO-1 and SUMO-2/3) occurring in the brains of 13-lined ground squirrels (Ictidomys tridecemlineatus) during hibernation torpor had opened the door to the studies on SUMO and ischemic tolerance reviewed here. Ischemic stress was shown to increase the levels of SUMO conjugation, especially SUMO-2/3, mostly during reperfusion in animal models and during restoration of oxygen and glucose in cell culture systems. Over-expression or depletion of SUMOs and/or Ubc9 (the SUMO E2 conjugating enzyme) increases or decreases (respectively) the levels of SUMO conjugates. Elevated global SUMO conjugations were shown to cytoprotect from ischemic insults; conversely, depressed SUMOylation sensitized cells. Global protein conjugation not only by SUMOs, but also by other ubiquitin-like modifiers (ULMs) including NEDD8, ISG15, UFM1 and FUB1 was shown to be significantly increased in the brains of hibernating ground squirrels during torpor. These increases in multiple ULM conjugations may orchestrate the cellular events in hibernating ground squirrels that induce a state of natural tolerance through their multipronged effects. Certain miRNAs such as the miR-200 family and the miR-182 family were shown, at least partly, to control the levels of these ULM conjugations. Lowering the levels of these miRNAs leads to an increase in global SUMOylation/ULM conjugation, thereby providing the tolerance to ischemia. This suggests that these miRNAs may be good targets for therapeutic intervention in stroke. C1 [Lee, Yang-ja; Hallenbeck, John M.] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Lee, YJ (reprint author), NINDS, Stroke Branch, NIH, Bldg10,Rm5B06,MSC 1401,10 Ctr Dr, Bethesda, MD 20892 USA. EM wicknery@ninds.nih.gov FU Intramural Research Program of the NINDS/NIH FX This research was supported by the Intramural Research Program of the NINDS/NIH. The authors thank to all colleagues and collaborators involved in this work including Shinichi Miyake, Hideaki Wakita, David McMullen, Yongshan Mou, Paola Castri, Dace Klimanis, Joliet Bembry, Dragan Maric, Kory Johnson, Sungyoung Auh, Yoshiaki Azuma, and Mary Dasso. NR 72 TC 12 Z9 13 U1 2 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD DEC PY 2013 VL 15 IS 4 BP 771 EP 781 DI 10.1007/s12017-013-8239-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 250XV UT WOS:000326891000010 PM 23775726 ER PT J AU Murphy, E Hou, LP Maher, BS Woldehawariat, G Kassem, L Akula, N Laje, G McMahon, FJ AF Murphy, Eleanor Hou, Liping Maher, Brion S. Woldehawariat, Girma Kassem, Layla Akula, Nirmala Laje, Gonzalo McMahon, Francis J. TI Race, Genetic Ancestry and Response to Antidepressant Treatment for Major Depression SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Pharmacology; Genetics; Ethnicity; African Americans; SSRI ID STAR-ASTERISK-D; CITALOPRAM TREATMENT; TREATMENT OUTCOMES; AFRICAN-AMERICANS; ASSOCIATION; POPULATION; ANXIETY; BLACK; TRIAL; PHARMACOGENETICS AB The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study revealed poorer antidepressant treatment response among black compared with white participants. This racial disparity persisted even after socioeconomic and baseline clinical factors were taken into account. Some studies have suggested genetic contributions to this disparity, but none have attempted to disentangle race and genetic ancestry. Here we used genome-wide single-nucleotide polymorphism (SNP) data to examine independent contributions of race and genetic ancestry to citalopram response. Secondary data analyses included 1877 STAR*D participants who completed an average of 10 weeks of citalopram treatment and provided DNA samples. Participants reported their race as White (n = 1464), black (n = 299) or other/mixed (n = 114). Genetic ancestry was estimated by multidimensional scaling (MDS) analyses of about 500 000 SNPs. Ancestry proportions were estimated by STRUCTURE. Structural equation modeling was used to examine the direct and indirect effects of observed and latent predictors of response, defined as change in the Quick Inventory of Depressive Symptomatology (QIDS) score from baseline to exit. Socioeconomic and baseline clinical factors, race, and anxiety significantly predicted response, as previously reported. However, direct effects of race disappeared in all models that included genetic ancestry. Genetic African ancestry predicted lower treatment response in all models. Although socioeconomic and baseline clinical factors drive racial differences in antidepressant response, genetic ancestry, rather than self-reported race, explains a significant fraction of the residual differences. Larger samples would be needed to identify the specific genetic mechanisms that may be involved, but these findings underscore the importance of including more African-American patients in drug trials. C1 [Murphy, Eleanor; Hou, Liping; Woldehawariat, Girma; Kassem, Layla; Akula, Nirmala; Laje, Gonzalo; McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Maher, Brion S.] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. RP Murphy, E (reprint author), NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept HHS, 35 Convent Dr,Bldg 35,Porter Bldg,RM 1A-209, Bethesda, MD 20892 USA. EM eleanor.murphy@nih.gov RI Laje, Gonzalo/L-2654-2014; Hou, Liping/G-1648-2011; OI Laje, Gonzalo/0000-0003-2763-3329; Hou, Liping/0000-0003-3972-245X; McMahon, Francis/0000-0002-9469-305X FU NIMH [MH-072802] FX STAR*D genotyping was supported by NIMH grant MH-072802 to the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco (Steven P Hamilton, principal investigator), whom we thank for making their genotyping data available through the NIMH Center for Genomic Studies of Mental Disorders (www.nimhgenetics.org). The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study is registered at www.clinicaltrials.gov with identifier number NCT00021528. NR 44 TC 9 Z9 9 U1 0 U2 13 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 DEC PY 2013 VL 38 IS 13 BP 2598 EP 2606 DI 10.1038/npp.2013.166 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 251VD UT WOS:000326958100005 PM 23827886 ER PT J AU Chefer, VI Backman, CM Gigante, ED Shippenberg, TS AF Chefer, Vladimir I. Baeckman, Cristina M. Gigante, Eduardo D. Shippenberg, Toni S. TI Kappa Opioid Receptors on Dopaminergic Neurons Are Necessary for Kappa-Mediated Place Aversion SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Kappa-opioid receptor; conditioned place aversion; dopamine ID NUCLEUS-ACCUMBENS SHELL; VENTRAL TEGMENTAL AREA; SELECTIVE DELETION; SALVINORIN-A; ACTIVATION; COCAINE; MICE; INHIBITION; PREFERENCE; SYSTEMS AB Kappa-opioid receptor (KOR) agonists have dysphoric properties in humans and are aversive in rodents. This has been attributed to the activation of KORs within the mesolimbic dopamine (DA) system. However, the role of DA in KOR-mediated aversion and stress remains divisive as recent studies have suggested that activation of KORs on serotonergic neurons may be sufficient to mediate aversive behaviors. To address this question, we used conditional knock-out (KO) mice with KORs deleted on DA neurons (DAT(Cre/wt)/KORloxp/loxp, or DATCre-KOR KO). In agreement with previous findings, control mice (DAT(Cre/wt)/KORwt/wt or WT) showed conditioned place aversion (CPA) to the systemically administered KOR agonist U69,593. In contrast, DATCre-KOR KO mice did not exhibit CPA with this same agonist. In addition, in vivo microdialysis showed that systemic U69,593 decreased overflow of DA in the nucleus accumbens (NAc) in WT mice, but had no effect in DATCre-KOR KO mice. Intra- ventral tegmental area (VTA) delivery of KORs using an adeno-associated viral gene construct, resulted in phenotypic rescue of the KOR-mediated NAc DA response and aversive behavior in DATCre-KOR KO animals. These results provide evidence that KORs on VTA DA neurons are necessary to mediate KOR-mediated aversive behavior. Therefore, our data, along with recent findings, suggest that the neuronal mechanisms of KOR-mediated aversive behavior may include both dopaminergic and serotonergic components. C1 [Chefer, Vladimir I.; Baeckman, Cristina M.; Gigante, Eduardo D.; Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, Integrat Neurosci Branch, Baltimore, MD 21221 USA. RP Chefer, VI (reprint author), NIDA, Behav Neurosci Sect, IRP, 251 Bayview Blvd,RM 8A721, Baltimore, MD 21221 USA. EM vchefer@intra.nida.nih.gov FU National Institute on Drug Abuse Intramural Research Program FX This work was supported by the National Institute on Drug Abuse Intramural Research Program. We thank Dr Carl Lupica for his helpful editorial comments and suggestions; and Dr Jennifer Whistler for providing KORloxp mice. NR 41 TC 26 Z9 26 U1 0 U2 4 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 DEC PY 2013 VL 38 IS 13 BP 2623 EP 2631 DI 10.1038/npp.2013.171 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 251VD UT WOS:000326958100008 PM 23921954 ER PT J AU Brady, LS Herkenham, M AF Brady, Linda S. Herkenham, Miles TI Candace B Pert Obituary SO NEUROPSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 [Brady, Linda S.] NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. [Herkenham, Miles] NIMH, Funct Neuroanat Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Brady, LS (reprint author), NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. EM lbrady@mail.nih.gov; herkenh@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 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 DEC PY 2013 VL 38 IS 13 BP 2730 EP 2730 DI 10.1038/npp.2013.269 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 251VD UT WOS:000326958100021 ER PT J AU Barrett, JE Bergman, J Katz, JL Morse, WH AF Barrett, James E. Bergman, Jack Katz, Jonathan L. Morse, W. H. TI Peter B Dews Obituary SO NEUROPSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 [Barrett, James E.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Bergman, Jack; Morse, W. H.] Harvard Univ, Sch Med, Boston, MA USA. [Katz, Jonathan L.] NIDA, Baltimore, MD USA. RP Barrett, JE (reprint author), Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. EM james.barrett@drexelmed.edu NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 IS 13 BP 2733 EP 2733 DI 10.1038/npp.2013.276 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 251VD UT WOS:000326958100023 ER PT J AU Persoskie, A Nelson, WL AF Persoskie, Alexander Nelson, Wendy L. TI Just Blowing Smoke? Social Desirability and Reporting of Intentions to Quit Smoking SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SENSITIVE QUESTIONS; DATA-COLLECTION; CESSATION; MODE; CONSUMPTION; NONRESPONSE; VALIDITY; ADULTS; HEALTH; SCORES AB Introduction: Do cigarette smokers really want to quit smoking or do they simply say they do in order to placate others and avoid criticism? In surveys of smokers, stated quit intentions and reports of quit attempts may be biased by social desirability concerns. This makes it difficult to interpret large-scale state and national surveys of smoking behavior that collect data through telephone and face-to-face interviews, methods that tend to evoke high levels of socially desirable responding. Methods: The 2007 Health Information National Trends Survey used a dual-frame design to query smokers' quit intentions and past quit attempts in 1 of 2 ways: A self-administered mail survey (low pressure for socially desirable responding; n = 563), or an interviewer-administered telephone survey (high pressure for socially desirable responding; n = 499). Estimates derived from the 2 formats were compared to test for social desirability effects. Results: In both survey modes, approximately two thirds of smokers reported seriously considering quitting in the next 6 months (mail: 64.9%; telephone: 68.9%), and approximately half reported making a quit attempt in the past year (mail: 54.9%; telephone: 52.3%). Neither difference approached significance in logistic regressions controlling for demographics (ps > .24). Conclusions: It appears that a large proportion of smokers in the United States aspire to live smoke-free lives and are not simply responding in a socially desirable manner to deflect criticism in an antismoking social climate. Future research should (1) replicate this study with greater statistical power, (2) examine the possible effects of survey context (e. g., health survey vs. smoking pleasure survey), and (3) explore survey mode effects in specific subpopulations. C1 [Persoskie, Alexander; Nelson, Wendy L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Persoskie, A (reprint author), NCI, Basic Biobehav & Psychol Sci Branch, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM persoskieai@mail.nih.gov NR 32 TC 6 Z9 6 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD DEC PY 2013 VL 15 IS 12 BP 2088 EP 2093 DI 10.1093/ntr/ntt101 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 252BD UT WOS:000326978400017 PM 23884318 ER PT J AU Siberry, GK Abzug, MJ Nachman, S AF Siberry, George K. Abzug, Mark J. Nachman, Sharon CA Panel Prevention Treatment Opportu TI Executive Summary: 2013 Update of the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-exposed and HIV-infected Children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; RECONSTITUTION INFLAMMATORY SYNDROME; UNITED-STATES; HAART ERA; VIRUS; INFANTS; TUBERCULOSIS; TRANSMISSION; ADOLESCENTS; MORTALITY C1 [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD 20892 USA. [Abzug, Mark J.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Abzug, Mark J.] Childrens Hosp Colorado, Aurora, CO USA. [Nachman, Sharon] Stony Brook Long Isl Childrens Hosp, Dept Pediat, Stony Brook, NY USA. RP Siberry, GK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Execut,Blvd,Off 4B11H, Bethesda, MD 20892 USA. EM siber-ryg@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 17 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2013 VL 32 IS 12 BP 1303 EP 1307 DI 10.1097/INF.0000000000000080 PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 254UH UT WOS:000327192800012 PM 24569304 ER PT J AU D'Angio, CT Murray, TE Li, L Heyne, RJ O'Shea, TM Schelonka, RL Shankaran, S Duara, S Goldberg, RN Stoll, BJ Stevenson, DK Vohr, BR Phelps, DL Carlo, WA Pichichero, ME Das, A Higgins, RD AF D'Angio, Carl T. Murray, Theresa E. Li, Lei Heyne, Roy J. O'Shea, T. Michael Schelonka, Robert L. Shankaran, Seetha Duara, Shahnaz Goldberg, Ronald N. Stoll, Barbara J. Stevenson, David K. Vohr, Betty R. Phelps, Dale L. Carlo, Waldemar A. Pichichero, Michael E. Das, Abhik Higgins, Rosemary D. CA NICHD Neonatal Res Network TI Immunogenicity of Haemophilus influenzae Type b Protein Conjugate Vaccines in Very Low Birth Weight Infants SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Letter ID PREMATURE C1 [D'Angio, Carl T.; Phelps, Dale L.] Univ Rochester, Sch Med & Dent, Dept Pediat, Rochester, NY 14642 USA. [Murray, Theresa E.] Spotsylvania Reg Med Ctr, Fredericksburg, VA USA. [Li, Lei] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Heyne, Roy J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [O'Shea, T. Michael] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Schelonka, Robert L.] Oregon Hlth & Sci Univ, Div Neonatol, Portland, OR USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Duara, Shahnaz] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Childrens Healthcare Atlanta, Atlanta, GA USA. [Stevenson, David K.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med,Lucile Packard Childrens H, Palo Alto, CA 94304 USA. [Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Pichichero, Michael E.] Rochester Gen Hosp, Rochester, NY 14621 USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci 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, Dept Pediat, Rochester, NY 14642 USA. FU NCRR NIH HHS [M01 RR007122, M01 RR016587, M01 RR16587, M01 RR30, M01 RR32, M01 RR39, M01 RR44, M01 RR633, M01 RR70, M01 RR7122]; NICHD NIH HHS [U10 HD036790, U10 HD021385, U10 HD021397, U10 HD027851, U10 HD027880, U10 HD034216, U10 HD040492, U10 HD040498, U10 HD040521, U10 HD040689, U10 HD068263, U10 HD21397, U10 HD27851, U10 HD27880, U10 HD36790, U10 HD40492, U10 HD40689, U10HD21385, U10HD34216, U10HD40498, U10HD40521] NR 6 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2013 VL 32 IS 12 BP 1400 EP 1402 DI 10.1097/01.inf.0000437263.04493.7c PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 254UH UT WOS:000327192800035 PM 24569312 ER PT J AU Tabarani, CM Bonville, CA Suryadevara, M Branigan, P Wang, DL Huang, DN Rosenberg, HF Domachowske, JB AF Tabarani, Christy M. Bonville, Cynthia A. Suryadevara, Manika Branigan, Patrick Wang, Dongliang Huang, Danning Rosenberg, Helene F. Domachowske, Joseph B. TI Novel Inflammatory Markers, Clinical Risk Factors and Virus Type Associated With Severe Respiratory Syncytial Virus Infection SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE respiratory syncytial virus; innate immunity; illness severity; hepatocyte growth factor ID HEPATOCYTE GROWTH-FACTOR; DISEASE SEVERITY; GENE POLYMORPHISMS; TRACT INFECTION; BRONCHIOLITIS; CHILDREN; INFANTS; POPULATION; RECEPTOR; PROTEIN-1-ALPHA AB Background: Virus-induced inflammation contributes to respiratory syncytial virus (RSV) pathogenesis. We sought to determine the specific mediators that are associated with more severe illness in young children. Methods: Children 5 years of age seen in our emergency department for respiratory symptoms from September 1998 to May 2008 were eligible for enrollment. Nasopharyngeal wash samples were collected from all eligible patients, and clinical data were recorded. Individuals were included in this study if nasopharyngeal wash samples were positive for RSV only. Patients enrolled in the study were stratified by disease severity, defined as mild (not hospitalized), moderate (hospitalized) or severe (requiring intensive care unit stay). Concentrations of individual inflammatory biomarkers in nasopharyngeal wash fluids were determined using the Luminex human 30-plex assay. Results: Eight hundred fifty-one patients met study criteria: 268 (31.5%) with mild, 503 (59.1%) with moderate and 80 (9.4%) with severe illness. As expected, illness severity was directly associated with young age, prematurity, heart or lung disease, infection with RSV group A and elevated concentrations of interleukin (IL)-2R, IL-6, CXCL8, tumor necrosis factor-, interferon-, CCL3, CCL4 and CCL2. In addition, we report several novel and mechanistically important inflammatory biomarkers of severe RSV disease, including IL-1, IL1-RA, IL-7, epidermal growth factor and hepatocyte growth factor. Conclusions: In a large, longitudinal study (10 years, 851 enrolled patients) limited to RSV infection only, in which well-known risk factors are confirmed, we identified 5 novel biomarkers specifically of severe disease. These markers may ultimately serve to elucidate disease mechanisms. C1 [Tabarani, Christy M.; Bonville, Cynthia A.; Suryadevara, Manika; Domachowske, Joseph B.] Upstate Golisano Childrens Hosp, Dept Pediat, Syracuse, NY 13210 USA. [Branigan, Patrick] Centocor Inc, Infect Dis Res, Radnor, PA USA. [Wang, Dongliang; Huang, Danning] SUNY Upstate Med Univ, Dept Publ Hlth & Prevent Med, Syracuse, NY 13210 USA. [Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Domachowske, JB (reprint author), Upstate Golisano Childrens Hosp, 1 Childrens Circle, Syracuse, NY 13210 USA. EM domachoj@upstate.edu OI Branigan, Patrick/0000-0001-9741-9067 FU Children's Miracle Network of Central New York; National Institute of Allergy and Infectious Diseases, Division of Intramural Research [Z01-AI000943] FX Funded by the Children's Miracle Network of Central New York (to J.B.D.) and the National Institute of Allergy and Infectious Diseases, Division of Intramural Research (Z01-AI000943 to H. F. R.). P. B. is employed by the Infectious Disease Research Division at Centocor, Radnor, PA. The authors have no other funding or conflicts of interest to disclose. NR 42 TC 15 Z9 15 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2013 VL 32 IS 12 BP E437 EP E442 DI 10.1097/INF.0b013e3182a14407 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 254UH UT WOS:000327192800004 PM 23804121 ER PT J AU Johnson, EO Calogero, AE Konstandi, M Kamilaris, TC La Vignera, S Chrousos, GP AF Johnson, Elizabeth O. Calogero, Aldo E. Konstandi, Maria Kamilaris, Themis C. La Vignera, Sandro Chrousos, George P. TI Effects of experimentally induced hyperthyroidism on central hypothalamic-pituitary-adrenal axis function in rats: in vitro and in situ studies (vol 16, pg 275, 2013) SO PITUITARY LA English DT Correction C1 [Johnson, Elizabeth O.] Univ Athens, Sch Med, Dept Anat, GR-11527 Athens, Greece. [Calogero, Aldo E.] Univ Catania, Osped Garibaldi, Dept Biomed Sci, Sect Endocrinol Androl & Internal Med, Catania, Italy. [Konstandi, Maria] Univ Ioannina, Sch Med, Dept Pharmacol, GR-45110 Ioannina, Greece. [Kamilaris, Themis C.] NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. [La Vignera, Sandro] Univ Catania, Dept Internal Med & Syst Dis, Sect Endocrinol Androl & Internal Med, Catania, Italy. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Johnson, EO (reprint author), Univ Athens, Sch Med, Dept Anat, 75 Mikras Asias Str, GR-11527 Athens, Greece. EM elizabethojohnson@gmail.com NR 1 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X EI 1573-7403 J9 PITUITARY JI Pituitary PD DEC PY 2013 VL 16 IS 4 BP 554 EP 554 DI 10.1007/s11102-012-0458-9 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 250XZ UT WOS:000326891400017 ER PT J AU Haller, J Goldberg, SR Pelczer, KG Aliczki, M Panlilio, LV AF Haller, Jozsef Goldberg, Steven R. Pelczer, Katalin Gyimesine Aliczki, Mano Panlilio, Leigh V. TI The effects of anandamide signaling enhanced by the FAAH inhibitor URB597 on coping styles in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Behavior; Endocannabinoid; FAAH; URB597; Context; Coping; Rats ID ENDOCANNABINOID SYSTEM; PLASMA-CORTICOSTERONE; STRESS; ACID; BEHAVIOR; MEMORY; RESPONSES; DOPAMINE; ANXIETY; MODULATION AB Rationale Coping styles are fundamental characteristics of behavior that affect susceptibility to, and resilience during, mental and physical illness. Shifts from passive to active coping are considered therapeutic goals in many stress-related disorders, but the neural control of coping is poorly understood. Based on earlier findings, we hypothesized that coping styles are influenced by endocannabinoids. Here, we tested whether FAAH inhibition by URB597 affects behaviors aimed at controlling a critical situation and the degree to which environmental stimuli influence behavior i.e., we studied the impact of URB597 on the two main attributes of coping styles. Rats were tested in the tail-pinch test of coping and in the elevated plus-maze test that was performed under highly divergent conditions. Under the effects of URB597, rats focused their behavior more on the discomfort-inducing clamp in the tail-pinch test, i.e., they coped with the challenge more actively. In the elevated plus-maze, URB597-treated rats demonstrated an autonomous behavioral control by reducing both "wariness" induced by aversive conditions and "carelessness" resulting from favorable conditions. URB597 treatment-induced behavioral changes indicated a shift towards active coping with challenges. This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis. Albeit further studies are required to characterize the role of endocannabinoids in coping, these findings suggest that the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders characterized by passive coping (e.g., anxiety and depression) and in physical diseases where active coping is therapeutically desirable. C1 [Haller, Jozsef; Pelczer, Katalin Gyimesine; Aliczki, Mano] Inst Expt Med, Dept Behav Neurobiol, Budapest, Hungary. [Goldberg, Steven R.; Panlilio, Leigh V.] Natl Inst Drug Abuse, NIH, Biomed Res Ctr,Preclin Pharmacol Sect, Dept Hlth & Human Serv,Intramural Res Program, Baltimore, MD USA. RP Haller, J (reprint author), Inst Expt Med, Dept Behav Neurobiol, Budapest, Hungary. EM haller@koki.hu OI Haller, Jozsef/0000-0002-1953-3726 FU OTKA [K101645]; National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services FX This research was made possible by grants from OTKA (Hungarian Scientific Research Fund) grant no. K101645 to JH and was also supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services to SRG, and LVP. NR 41 TC 7 Z9 7 U1 0 U2 9 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 DEC PY 2013 VL 230 IS 3 BP 353 EP 362 DI 10.1007/s00213-013-3161-2 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 253MF UT WOS:000327090500003 PM 23743650 ER PT J AU Bjork, K Tronci, V Thorsell, A Tanda, G Hirth, N Heilig, M Hansson, AC Sommer, WH AF Bjork, Karl Tronci, Valeria Thorsell, Annika Tanda, Gianluigi Hirth, Natalie Heilig, Markus Hansson, Anita C. Sommer, Wolfgang H. TI beta-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol SO PSYCHOPHARMACOLOGY LA English DT Article DE Arrestin; Opioid; Dopamine; Alcohol; Reward; Nucleus accumbens ID OPIOID RECEPTOR GENE; NUCLEUS-ACCUMBENS; VENTRAL PALLIDUM; DEPENDENCE; BETA-ARRESTIN-2; POLYMORPHISM; ASSOCIATION; NALTREXONE; MORPHINE; COCAINE AB Rationale The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of beta-arrestin 2 (Arrb2), a crucial regulator of mu-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens. Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for mu-opioid receptor surface expression and signaling following an acute alcohol challenge. Alcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by mu-receptor binding and [S-35]GTP-gamma-S autoradiography. In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased mu-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice. Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including mu-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors. C1 [Bjork, Karl] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Tronci, Valeria; Tanda, Gianluigi] NIDA, Psychobiol Sect, NIH, Baltimore, MD USA. [Bjork, Karl; Thorsell, Annika; Heilig, Markus; Hansson, Anita C.; Sommer, Wolfgang H.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Thorsell, Annika] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Hirth, Natalie; Hansson, Anita C.; Sommer, Wolfgang H.] Heidelberg Univ, Inst Psychopharmacol, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany. [Bjork, Karl] L8 01 Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Sect Translat Neuropharmacol, S-17176 Stockholm, Sweden. RP Bjork, K (reprint author), L8 01 Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Sect Translat Neuropharmacol, S-17176 Stockholm, Sweden. EM karl.bjork@ki.se RI Tanda, Gianluigi/B-3318-2009; OI Tanda, Gianluigi/0000-0001-9526-9878; Heilig, Markus/0000-0003-2706-2482 FU Svenska Stiftelsen for Medicinsk Forskning; Deutsche Forschungsgemeinschaft (DFG) [HA 6102/1]; NIAAA; NIDA, National Institutes of Health, Department of Health and Human Services FX KB was supported by a grant from Svenska Stiftelsen for Medicinsk Forskning. NH and ACH were supported by a grant from the "Deutsche Forschungsgemeinschaft" (DFG, HA 6102/1). This report was also funded by the Intramural Research Programs of NIAAA and NIDA, National Institutes of Health, Department of Health and Human Services. NR 43 TC 6 Z9 6 U1 0 U2 3 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 DEC PY 2013 VL 230 IS 3 BP 439 EP 449 DI 10.1007/s00213-013-3166-x PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 253MF UT WOS:000327090500010 PM 23779257 ER PT J AU Hsu, ER Williams, DE DiJoseph, LG Schnell, JD Finstad, SL Lee, JSH Greenspan, EJ Corrigan, JG AF Hsu, Elizabeth R. Williams, Duane E. DiJoseph, Leo G. Schnell, Joshua D. Finstad, Samantha L. Lee, Jerry S. H. Greenspan, Emily J. Corrigan, James G. TI Piloting an approach to rapid and automated assessment of a new research initiative: Application to the National Cancer Institute's Provocative Questions initiative SO RESEARCH EVALUATION LA English DT Article ID TECHNOLOGY; NOVELTY AB Funders of biomedical research are often challenged to understand how a new funding initiative fits within the agency's portfolio and the larger research community. While traditional assessment relies on retrospective review by subject matter experts, it is now feasible to design portfolio assessment and gap analysis tools leveraging administrative and grant application data that can be used for early and continued analysis. We piloted such methods on the National Cancer Institute's Provocative Questions (PQ) initiative to address key questions regarding diversity of applicants; whether applicants were proposing new avenues of research; and whether grant applications were filling portfolio gaps. For the latter two questions, we defined measurements called focus shift and relevance, respectively, based on text similarity scoring. We demonstrate that two types of applicants were attracted by the PQs at rates greater than or on par with the general National Cancer Institute applicant pool: those with clinical degrees and new investigators. Focus shift scores tended to be relatively low, with applicants not straying far from previous research, but the majority of applications were found to be relevant to the PQ the application was addressing. Sensitivity to comparison text and inability to distinguish subtle scientific nuances are the primary limitations of our automated approaches based on text similarity, potentially biasing relevance and focus shift measurements. We also discuss potential uses of the relevance and focus shift measures including the design of outcome evaluations, though further experimentation and refinement are needed for a fuller understanding of these measures before broad application. C1 [Hsu, Elizabeth R.; Finstad, Samantha L.; Corrigan, James G.] NCI, Off Sci Planning & Assessment, Bethesda, MD 20892 USA. [Williams, Duane E.; DiJoseph, Leo G.; Schnell, Joshua D.] Thomson Reuters, Rockville, MD 20850 USA. [Lee, Jerry S. H.; Greenspan, Emily J.] NCI, Ctr Strateg Sci Initiat, Bethesda, MD 20892 USA. RP Hsu, ER (reprint author), NCI, Off Sci Planning & Assessment, Bethesda, MD 20892 USA. EM hsuel@mail.nih.gov RI Lee, Jerry/K-4553-2014; Schnell, Joshua/J-4000-2012; OI Schnell, Joshua/0000-0001-9241-7441; Finstad, Samantha/0000-0002-3460-6428 NR 24 TC 0 Z9 0 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0958-2029 EI 1471-5449 J9 RES EVALUAT JI Res. Evaluat. PD DEC PY 2013 VL 22 IS 5 BP 272 EP 284 DI 10.1093/reseval/rvt024 PG 13 WC Information Science & Library Science SC Information Science & Library Science GA 250UT UT WOS:000326882300002 ER PT J AU Basner, JE Theisz, KI Jensen, US Jones, CD Ponomarev, I Sulima, P Jo, K Eljanne, M Espey, MG Franca-Koh, J Hanlon, SE Kuhn, NZ Nagahara, LA Schnell, JD Moore, NM AF Basner, Jodi E. Theisz, Katrina I. Jensen, Unni S. Jones, C. David Ponomarev, Ilya Sulima, Pawel Jo, Karen Eljanne, Mariam Espey, Michael G. Franca-Koh, Jonathan Hanlon, Sean E. Kuhn, Nastaran Z. Nagahara, Larry A. Schnell, Joshua D. Moore, Nicole M. TI Measuring the evolution and output of cross-disciplinary collaborations within the NCI Physical Sciences-Oncology Centers Network SO RESEARCH EVALUATION LA English DT Article ID TEAM SCIENCE; TRANSDISCIPLINARY RESEARCH; SCIENTIFIC COLLABORATION; INTERDISCIPLINARY; INTEGRATION AB Development of effective quantitative indicators and methodologies to assess the outcomes of cross-disciplinary collaborative initiatives has the potential to improve scientific program management and scientific output. This article highlights an example of a prospective evaluation that has been developed to monitor and improve progress of the National Cancer Institute Physical Sciences-Oncology Centers (PS-OC) program. Study data, including collaboration information, was captured through progress reports and compiled using the web-based analytic database: Interdisciplinary Team Reporting, Analysis, and Query Resource. Analysis of collaborations was further supported by data from the Thomson Reuters Web of Science database, MEDLINE database, and a web-based survey. Integration of novel and standard data sources was augmented by the development of automated methods to mine investigator pre-award publications, assign investigator disciplines, and distinguish cross-disciplinary publication content. The results highlight increases in cross-disciplinary authorship collaborations from pre- to post-award years among the primary investigators and confirm that a majority of cross-disciplinary collaborations have resulted in publications with cross-disciplinary content that rank in the top third of their field. With these evaluation data, PS-OC Program officials have provided ongoing feedback to participating investigators to improve center productivity and thereby facilitate a more successful initiative. Future analysis will continue to expand these methods and metrics to adapt to new advances in research evaluation and changes in the program. C1 [Theisz, Katrina I.] Kelly Govt Solut, Rockville, MD 20852 USA. [Theisz, Katrina I.; Jo, Karen; Eljanne, Mariam; Espey, Michael G.; Franca-Koh, Jonathan; Hanlon, Sean E.; Kuhn, Nastaran Z.; Nagahara, Larry A.; Moore, Nicole M.] NCI, Off Phys Sci Oncol, Ctr Strateg Sci Initiat, Off Director, Bethesda, MD 20892 USA. RP Moore, NM (reprint author), NCI, Off Phys Sci Oncol, Ctr Strateg Sci Initiat, Off Director, Bethesda, MD 20892 USA. EM nicole.moore@nih.gov RI Ponomarev, Ilya/F-5183-2010; Schnell, Joshua/J-4000-2012 OI Ponomarev, Ilya/0000-0002-8584-6034; Schnell, Joshua/0000-0001-9241-7441 NR 19 TC 6 Z9 6 U1 7 U2 39 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0958-2029 EI 1471-5449 J9 RES EVALUAT JI Res. Evaluat. PD DEC PY 2013 VL 22 IS 5 BP 285 EP 297 DI 10.1093/reseval/rvt025 PG 13 WC Information Science & Library Science SC Information Science & Library Science GA 250UT UT WOS:000326882300003 ER PT J AU Terracciano, A Piras, MG Lobina, M Mulas, A Meirelles, O Sutin, AR Chan, W Sanna, S Uda, M Crisponi, L Schlessinger, D AF Terracciano, Antonio Piras, Maria Grazia Lobina, Monia Mulas, Antonella Meirelles, Osorio Sutin, Angelina R. Chan, Wayne Sanna, Serena Uda, Manuela Crisponi, Laura Schlessinger, David TI Genetics of serum BDNF: Meta-analysis of the Val66Met and genome-wide association study SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE Brain-derived neurotrophic factor ( BDNF); serum; Val66Met; NTRK3; GWAS ID MILD COGNITIVE IMPAIRMENT; NEUROTROPHIC FACTOR; MAJOR DEPRESSION; PERSONALITY-TRAITS; MOOD DISORDERS; POLYMORPHISM; VARIANTS; NTRK3; PROGRESSION; NEUROTICISM AB Objectives. Lower levels of serum brain derived neurotrophic factor (BDNF) is one of the best known biomarkers of depression. To identify genetic variants associated with serum BDNF, we tested the Val66Met (rs6265) functional variant and conducted a genome-wide association scan (GWAS). Methods. In a community-based sample (N = 2054; aged 19-101, M = 51, SD = 15) from Sardinia, Italy, we measured serum BDNF concentration and conducted a GWAS. Results. We estimated the heritability of serum BDNF to be 0.48 from sib-pairs. There was no association between serum BDNF and Val66Met in the SardiNIA sample and in a meta-analysis of published studies (k = 13 studies, total n = 4727, P = 0.92). Although no genome-wide significant associations were identified, some evidence of association was found in the BDNF gene (rs11030102, P = 0.001) and at two loci (rs7170215, P = 4.8 x 10 (5) and rs11073742 P = 1.2 x 10 (5)) near and within NTRK3 gene, a neurotrophic tyrosine kinase receptor. Conclusions. Our study and meta-analysis of the literature indicate that the BDNF Val66Met variant is not associated with serum BDNF, but other variants in the BDNF and NTRK3 genes might regulate the level of serum BDNF. C1 [Terracciano, Antonio; Meirelles, Osorio; Sutin, Angelina R.; Chan, Wayne; Schlessinger, David] NIA, NIH, DHHS, Baltimore, MD 21224 USA. [Piras, Maria Grazia; Lobina, Monia; Mulas, Antonella; Sanna, Serena; Uda, Manuela; Crisponi, Laura] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. RP Terracciano, A (reprint author), NIA, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM terraccianoa@mail.nih.gov OI Mulas, Antonella/0000-0002-6856-1483; piras, maria grazia/0000-0001-9004-0900; Lobina, Monia/0000-0003-3620-3160; Chan, Wayne/0000-0001-5061-1713; sanna, serena/0000-0002-3768-1749 FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 49 TC 19 Z9 20 U1 1 U2 13 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD DEC PY 2013 VL 14 IS 8 BP 583 EP 589 DI 10.3109/15622975.2011.616533 PG 7 WC Psychiatry SC Psychiatry GA 256JT UT WOS:000327307100005 PM 22047184 ER PT J AU Bigdeli, TB Maher, BS Zhao, ZM Sun, JC Medeiros, H Akula, N McMahon, FJ Carvalho, C Ferreira, SR Azevedo, MH Knowles, JA Pato, MT Pato, CN Fanous, AH AF Bigdeli, T. Bernard Maher, Brion S. Zhao, Zhongming Sun, Jingchun Medeiros, Helena Akula, Nirmala McMahon, Francis J. Carvalho, Celia Ferreira, Susana R. Azevedo, Maria H. Knowles, James A. Pato, Michele T. Pato, Carlos N. Fanous, Ayman H. TI Association Study of 83 Candidate Genes for Bipolar Disorder in Chromosome 6q Selected Using an Evidence-Based Prioritization Algorithm SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE bipolar disorder; 6q; genetic association; gene-based association ID LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY LOCUS; SCHIZOPHRENIA; POPULATION; PEDIGREES; GENETICS; SCAN; HETEROGENEITY; METAANALYSIS; FAMILIES AB BackgroundPrior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. MethodsWe analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N=1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. ResultsNo single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. ConclusionsUsing a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA C1 [Bigdeli, T. Bernard; Fanous, Ayman H.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Maher, Brion S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Zhao, Zhongming; Sun, Jingchun] Vanderbilt Univ, Med Ctr, Dept Psychiat, Vanderbilt, TN USA. [Zhao, Zhongming; Sun, Jingchun] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Vanderbilt, TN USA. [Zhao, Zhongming; Sun, Jingchun] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Vanderbilt, TN USA. [Medeiros, Helena; Knowles, James A.; Pato, Michele T.; Pato, Carlos N.; Fanous, Ayman H.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [Akula, Nirmala; McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Carvalho, Celia] Univ Azores, Dept Sci Educ, Azores, Portugal. [Ferreira, Susana R.] Dept Psychiat, Sao Miguel, Azores, Portugal. [Azevedo, Maria H.] Univ Coimbra, Dept Psychiat, Coimbra, Portugal. [Fanous, Ayman H.] Washington VA Med Ctr, Mental Hlth Serv Line, Washington, DC USA. [Fanous, Ayman H.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. RP Fanous, AH (reprint author), VA Med Ctr, Psychiat Genet Res Program, 50 Irving St NW, Washington, DC 20422 USA. EM ayman.fanous@va.gov OI de Oliveira Barreto Coimbra Carvalho, Celia Maria/0000-0003-4453-8139; McMahon, Francis/0000-0002-9469-305X FU Department of Veterans Affairs Merit Review Program; US National Institute of Health [AA017437]; NARSAD Maltz Investigator Award [5R01MH085548-05] FX Grant sponsor: Department of Veterans Affairs Merit Review Program; Grant sponsor: US National Institute of Health; Grant number: AA017437; Grant sponsor: NARSAD Maltz Investigator Award; Grant number: 5R01MH085548-05. NR 43 TC 2 Z9 2 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC PY 2013 VL 162 IS 8 BP 898 EP 906 DI 10.1002/ajmg.b.32200 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 246AE UT WOS:000326506700013 PM 24123842 ER PT J AU Coughlin, JW Gullion, CM Brantley, PJ Stevens, VJ Bauck, A Champagne, CM Dalcin, AT Funk, KL Hollis, JF Jerome, GJ Lien, LF Loria, CM Myers, VH Appel, LJ AF Coughlin, J. W. Gullion, C. M. Brantley, P. J. Stevens, V. J. Bauck, A. Champagne, C. M. Dalcin, A. T. Funk, K. L. Hollis, J. F. Jerome, G. J. Lien, L. F. Loria, C. M. Myers, V. H. Appel, L. J. TI Behavioral Mediators of Treatment Effects in the Weight Loss Maintenance Trial SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Obesity; Weight maintenance; Weight regain; Behavioral strategies; Mediators ID RANDOMIZED CLINICAL-TRIALS; PHYSICAL-ACTIVITY; DIETARY PATTERNS; BODY-MASS; ADULTS; INTERVENTION; MODERATORS; PREVENTION; GAIN; FAT AB The Weight Loss Maintenance Trial tested strategies for maintenance of weight loss. Personal contact was superior to interactive technology and self-directed conditions. We aimed to identify behavioral mediators of the superior effect of personal contact vs. interactive technology and of personal contact vs. self-directed arms. Overweight/obese adults at risk for cardiovascular disease (n = 1,032) who lost at least 4 kg were randomized to personal contact, interactive technology, or self-directed. After 30 months, 880 participants had data on weight and behavioral strategies. Reported increase of intake of fruits and vegetables and physical activity and more frequent self-weighing met criteria as mediators of the better outcome of personal contact vs. interactive technology. Increased intake of fruits and vegetables, more frequent self-weighing, and decreased dessert consumption were mediators of the difference between personal contact vs. self-directed. Inducing changes in the identified behaviors might yield better outcomes in future weight loss maintenance trials. (ClinicalTrials.gov number NCT00054925). C1 [Coughlin, J. W.; Dalcin, A. T.; Appel, L. J.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Gullion, C. M.; Stevens, V. J.; Bauck, A.; Funk, K. L.; Hollis, J. F.] Kaiser Permanente Ctr Hlth Res, Oakland, CA USA. [Brantley, P. J.; Champagne, C. M.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Jerome, G. J.] Towson Univ, Towson, MD USA. [Lien, L. F.] Duke Univ, Med Ctr, Durham, NC USA. [Loria, C. M.] NHLBI, Bethesda, MD 20892 USA. [Myers, V. H.] Klein Buendel Inc, Golden, CO USA. RP Coughlin, JW (reprint author), Johns Hopkins Univ, Sch Med, 600 North Wolfe St,Meyer 101, Baltimore, MD 21287 USA. EM jwilder3@jhmi.edu OI Jerome, Gerald/0000-0003-0612-2626 FU NHLBI NIH HHS [5-U01 HL68790, 5-U01 HL68676, 5-U01 HL68920, 5U01 HL68734, HL68955, U01 HL068676, U01 HL068734, U01 HL068790, U01 HL068920, U01 HL068955] NR 37 TC 11 Z9 11 U1 1 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2013 VL 46 IS 3 BP 369 EP 381 DI 10.1007/s12160-013-9517-3 PG 13 WC Psychology, Multidisciplinary SC Psychology GA 248HX UT WOS:000326690300014 PM 23813320 ER PT J AU Usategui, A Criado, G Izquierdo, E Del Rey, MJ Carreira, PE Ortiz, P Leonard, WJ Pablos, JL AF Usategui, Alicia Criado, Gabriel Izquierdo, Elena Del Rey, Manuel J. Carreira, Patricia E. Ortiz, Pablo Leonard, Warren J. Pablos, Jose L. TI A profibrotic role for thymic stromal lymphopoietin in systemic sclerosis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article DE Systemic Sclerosis; Autoimmunity; Cytokines; Fibroblasts ID BLEOMYCIN-INDUCED SCLERODERMA; AIRWAY EPITHELIAL-CELLS; INDUCED SKIN FIBROSIS; FACTOR T-BET; MAST-CELLS; PULMONARY-FIBROSIS; GENE-EXPRESSION; UP-REGULATION; ANIMAL-MODEL; LUNG-DISEASE AB Objetive Systemic sclerosis (SSc) is an autoimmune disease characterised by progressive fibrosis. Although SSc shares pathogenetic features with other autoimmune diseases, the participation of profibrotic Th2 cytokines is unique to SSc, but the mechanisms of Th2 skewing are unknown. We have analysed the expression and function of thymic stromal lymphopoietin (TSLP), a central regulator of Th2-mediated allergic inflammation, in human SSc, primary lung fibrosis and in a mouse model of scleroderma. Methods TSLP expression was analysed by immunohistochemistry in human SSc skin, primary lung fibrosis and mouse bleomycin-induced skin fibrosis, and by quantitative RT-PCR in mouse skin and cultured fibroblasts. The regulation of TSLP expression by specific toll-like receptors (TLR)-2, -3 and -4 agonists was analysed in human dermal fibroblast cultures. The role of TSLP in skin fibrosis and local cytokine expression was analysed in TSLP receptor (TSLPR)-deficient mice. Results TSLP was overexpressed by epithelial cells, mast cells and fibroblasts in human SSc skin and lung fibrosis, and in the bleomycin model of scleroderma. In cultured human and mouse skin fibroblasts, TSLP expression was inducible by activation of TLR, particularly TLR3. In TSLPR-deficient mice, bleomycin-induced fibrosis was significantly reduced in parallel with significantly reduced local expression of IL-13. Conclusions These data provide the first evidence of TSLP overexpression in SSc and other non-allergic fibrotic conditions, and demonstrate a profibrotic role that is potentially meditated by specific changes in the local cytokine milieu. Thus, modulating TSLP may have antifibrotic therapeutic implications. C1 [Usategui, Alicia; Criado, Gabriel; Izquierdo, Elena; Del Rey, Manuel J.; Carreira, Patricia E.; Pablos, Jose L.] Inst Invest Hosp 12 Octubre I 12, Serv Reumatol, Madrid, Spain. [Ortiz, Pablo] Inst Invest Hosp 12 Octubre I 12, Serv Dermatol, Madrid, Spain. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. RP Pablos, JL (reprint author), Hosp 12 Octubre, Serv Reumatol, E-28041 Madrid, Spain. EM jlpablos@h12o.es RI Del Rey, Manuel /O-6114-2014; Usategui, Alicia/O-6476-2014; OI Del Rey, Manuel /0000-0002-8180-1584; Criado, Gabriel/0000-0003-4824-0890 FU Fondo de Investigacion Sanitaria [PI08/0316, PI12/439, RIER RD12/09/016]; Division of Intramural Research National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by Fondo de Investigacion Sanitaria through grants PI08/0316 and PI12/439 and RIER RD12/09/016 and by the Division of Intramural Research National Heart, Lung, and Blood Institute, National Institutes of Health. NR 44 TC 14 Z9 15 U1 1 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD DEC PY 2013 VL 72 IS 12 BP 2018 EP 2023 DI 10.1136/annrheumdis-2012-202279 PG 6 WC Rheumatology SC Rheumatology GA 250TJ UT WOS:000326877500025 PM 23413283 ER PT J AU Kelly, PA Viding, E Wallace, GL Schaer, M De Brito, SA Robustelli, B McCrory, EJ AF Kelly, Philip A. Viding, Essi Wallace, Gregory L. Schaer, Marie De Brito, Stephane A. Robustelli, Briana McCrory, Eamon J. TI Cortical Thickness, Surface Area, and Gyrification Abnormalities in Children Exposed to Maltreatment: Neural Markers of Vulnerability? SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Child abuse; cortical thickness; local gyrification; maltreatment; psychopathology; surface area ID POSTTRAUMATIC-STRESS-DISORDER; HUMAN CEREBRAL-CORTEX; ANTERIOR CINGULATE CORTEX; MAGNETIC-RESONANCE IMAGES; GRAY-MATTER VOLUME; CHILDHOOD MALTREATMENT; ORBITOFRONTAL CORTEX; MAJOR DEPRESSION; REDUCED VOLUME; VISUAL-CORTEX AB Background: Childhood maltreatment has been shown to significantly elevate the risk of psychiatric disorder. Previous neuroimaging studies of children exposed to maltreatment have reported atypical neural structure in several regions, including the prefrontal cortex and temporal lobes. These studies have exclusively investigated volumetric differences rather than focusing on genetically and developmentally distinct indices of brain structure. Methods: Here we used surface-based methods to examine cortical thickness, surface area, and local gyrification in a community sample of children with documented experiences of abuse (n = 22) and a group of carefully matched nonmaltreated peers (n = 21). Results: Reduced cortical thickness in the maltreated compared with the nonmaltreated group was observed in an extended cluster that incorporated the anterior cingulate, superior frontal gyrus, and orbitofrontal cortex. In addition, reduced cortical surface area was observed within the parcellated regions of the left middle temporal area and lingual gyrus. Local gyrification deficits within the maltreated group were located within two clusters, the lingual gyrus and the insula extending into pars opercularis. Conclusions: This is the first time structural abnormalities in the anterior cingulate and lingual gyrus have been detected in children exposed to maltreatment. Surface-based methods seem to capture subtle, previously undetected, morphological abnormalities associated with maltreatment. We suggest that these approaches detect developmental precursors of brain volume differences seen in adults with histories of abuse. Because the reported regions are implicated in several clinical disorders, they might constitute biological markers of vulnerability, linking exposure to early adversity and psychiatric risk. C1 [Kelly, Philip A.; Viding, Essi; McCrory, Eamon J.] UCL, Div Psychol & Language Sci, London WC1H 0AP, England. [Viding, Essi] UCL, Inst Cognit Neurosci, London WC1H 0AP, England. [Kelly, Philip A.; McCrory, Eamon J.] Anna Freud Ctr, London, England. [De Brito, Stephane A.] Univ Birmingham, Sch Psychol, Birmingham, W Midlands, England. [Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Schaer, Marie] Univ Geneva, Dept Psychiat, Geneva, Switzerland. RP McCrory, EJ (reprint author), UCL, Div Psychol & Language Sci, 26 Bedford Way, London WC1H 0AP, England. EM e.mccrory@ucl.ac.uk OI De Brito, Stephane/0000-0002-9082-6185; Wallace, Gregory/0000-0003-0329-5054 FU United Kingdom Economic and Social Research Council [RES-061-250189] FX This work was supported by a grant from the United Kingdom Economic and Social Research Council (RES-061-250189) to EMC. NR 68 TC 32 Z9 32 U1 3 U2 16 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 DEC 1 PY 2013 VL 74 IS 11 BP 845 EP 852 DI 10.1016/j.biopsych.2013.06.020 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 252CJ UT WOS:000326981800010 PM 23954109 ER PT J AU Maggio, M Lauretani, F Ceda, GP De Vita, F Bondi, G Corsonello, A Cattabiani, C Lattanzio, F Ruggiero, C Nouvenne, A Meschi, T Bandinelli, S Ferrucci, L AF Maggio, Marcello Lauretani, Fulvio Ceda, Gian Paolo De Vita, Francesca Bondi, Giuliana Corsonello, Andrea Cattabiani, Chiara Lattanzio, Fabrizia Ruggiero, Carmelinda Nouvenne, Antonio Meschi, Tiziana Bandinelli, Stefania Ferrucci, Luigi TI Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals SO BONE LA English DT Article DE Bone mineral density; Trabecular bone mineral density; Proton pump inhibitors; InCHIANTI Study; Elderly ID COMMUNITY-ACQUIRED PNEUMONIA; CLOSTRIDIUM-DIFFICILE INFECTION; ACID-SUPPRESSIVE DRUGS; MINERAL DENSITY; HIP FRACTURE; POSTMENOPAUSAL WOMEN; RISK; OSTEOPOROSIS; METAANALYSIS; OMEPRAZOLE AB Proton pump inhibitors (PPIs) are highly effective in the treatment of upper gastrointestinal acid-related conditions and are fast becoming one of the most frequently prescribed treatments in adult or older persons. Recent data show that long-term use of PPIs in older subjects is associated with important undesirable effects, including a higher risk of osteoporotic fractures. The mechanisms of this association are unclear and the relationship between the use of PPIs and parameters of bone mass and geometry has never been fully explored. This study investigates the relationship between the chronic use of PPIs and the parameters of bone mass (cortical and trabecular bone mineral density - vBMDc and vBMDt) and bone geometry (cortical and trabecular cross sectional area - tCSA and cCSA) in older individuals. The study population consisted of 1038 subjects (452 men and 586 women) 65 years or older, selected from the InCHIANTI study, with complete information on computerized tomography performed at tibial level (pQCT) and on medications. Participants were classified as PPI users and nonusers based on self-report of PPI use over the last 15 days, with PPI users (36 subjects, 14 men and 22 women) making up 3.4% of the study population (mean age 75.7 +/- 7.4 years). The relationship between use of PPIs and pQCT bone parameters was tested by multivariate linear regression analysis adjusted for age, sex and several clinical factors and/or statistically confounding variables identified by partial correlation coefficient and Spearman partial rank order correlation coefficients, as appropriate (age, sex, EMI, caloric intake, IGF-1, IL-6, calcium, estradiol, bioavailable testosterone, vitamin D, parathyroid hormone, cross-sectional muscle area, and level of physical activity). PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5 +/- 54.8 vs. 207.9 +/- 59.4, p = 0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple confounders. There was no statistically significant difference in vBMDc, tCSA and cCSA between PPI users and nonusers. In community dwelling older persons, the use of PPIs is inversely associated with vBMDt, an early marker of the osteoporotic process. These findings suggest that PPI use might increase the risk of fractures in older subjects through its detrimental effects on trabecular bone. (C) 2013 Elsevier Inc. All rights reserved. C1 [Maggio, Marcello; Ceda, Gian Paolo; Bondi, Giuliana; Meschi, Tiziana] Univ Parma, Sect Geriatr, Dept Clin & Expt Med, I-43126 Parma, PR, Italy. [Maggio, Marcello; Lauretani, Fulvio; Ceda, Gian Paolo; De Vita, Francesca; Nouvenne, Antonio; Meschi, Tiziana] Univ Hosp Parma, Geriatr Rehabil Dept, I-43126 Parma, PR, Italy. [Corsonello, Andrea] INRCA, Unit Geriatr Pharmacoepidemiol, Contrada Muoio Piccolo Snc, I-87100 Cosenza, CS, Italy. [Lattanzio, Fabrizia] INRCA Ancona, Sci Direct, I-60124 Ancona, AN, Italy. [Ruggiero, Carmelinda] Univ Perugia, Sch Med, Inst Gerontol & Geriatr, Dept Clin & Expt Med, I-06100 Perugia, PG, Italy. [Bandinelli, Stefania] Local Hlth Agcy, Geriatr Unit, I-50122 Florence, FI, Italy. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. RP Maggio, M (reprint author), Univ Parma, Sect Geriatr, Dept Clin & Expt Med, Via Gramsci 14, I-43126 Parma, PR, Italy. EM marcellomaggio2001@yahoo.it RI Lauretani, Fulvio/K-5115-2016; meschi, tiziana/K-5032-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; meschi, tiziana/0000-0002-7538-6863; Ceda, Gian Paolo/0000-0002-9648-8295; Nouvenne, Antonio/0000-0002-2680-2242 FU Italian Ministry of Health [ICS 110.1/RS97.71]; US National Institute on Aging [N01-AG-916413, N01-AG-821336]; Intramural Research Program of the US National Institute on Aging [263 MD 9164 13, 263 MD 821336]; Italian Ministry of Health and Emilia Romagna Region [RF-2010-2312659] FX The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts N01-AG-916413 and N01-AG-821336), and by the Intramural Research Program of the US National Institute on Aging (Contracts 263 MD 9164 13 and 263 MD 821336) and by grant RF-2010-2312659 from the Italian Ministry of Health and Emilia Romagna Region. None of the sponsoring institutions interfered with the collection, analysis, presentation, or interpretation of the data reported here. NR 52 TC 14 Z9 16 U1 0 U2 19 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 DEC PY 2013 VL 57 IS 2 BP 437 EP 442 DI 10.1016/j.bone.2013.09.014 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 250JB UT WOS:000326848000016 PM 24076021 ER PT J AU Palmore, TN Henderson, DK AF Palmore, Tara N. Henderson, David K. TI Managing Transmission of Carbapenem-Resistant Enterobacteriaceae in Healthcare Settings: A View From the Trenches SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE carbapenem-resistant enterobacteriaceae; whole genome sequencing; isolation; transmission; multidrug resistance ID HYDROGEN-PEROXIDE VAPOR; KLEBSIELLA-PNEUMONIAE; ACINETOBACTER-BAUMANNII; HANDWASHING SINKS; K. PNEUMONIAE; UNIT PATIENTS; OUTBREAK; DISINFECTION; EPIDEMIOLOGY; BACTERIA AB In 2011, the National Institutes of Health Clinical Center experienced a cluster of infection and colonization caused by carbapenem-resistant Klebsiella pneumoniae among profoundly immunocompromised inpatients. This manuscript describes the approach and interventions that were implemented in an attempt to curtail the cluster. Interventions employed included engagement of all stakeholders involved in care of at-risk patients; detailed and frequent communication with hospital staff about issues relating to the outbreak; aggressive microbial surveillance; use of techniques that facilitate rapid identification of resistant organisms; rapid characterization of resistance mechanisms; whole-genome sequencing of outbreak isolates to characterize the spread and to investigate mechanisms of healthcare-associated spread; implementation of enhanced contact precautions for all infected or colonized patients; geographic and personnel cohorting; daily chlorhexidine gluconate baths; dedicating equipment to be used solely for cohorted patients and aggressive decontamination of equipment that had to be reused on uncohorted patients; monitoring adherence to infection control precautions, including unwavering attention to adherence to appropriate hand hygiene procedures; and attention to the details of environmental decontamination. In addition, the manuscript discusses some of the challenges associated with managing such an event, as well as a few of the unanticipated consequences associated with the aftermath of the case cluster. C1 Hosp Epidemiol Serv, Bethesda, MD USA. NIH, Ctr Clin, Off Deputy Director Clin Care, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm 6-1480, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 40 TC 31 Z9 31 U1 3 U2 17 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 DEC 1 PY 2013 VL 57 IS 11 BP 1593 EP 1599 DI 10.1093/cid/cit531 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 247XK UT WOS:000326657000017 PM 23934166 ER PT J AU Blanchet, EM Martucci, V Millo, C Chen, CC Herscovitch, P Pacak, K AF Blanchet, Elise M. Martucci, Victoria Millo, Corina Chen, Clara C. Herscovitch, Peter Pacak, Karel TI Multitracer PET imaging of bone metastases from paraganglioma: peripheral halo of uptake on F-18-FLT PET mismatching with central uptake of F-18-FDOPA, F-18-fluorodopamine, and F-18-FDG SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Editorial Material C1 [Blanchet, Elise M.; Martucci, Victoria; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. [Millo, Corina; Herscovitch, Peter] NIH, PET Dept, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Chen, Clara C.] NIH, Dept Nucl Med, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,1 East,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural NIH HHS [ZIA HD008735-12] NR 3 TC 1 Z9 1 U1 0 U2 2 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 DEC PY 2013 VL 40 IS 12 BP 1928 EP 1929 DI 10.1007/s00259-013-2507-7 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 248HZ UT WOS:000326690600020 PM 23880966 ER PT J AU Muscillo, M Fratini, M Graffeo, R Sanguinetti, M Martella, V Green, KY Della Libera, S La Rosa, G AF Muscillo, M. Fratini, M. Graffeo, R. Sanguinetti, M. Martella, V. Green, K. Y. Della Libera, S. La Rosa, Giuseppina TI GIV Noroviruses in Wastewaters and in Stool Specimens from Hospitalized Patients SO FOOD AND ENVIRONMENTAL VIROLOGY LA English DT Article DE Norovirus genogroup IV; Nested PCR; Real-time PCR; Sewage; Stool samples ID GENOGROUP IV NOROVIRUSES; NORWALK-LIKE VIRUSES; GENETIC DIVERSITY; WASTE-WATER; MOLECULAR CHARACTERIZATION; TREATMENT PLANTS; ENTERIC VIRUSES; JAPAN; GASTROENTERITIS; OUTBREAKS AB Noroviruses (NoVs) are important human pathogens associated with foodborne and waterborne gastroenteritis. These viruses are genetically highly heterogeneous, with more than forty genotypes within three genogroups (GI, GII, and GIV) identified in humans. However, the vast majority of human infections are associated with variants of a unique genotype, GII.4. Aside from these NoV strains of epidemiological relevance, NoV strains of genogroup GIV (Alphatron-like) are reported in a sporadic fashion and their overall prevalence in the community is unknown and this likely reflects the lack of specific diagnostic tools. We analyzed raw sewages collected from 32 wastewater treatment plants distributed throughout Italy (307 samples) and stool specimens collected from hospitalized patients with clinical signs of diarrhea of unknown etiology (285 samples). By using specific qualitative and quantitative RT-PCR assays, 21.8 % of the sewage samples and 3.2 % of the stool specimens tested positive for GIV NoVs. The number of genome copies in fecal samples ranged from 5.08 x 10(4) to 1.73x 10(6)/g of feces. Sequence analysis showed limited genetic variability in human GIV viruses. The presence of GIV NoV both in sewage and in clinical samples confirms that not only GI and GII NoVs but also GIV strains are circulating in humans. Monitoring of GIV NoV is recommended in order to understand the dynamics of circulation in human populations, environmental contamination, and potential health risks. C1 [Muscillo, M.; Fratini, M.; Della Libera, S.; La Rosa, Giuseppina] Ist Super Sanita, Dept Environm & Primary Prevent, I-00161 Rome, Italy. [Graffeo, R.; Sanguinetti, M.] Univ Cattolica Sacro Cuore, Ist Microbiol, Policlin A Gemelli, Rome, Italy. [Martella, V.] Univ Aldo Moro, Dipartimento Sanita Pubbl & Zootecnia, Bari, Italy. [Green, K. Y.] NIAID, Infect Dis Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP La Rosa, G (reprint author), Ist Super Sanita, Dept Environm & Primary Prevent, Viale Regina Elena 299, I-00161 Rome, Italy. EM giuseppina.larosa@iss.it RI La Rosa, Giuseppina/I-8532-2016; Martella, Vito/K-3146-2016; OI La Rosa, Giuseppina/0000-0002-2657-100X; Martella, Vito/0000-0002-5740-6947; Sanguinetti, Maurizio/0000-0002-9780-7059 FU Italian-American Project "Assessing the Impact of GIV Norovirus on Human Health: a Molecular Epidemiological Investigation on Environmental and Clinical Samples as a Basis for the Design of Novel Diagnostic Tools for an Emerging Pathogen"; Grant "Calicivirus nei carnivori e nell'uomo: caratterizzazione molecolare, epidemiologia, implicazioni zoonosiche"-PRIN FX This study was financed by the joint Italian-American Project "Assessing the Impact of GIV Norovirus on Human Health: a Molecular Epidemiological Investigation on Environmental and Clinical Samples as a Basis for the Design of Novel Diagnostic Tools for an Emerging Pathogen," and partially by the Grant "Calicivirus nei carnivori e nell'uomo: caratterizzazione molecolare, epidemiologia, implicazioni zoonosiche"-PRIN 2008. We thank Professor Herbert W. Virgin, Washington University (St. Louis, Missouri, United States) for providing the murine NoV stain used as sample process control. We gratefully acknowledge for wastewater sample collection: 1-2. E. Lorenzi, L. Meucci, M. Deceglie (SMAT Spa, Torino), E. Garrou, M. Morello, G. Mantovani (ARPA Piemonte, Torino); 3-4. G. Manassero (Arpa Valle d'Aosta), A. Martello (Corpo Forestale Valdostano); 5. W. Bodini, C. Amadasi (Vettabbia Spa, Milano); 6. L. Boscolo (Amiacque Spa, Milano); 7. M. Tomasoni, D. Monteverdi (A2A Spa, Brescia); 8-9. M. Poli, M. Dekas (Eco Center Spa AG, Bolzano), W. Strobl, E. Scarperi (APPA, Bolzano); 10-11. L. Bruni, G. Gatti, L. Tomasi, G. Cimadon (APPA, Trento); 12-13. P. Parati, E. Dell'Andrea, G. Gambillara (Arpa Veneto, Venezia); 14-15. S. Gaiter, L. Sola (ARPA Liguria, Genova); 16. F.Cornia, M. A. Corvaglia, P. Albertelli (ARPA Emilia Romagna, Bologna); 17. A. Gambaccioni, M. Razzolini (Publiacqua S. p. A. Firenze); 18. E. Renna, G. Saltalamacchia, M. Lucarini (ARPA Umbria, Perugia); 19-20. C. Mengarelli, Trimboli (ARPA Marche, Ancona); 21-24. C. Gala, R. Tomassini (Arpalazio, Roma), G. Ranalletta (ACEA ATO2 S. p. A., Roma); 25. E. Rufolo, R. Martino (ARPA Campania, Sezione provinciale di Napoli); 26-27. G. Assennato, G. Blonda, (Regione Puglia, Direzione Scientifica), V. Perrino, M. Mariani (ARPA Puglia, Bari); 28. R. Vita, R. Masotti, R. Martoccia (ARPA Basilicata, Potenza); 29. F. Pedulla, G. Belmusto (ARPA Calabria, Reggio Calabria); 30. L. Librici G. Abbate (ARPA Sicilia, Palermo); 31-32. M. G. Mulas, G. Campus (Regione Sardegna), A. M. Mereu, M. Secci (ARPA Sardegna, Cagliari). NR 39 TC 15 Z9 15 U1 1 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-0334 EI 1867-0342 J9 FOOD ENVIRON VIROL JI Food Environ. Virol. PD DEC PY 2013 VL 5 IS 4 BP 194 EP 202 DI 10.1007/s12560-013-9121-5 PG 9 WC Environmental Sciences; Microbiology; Virology SC Environmental Sciences & Ecology; Microbiology; Virology GA 248IE UT WOS:000326691400002 ER PT J AU Singh, UP Singh, NP Guan, HB Busbee, B Price, RL Taub, DD Mishra, MK Fayad, R Nagarkatti, M Nagarkatti, PS AF Singh, Udai P. Singh, Narendra P. Guan, Hongbing Busbee, Brandon Price, Robert L. Taub, Dennis D. Mishra, Manoj K. Fayad, Raja Nagarkatti, Mitzi Nagarkatti, Prakash S. TI Leptin antagonist ameliorates chronic colitis in IL-10(-/-) mice SO IMMUNOBIOLOGY LA English DT Article DE Inflammation; Inflammatory bowel disease (IBD); Leptin; Antagonist; Pegylated; Ulcerative colitis (UC); Crohn's disease (CD) ID INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; TGF-BETA; INTESTINAL INFLAMMATION; CROHNS-DISEASE; CUTTING EDGE; AUTOIMMUNE ENCEPHALOMYELITIS; ULCERATIVE-COLITIS; STAT3 ACTIVATION; IMMUNE-RESPONSE AB Background: Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF-beta 1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression. Aim: We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis. Results: Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39(+) Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-beta 1, -beta 2 and -beta 3 expressing CD4(+) T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-beta 1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis. Conclusion: This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD. Published by Elsevier GmbH. C1 [Singh, Udai P.; Singh, Narendra P.; Guan, Hongbing; Busbee, Brandon; Nagarkatti, Mitzi; Nagarkatti, Prakash S.] Univ S Carolina, Sch Med, Columbia, SC 29208 USA. [Price, Robert L.] Univ S Carolina, Dept Cell & Dev Biol, Columbia, SC 29208 USA. [Taub, Dennis D.] NIA, Lab Mol Biol & Immunol, IRP, NIH, Baltimore, MD 21224 USA. [Mishra, Manoj K.] Alabama State Univ, Dept Math & Sci, Montgomery, AL 36104 USA. [Fayad, Raja] Univ S Carolina, Arnold Sch Publ Hlth, Dept Exercise Sci, Columbia, SC 29208 USA. RP Singh, UP (reprint author), Univ S Carolina, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA. EM Udai.singh@uscmed.sc.edu OI Nagarkatti, Mitzi/0000-0002-5977-5615 FU NIH [R56 DK087836, R01 AT006888, R01 ES019313, R01 MH094755, P01 AT003961]; University of South Carolina School of Medicine; National Institute on Aging, NIH FX This work was supported, in part by NIH grants R56 DK087836, R01 AT006888, R01 ES019313, R01 MH094755, P01 AT003961, Research and Development Funds from the University of South Carolina School of Medicine and Intramural Program of the National Institute on Aging, NIH. NR 70 TC 14 Z9 15 U1 0 U2 9 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD DEC PY 2013 VL 218 IS 12 BP 1439 EP 1451 DI 10.1016/j.imbio.2013.04.020 PG 13 WC Immunology SC Immunology GA 250NF UT WOS:000326858800001 PM 23726523 ER PT J AU Anderson, TK Nelson, MI Kitikoon, P Swenson, SL Korslund, JA Vincent, AL AF Anderson, Tavis K. Nelson, Martha I. Kitikoon, Pravina Swenson, Sabrina L. Korslund, John A. Vincent, Amy L. TI Population dynamics of cocirculating swine influenza A viruses in the United States from 2009 to 2012 SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article; Proceedings Paper CT 2nd ISIRV International Symposium on Neglected Influenza Viruses CY MAR 07-08, 2013 CL Dublin, IRELAND DE Epidemiology; influenza A virus; surveillance; swine; vaccines; zoonotic diseases ID GENETIC-CHARACTERIZATION; MAXIMUM-LIKELIHOOD; H3N2 VIRUS; PIGS; TRANSMISSION; REASSORTMENT; EVOLUTION; HUMANS; SEASONALITY; INFECTIONS AB BackgroundUnderstanding the ecology and evolution of influenza A viruses (IAV) in mammalian hosts is critical to reduce disease burden in production animals and lower zoonotic infection risk in humans. Recent advances in influenza surveillance in US swine populations allow for timely epidemiological, phylogenetic, and virological analyses that monitor emergence of novel viruses and assess changes in viral population dynamics. MethodsTo better understand IAV in the North American swine population, we undertook a phylogenetic analysis of 1075 HA, 1049 NA, and 1040M sequences of IAV isolated from US swine during 2009-2012 through voluntary and anonymous submissions to the US Department of Agriculture IAV swine surveillance system. ResultsAnalyses revealed changes in population dynamics among multiple clades of A/H1N1, A/H3N2, and A/H1N2 cocirculating in US swine populations during 2009-2012. Viral isolates were categorized into one of seven genetically and antigenically distinct hemagglutinin lineages: H1, H1, H1, H11, H12, H1pdm09, and H3 cluster IV. There was an increase in occurrence of H11 in samples submitted, with a concurrent decrease in H1pdm09. H3 cluster IV exhibited increasing diversification, warranting a re-evaluation of phylogenetic nomenclature criteria. Although H3N2 represented 25% of identified viruses, this subtype was reported in increasing proportion of sequenced isolates since late 2011. ConclusionsSurveillance and reporting of IAV in US swine have increased since 2009, and we demonstrate a period of expanded viral diversity. These data may be used to inform intervention strategies of vaccine and diagnostic updates and changes in swine health management. C1 [Anderson, Tavis K.; Kitikoon, Pravina; Vincent, Amy L.] USDA ARS, Virus & Prion Res Unit, Natl Anim Dis Ctr, Ames, IA 50010 USA. [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Swenson, Sabrina L.] USDA APHIS, Natl Vet Serv Labs, Ames, IA USA. [Korslund, John A.] USDA APHIS, Ctr Epidemiol & Anim Hlth, Riverdale, MD USA. RP Vincent, AL (reprint author), USDA ARS, Virus & Prion Res Unit, NADC, 1920 Dayton Ave,POB 70, Ames, IA 50010 USA. EM amy.vincent@ars.usda.gov OI Anderson, Tavis/0000-0002-3138-5535 FU Supplemental Appropriations Act FX We are grateful to the pork producers, swine veterinarians, and laboratories for participating in the USDA Influenza Virus Surveillance System for swine. Funding was provided from the Supplemental Appropriations Act of 2009 for pandemic influenza preparedness and response to the Department of Health and Human Services, as well as base funding to the USDA-ARS and USDA-APHIS-VS. Disclaimer: Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. USDA is an equal opportunity provider and employer. NR 55 TC 28 Z9 28 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD DEC PY 2013 VL 7 SU S4 SI SI BP 42 EP 51 DI 10.1111/irv.12193 PG 10 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 250YC UT WOS:000326891700008 PM 24224819 ER PT J AU Schelman, WR Traynor, AM Holen, KD Kolesar, JM Attia, S Hoang, T Eickhoff, J Jiang, ZS Alberti, D Marnocha, R Reid, JM Ames, MM McGovern, RM Espinoza-Delgado, I Wright, JJ Wilding, G Bailey, HH AF Schelman, William R. Traynor, Anne M. Holen, Kyle D. Kolesar, Jill M. Attia, Steven Hoang, Tien Eickhoff, Jens Jiang, Zhisheng Alberti, Dona Marnocha, Rebecca Reid, Joel M. Ames, Matthew M. McGovern, Renee M. Espinoza-Delgado, Igor Wright, John J. Wilding, George Bailey, Howard H. TI A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE SAHA; Vorinostat; PS-341; Bortezomib; Phase I ID HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; CANCER CELLS; PROTEASOME INHIBITORS; INDUCED APOPTOSIS; MULTIPLE-MYELOMA; DOWN-REGULATION; LEUKEMIA CELLS; LUNG-CANCER; BCR-ABL AB Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9 %), fatigue (34.8 %), diaphoresis (34.8 %), anorexia (30.4 %) and constipation (26.1 %). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily x 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle. C1 [Schelman, William R.; Traynor, Anne M.; Holen, Kyle D.; Kolesar, Jill M.; Attia, Steven; Hoang, Tien; Eickhoff, Jens; Jiang, Zhisheng; Alberti, Dona; Marnocha, Rebecca; Wilding, George; Bailey, Howard H.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53792 USA. [Espinoza-Delgado, Igor; Wright, John J.] NCI, Clin Treatment Evaluat Program, Bethesda, MD 20892 USA. [Reid, Joel M.; Ames, Matthew M.; McGovern, Renee M.] Mayo Clin, Ctr Canc, Rochester, MN USA. RP Schelman, WR (reprint author), Univ Wisconsin, Carbone Canc Ctr, 600 Highland Ave,K6-568 CSC, Madison, WI 53792 USA. EM wrs@medicine.wisc.edu FU NCI [UO1 CA062491]; CTEP Translational Research Initiative; Clinical and Translational Science Award, National Center for Research Resources, NIH [1UL 1RR025011]; Mayo Clinic [U01 CA69912]; CTEP Translational Research Initiative-Support Subcontracts, Correlative Studies Core Laboratory for SAHA Phase I and Phase II Clinical Protocols (Mayo Clinic), SAIC-FREDERICK, INC. [23XS026] FX UO1 CA062491, Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis, NCI; CTEP Translational Research Initiative, Contract; 1UL 1RR025011, Clinical and Translational Science Award, National Center for Research Resources, NIH; U01 CA69912, Phase I Trials of Anticancer Agents (Mayo Clinic); and 23XS026, CTEP Translational Research Initiative-Support Subcontracts, Correlative Studies Core Laboratory for SAHA Phase I and Phase II Clinical Protocols (Mayo Clinic), SAIC-FREDERICK, INC. NR 37 TC 9 Z9 9 U1 2 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD DEC PY 2013 VL 31 IS 6 BP 1539 EP 1546 DI 10.1007/s10637-013-0029-6 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 247FT UT WOS:000326602500015 PM 24114121 ER PT J AU Alexander, J Kwon, HT Strecher, R Bartholomew, J AF Alexander, James Kwon, Harry T. Strecher, Rachael Bartholomew, Jill TI Multicultural Media Outreach: Increasing Cancer Information Coverage in Minority Communities SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer health disparities; Ethnic media; Minority and underserved; Cancer education AB Ethnic media can serve as an opportunity for cancer education and outreach to minority communities. The National Cancer Institute developed the Multicultural Media Outreach (MMO) program which utilizes an integrated approach of both traditional and social media to disseminate evidence-based cancer education information for minority communities. The MMO program is the contact point for multicultural media outlets seeking evidence-based cancer information, education materials, minority spokespersons, and news tailored to minority communities affected by cancer health disparities. MMO developed LifelinesA (R), a cancer education series that addresses cancer prevention, treatment, survivorship, clinical trials, and other cancer-related topics for African American, Hispanic, Asian American, American Indian, and Alaska Native audiences. LifelinesA (R) content is disseminated through traditional media (radio, print, and television) as well as social media (web, Twitter, YouTube, and RSS feed). This article describes the MMO program and lessons learned to date. C1 [Alexander, James; Kwon, Harry T.; Strecher, Rachael; Bartholomew, Jill] NCI, Off Commun & Educ, NIH, Bethesda, MD 20892 USA. RP Kwon, HT (reprint author), NCI, Off Commun & Educ, NIH, 9609 Med Ctr Dr,Room 2E532,MSC 9760, Bethesda, MD 20892 USA. EM harry.kwon@nih.gov NR 9 TC 5 Z9 5 U1 2 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD DEC PY 2013 VL 28 IS 4 BP 744 EP 747 DI 10.1007/s13187-013-0534-5 PG 4 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 242ZQ UT WOS:000326286200023 PM 23963725 ER PT J AU Sarkin, AJ Tally, SR Wooldridge, JS Choi, K Shieh, M Kaplan, RM AF Sarkin, Andrew J. Tally, Steven R. Wooldridge, Jennalee S. Choi, Kyle Shieh, Marian Kaplan, Robert M. TI Gender Differences in Adapting Driving Behavior to Accommodate Visual Health Limitations SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Driving; Gender; Cataracts; Visual acuity; Public safety ID MOTOR-VEHICLE CRASH; OLDER DRIVERS; CATARACT-SURGERY; FUNCTION QUESTIONNAIRE; SELF-REGULATION; UNITED-STATES; RISK; EYE; IMPAIRMENT; ADULTS AB This study investigated whether men and women are equally likely to adapt their driving behaviors in response to visual limitations. Participants were 376 (222 women and 154 men) pre-surgical cataract patients from the Shiley Eye Center in La Jolla, California. All participants completed the National Eye Institute Visual Functioning Questionnaire, which assesses self-reported visual symptoms, functional limitations, and behaviors including driving during the day, at night, or in difficult conditions. Visual acuity was assessed using the log of the minimal angle of resolution (LogMAR) scale. There were no significant differences in LogMAR visual acuity between men and women who reported either that they stopped driving at night because of visual impairment or reported having no difficulty driving at night. Of participants who reported having difficulty driving at night, mean weighted LogMAR scores indicated significantly better visual acuity for women than men. There were no significant differences in LogMAR visual acuity between women and men in any of the difficult driving condition categories. Significantly more women than men reported that they stopped driving in difficult conditions because of eyesight, despite the lack of gender differences in visual acuity for this sample. We found no evidence that cataract disease had different effects on the visual acuity of older adult men and women. However, there was a significant difference between genders in self-reported driving behavior. It is possible that some women are more cautious or have less need to drive. However, failing to adapt driving behaviors to accommodate visual limitations may represent a potential behavioral public health risk for men. C1 [Sarkin, Andrew J.; Tally, Steven R.; Wooldridge, Jennalee S.; Choi, Kyle; Shieh, Marian] Univ Calif San Diego, Hlth Serv Res Ctr, San Diego, CA 92093 USA. [Kaplan, Robert M.] NIH, Dept Rehabil Med, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Sarkin, AJ (reprint author), Univ Calif San Diego, Hlth Serv Res Ctr, 9500 Gilman Dr 0994, San Diego, CA 92093 USA. EM asarkin@ucsd.edu NR 36 TC 3 Z9 3 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 EI 1573-3610 J9 J COMMUN HEALTH JI J. Community Health PD DEC PY 2013 VL 38 IS 6 BP 1175 EP 1181 DI 10.1007/s10900-013-9730-9 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 248IW UT WOS:000326693600024 PM 23852327 ER PT J AU Clark, K Vendt, B Smith, K Freymann, J Kirby, J Koppel, P Moore, S Phillips, S Maffitt, D Pringle, M Tarbox, L Prior, F AF Clark, Kenneth Vendt, Bruce Smith, Kirk Freymann, John Kirby, Justin Koppel, Paul Moore, Stephen Phillips, Stanley Maffitt, David Pringle, Michael Tarbox, Lawrence Prior, Fred TI The Cancer Imaging Archive (TCIA): Maintaining and Operating a Public Information Repository SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE TCIA; NBIA; Cancer imaging; Image archive; Biomedical image analysis; Cancer detection AB The National Institutes of Health have placed significant emphasis on sharing of research data to support secondary research. Investigators have been encouraged to publish their clinical and imaging data as part of fulfilling their grant obligations. Realizing it was not sufficient to merely ask investigators to publish their collection of imaging and clinical data, the National Cancer Institute (NCI) created the open source National Biomedical Image Archive software package as a mechanism for centralized hosting of cancer related imaging. NCI has contracted with Washington University in Saint Louis to create The Cancer Imaging Archive (TCIA)-an open-source, open-access information resource to support research, development, and educational initiatives utilizing advanced medical imaging of cancer. In its first year of operation, TCIA accumulated 23 collections (3.3 million images). Operating and maintaining a high-availability image archive is a complex challenge involving varied archive-specific resources and driven by the needs of both image submitters and image consumers. Quality archives of any type (traditional library, PubMed, refereed journals) require management and customer service. This paper describes the management tasks and user support model for TCIA. C1 [Clark, Kenneth; Vendt, Bruce; Smith, Kirk; Koppel, Paul; Moore, Stephen; Phillips, Stanley; Maffitt, David; Pringle, Michael; Tarbox, Lawrence; Prior, Fred] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Freymann, John; Kirby, Justin] SAIC Frederick Inc, Clin Res Directorate, CMRP, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Clark, K (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, ERL 510 South Kingshighway Blvd, St Louis, MO 63110 USA. EM clarkk@mir.wustl.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Image Archive Hosting; [10XS220: SAIC-F] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The Washington University component is funded by SUBCONTRACT 10XS220: SAIC-F (PI: Prior) Image Archive Hosting. NR 23 TC 66 Z9 66 U1 1 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 EI 1618-727X J9 J DIGIT IMAGING JI J. Digit. Imaging PD DEC PY 2013 VL 26 IS 6 BP 1045 EP 1057 DI 10.1007/s10278-013-9622-7 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 248KR UT WOS:000326698800008 PM 23884657 ER PT J AU Schwartz, LM Castle, PE Follansbee, S Borgonovo, S Fetterman, B Tokugawa, D Lorey, TS Sahasrabuddhe, VV Luhn, P Gage, JC Darragh, TM Wentzensen, N AF Schwartz, Lauren M. Castle, Philip E. Follansbee, Stephen Borgonovo, Sylvia Fetterman, Barbara Tokugawa, Diane Lorey, Thomas S. Sahasrabuddhe, Vikrant V. Luhn, Patricia Gage, Julia C. Darragh, Teresa M. Wentzensen, Nicolas TI Risk Factors for Anal HPV Infection and Anal Precancer in HIV-Infected Men Who Have Sex With Men SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE anal cancer; human papillomavirus (HPV); human immunodeficiency virus (HIV); men who have sex with men (MSM); anal intraepithelial neoplasia (AIN) ID HUMAN-PAPILLOMAVIRUS INFECTION; INTRAEPITHELIAL NEOPLASIA; ANTIRETROVIRAL THERAPY; CANCER PRECURSORS; HOMOSEXUAL-MEN; UNITED-STATES; END-POINTS; PREVALENCE; EPIDEMIOLOGY; METAANALYSIS AB Background. Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM. Methods. Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer. Results. Low CD4 count (<350 cells/mm(3)) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28-10.40 and OR, 4.24; 95% CI, 1.16-15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43-5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection. Conclusions. We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression. C1 [Schwartz, Lauren M.; Sahasrabuddhe, Vikrant V.; Luhn, Patricia; Gage, Julia C.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Castle, Philip E.] Global Canc Initiat Inc, Chestertown, MD USA. [Follansbee, Stephen; Borgonovo, Sylvia] Kaiser Permanente Med Ctr, San Francisco, CA USA. [Fetterman, Barbara; Tokugawa, Diane; Lorey, Thomas S.] Kaiser Permanente, TPMG Reg Lab, Berkeley, CA USA. [Darragh, Teresa M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 39 TC 18 Z9 18 U1 1 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 DEC 1 PY 2013 VL 208 IS 11 BP 1768 EP 1775 DI 10.1093/infdis/jit374 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 247WQ UT WOS:000326654300007 PM 23908478 ER PT J AU Sourial, N Bergman, H Karunananthan, S Wolfson, C Payette, H Gutierrez-Robledo, LM Beland, F Fletcher, JD Guralnik, J AF Sourial, Nadia Bergman, Howard Karunananthan, Sathya Wolfson, Christina Payette, Helene Gutierrez-Robledo, Luis Miguel Beland, Franois Fletcher, John D. Guralnik, Jack TI Implementing Frailty Into Clinical Practice: A Cautionary Tale SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Frailty; Epidemiology; Functional performance; Risk factors; Outcomes ID ELDERLY-PATIENTS; MAJOR MORBIDITY; CARDIAC-SURGERY; OLDER-ADULTS; GAIT SPEED; ROC CURVE; MORTALITY; OUTCOMES; WOMEN; RISK AB Little is known about the contribution of frailty in improving patient-level prediction beyond readily available clinical information. The objective of this study is to compare the predictive ability of 129 combinations of seven frailty markers (cognition, energy, mobility, mood, nutrition, physical activity, and strength) and quantify their contribution to predictive accuracy beyond age, sex, and number of chronic diseases. Two cohorts from the Established Populations for Epidemiologic Studies of the Elderly were used. The model with the best predictive fit in predicting 6-year incidence of disability was determined using the Akaike Information Criterion. Predictive accuracy was measured by the C statistic. Incident disability was 23% in one cohort and 20% in the other cohort. The best model in each cohort was found to be a model including between five and seven frailty markers including cognition, mobility, nutrition, physical activity, and strength. Predictive accuracy of the 129 models ranged from 0.73 to 0.77 across both cohorts. Adding frailty markers to age, sex, and chronic disease increased predictive accuracy by up to 3% in both cohorts (p < .001). The contribution of frailty increased up to 9% in the oldest age group. Adding frailty markers provided a modest increase in patient-level prediction of disability. Such a modest increase may still be worthwhile because while age, sex, and the number of chronic diseases are not modifiable, frailty may be. Further studies examining the contribution of frailty in improving prediction are needed before adopting frailty as a prognostic tool. C1 [Sourial, Nadia; Bergman, Howard; Karunananthan, Sathya; Beland, Franois; Fletcher, John D.] Jewish Gen Hosp, SOLIDAGE, McGill Univ Univ Montreal Res Grp Frailty & Aging, Ctr Clin Epidemiol, Montreal, PQ, Canada. [Bergman, Howard] McGill Univ, Dept Family Med, Montreal, PQ H2W LS4, Canada. [Bergman, Howard; Beland, Franois] McGill Univ, Div Geriatr Med, Jewish Gen Hosp, Montreal, PQ H2W LS4, Canada. [Bergman, Howard; Beland, Franois] Univ Montreal, Dept Hlth Adm, Montreal, PQ H3C 3J7, Canada. [Karunananthan, Sathya; Wolfson, Christina] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H2W LS4, Canada. [Wolfson, Christina] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ H2W LS4, Canada. [Payette, Helene] Univ Sherbrooke, Res Ctr Aging, Hlth & Social Serv Ctr, Quebec City, PQ, Canada. [Payette, Helene] Univ Sherbrooke, Univ Inst Geriatr Sherbrooke, Quebec City, PQ, Canada. [Guralnik, Jack] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Bergman, H (reprint author), McGill Univ, Dept Family Med, 515-517 Pine Ave West, Montreal, PQ H2W LS4, Canada. EM howard.bergman@mcgill.ca FU Solidage Research Group and Dr. Joseph Kaufmann Chair in Geriatric Medicine, McGill University; Canadian Initiative on Frailty and Aging; Canadian Institutes of Health Research (CIHR) International Opportunity Program Development [68739]; CIHR team grant in frailty and aging [82945]; Fonds de la recherche en sante du Quebec FX This study was supported by grants from the Solidage Research Group and Dr. Joseph Kaufmann Chair in Geriatric Medicine, McGill University; the Canadian Initiative on Frailty and Aging; the Canadian Institutes of Health Research (CIHR) International Opportunity Program Development (68739); the CIHR team grant in frailty and aging (82945); and the Fonds de la recherche en sante du Quebec. NR 40 TC 33 Z9 33 U1 2 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2013 VL 68 IS 12 BP 1505 EP 1511 DI 10.1093/gerona/glt053 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 248DX UT WOS:000326675000006 PM 23640761 ER PT J AU Hirt, C Weitmann, K Schuler, F Kiefer, T Rabkin, CS Hoffmann, W Dolken, G AF Hirt, Carsten Weitmann, Kerstin Schueler, Frank Kiefer, Thomas Rabkin, Charles S. Hoffmann, Wolfgang Doelken, Gottfried TI Circulating t(14;18)-positive cells in healthy individuals: association with age and sex but not with smoking SO LEUKEMIA & LYMPHOMA LA English DT Article DE Follicular lymphoma; t(14;18); lymphomagenesis; healthy individuals ID NON-HODGKINS-LYMPHOMA; OCCUPATIONAL RISK-FACTORS; B-CELLS; T(14/18) TRANSLOCATIONS; BCL-2/IGH REARRANGEMENT; FOLLICULAR LYMPHOMA; CIGARETTE-SMOKING; PERIPHERAL-BLOOD; CARRYING CELLS; UNITED-STATES AB t(14;18)-positive cells can be detected not only in patients with follicular lymphoma (FL) but also in healthy individuals (HIs). We used epidemiological data and blood samples of the population-based Study of Health in Pomerania (SHIP) to analyze associations of FL risk factors and t(14; 18)-positive cells in HIs. Buffy coat samples from 4152 study participants were tested by real-time polymerase chain reaction (PCR) for t(14; 18)-positive cells. Of 3966 evaluable subjects, 1526 were t(14; 18)-PCR positive [38.5%, median 3.9 t(14; 18)-positive per million nucleated cells, range 0.6-9299]. In multivariable analyses, age and sex but not parameters of smoking exposure were significantly associated with t(14; 18) prevalence (logistic regression, p < 0.001). Multivariable analyses of t(14; 18)-frequency showed a positive association with age but not with sex or smoking. These age and sex associations in HIs require careful control in future studies of t(14; 18) as a potential biomarker of lymphoma risk. C1 [Hirt, Carsten; Schueler, Frank; Kiefer, Thomas; Doelken, Gottfried] Univ Med, Dept Hematol & Oncol, Greifswald, Germany. [Weitmann, Kerstin; Hoffmann, Wolfgang] Univ Med, Inst Community Med, Greifswald, Germany. [Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hirt, C (reprint author), Ernst Moritz Arndt Univ Greifswald, Med Ctr, Dept Hematol & Oncol, Ferdinand Sauerbruchstr, D-17475 Greifswald, Germany. EM hirtonko@uni-greifswald.de FU German Federal Ministry of Education and Research (BMBF) [01ZZ96030, 01ZZ0701]; Ministry for Education, Research, and Cultural Affairs; Ministry for Social Affairs of the Federal State of Mecklenburg-West Pomerania FX SHIP is part of the Community Medicine Net (http://www.medizin.uni-greifswald.de/icm) of the University of Greifswald, which is funded by grants from the German Federal Ministry of Education and Research (BMBF, grant 01ZZ96030, 01ZZ0701); the Ministry for Education, Research, and Cultural Affairs; and the Ministry for Social Affairs of the Federal State of Mecklenburg-West Pomerania. NR 34 TC 4 Z9 4 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD DEC PY 2013 VL 54 IS 12 BP 2678 EP 2684 DI 10.3109/10428194.2013.788177 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 247QK UT WOS:000326633700021 PM 23527525 ER PT J AU Bagci, U Udupa, JK Mendhiratta, N Foster, B Xu, ZY Yao, JH Chen, XJ Mollura, DJ AF Bagci, Ulas Udupa, Jayaram K. Mendhiratta, Neil Foster, Brent Xu, Ziyue Yao, Jianhua Chen, Xinjian Mollura, Daniel J. TI Joint segmentation of anatomical and functional images: Applications in quantification of lesions from PET, PET-CT, MRI-PET, and MRI-PET-CT images SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Simultaneous segmentation; PET segmentation; Random Walk; MRI-PET Co-segmentation; PET-CT Co-segmentation ID CELL LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; TARGET VOLUME DELINEATION; FDG-PET; THRESHOLD SEGMENTATION; TUMOR VOLUME; INTEROBSERVER VARIABILITY; ACTIVE CONTOURS; F-18-FDG PET; NECK-CANCER AB We present a novel method for the joint segmentation of anatomical and functional images. Our proposed methodology unifies the domains of anatomical and functional images, represents them in a product lattice, and performs simultaneous delineation of regions based on random walk image segmentation. Furthermore, we also propose a simple yet effective object/background seed localization method to make the proposed segmentation process fully automatic. Our study uses PET, PET-CT, MRI-PET, and fused MRI-PET-CT scans (77 studies in all) from 56 patients who had various lesions in different body regions. We validated the effectiveness of the proposed method on different PET phantoms as well as on clinical images with respect to the ground truth segmentation provided by clinicians. Experimental results indicate that the presented method is superior to threshold and Bayesian methods commonly used in PET image segmentation, is more accurate and robust compared to the other PET-CT segmentation methods recently published in the literature, and also it is general in the sense of simultaneously segmenting multiple scans in real-time with high accuracy needed in routine clinical use. Published by Elsevier B.V. C1 [Bagci, Ulas; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Bethesda, MD 20892 USA. [Bagci, Ulas; Mendhiratta, Neil; Foster, Brent; Xu, Ziyue; Yao, Jianhua; Mollura, Daniel J.] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Udupa, Jayaram K.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Mendhiratta, Neil] NYU, Sch Med, New York, NY USA. [Chen, Xinjian] Soochow Univ, Sch Elect & Informat Engn, Suzhou, Peoples R China. RP Bagci, U (reprint author), NIH, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM ulasbagci@gmail.com RI Xy, Ziyue/K-9438-2014; Chen, Xinjian/E-8592-2016 OI Xy, Ziyue/0000-0002-5728-6869; Bagci, Ulas/0000-0001-7379-6829; FU Center for Infectious Disease Imaging (CIDI); National Institutes of Allergy and Infectious Diseases (NIAID); National Institutes of Bio-imaging and Bioengineering (NIBIB) at the National Institutes of Health (NIH) FX This research is supported by the Center for Infectious Disease Imaging (CIDI), the Intramural Program of the National Institutes of Allergy and Infectious Diseases (NIAID), and the National Institutes of Bio-imaging and Bioengineering (NIBIB) at the National Institutes of Health (NIH). We thank Kristine S. Evers for her editing of this manuscript. NR 72 TC 46 Z9 47 U1 3 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD DEC PY 2013 VL 17 IS 8 BP 929 EP 945 DI 10.1016/j.media.2013.05.004 PG 17 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 247YX UT WOS:000326662000005 PM 23837967 ER PT J AU Yotter, RA Doshi, J Clark, V Sojkova, J Zhou, Y Wong, DF Ferrucci, L Resnick, SM Davatzikos, C AF Yotter, Rachel A. Doshi, Jimit Clark, Vanessa Sojkova, Jitka Zhou, Yun Wong, Dean F. Ferrucci, Luigi Resnick, Susan M. Davatzikos, Christos TI Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyloid; PiB; PET; CVLT; Cognition ID PITTSBURGH COMPOUND-B; PRECLINICAL ALZHEIMERS-DISEASE; MILD COGNITIVE IMPAIRMENT; REFERENCE TISSUE MODEL; A-BETA DEPOSITION; NONDEMENTED INDIVIDUALS; ELDERLY SUBJECTS; OLDER-ADULTS; PET; PIB AB The development of amyloid imaging compounds has allowed in vivo imaging of amyloid deposition. In this study, we examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue (C-11-PiB) positron emission tomography data from the Baltimore Longitudinal Study of Aging. We used a new methodology that allowed us to approximate spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Our results are consistent with patterns of progression known from autopsy studies, with frontal and precuneus regions affected early and occipital and sensorimotor cortices affected later in disease progression-here, disease progression means lower-to-higher total amyloid burden. Furthermore, we divided participants into subgroups based on longitudinal change in memory performance, and demonstrated significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. Our results indicate that the spatial pattern of amyloid deposition is related to cognitive performance and may be more informative than a biomarker reflecting total amyloid burden, the use of which is the current practice. This finding has broad implications for our understanding of the relationship between cognitive decline/resilience and amyloid deposition, as well as for the use of amyloid imaging as a biomarker in research and clinical applications. (C) 2013 Elsevier Inc. All rights reserved. C1 [Yotter, Rachel A.; Doshi, Jimit; Clark, Vanessa; Davatzikos, Christos] Univ Penn, Dept Radiol, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA. [Sojkova, Jitka; Resnick, Susan M.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Sojkova, Jitka; Zhou, Yun; Wong, Dean F.] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Yotter, RA (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, 3600 Market St,Suite 380, Philadelphia, PA 19104 USA. EM rachel.yotter@uphs.upenn.edu FU National Institutes of Health (NIH) [NIA-R01-14971]; Intramural Research Program of the NIH, National Institute on Aging (NIA); NIA Research and Development Contract [HHSN-260-2004-00012C] FX This research was supported in part by National Institutes of Health (NIH) grant NIA-R01-14971, by the Intramural Research Program of the NIH, National Institute on Aging (NIA), and by NIA Research and Development Contract HHSN-260-2004-00012C. R.A.Y. received support from an NIH T-32 Training Grant. We thank the staff of the Johns Hopkins PET facility for their efforts and the BLSA participants for their participation. NR 44 TC 15 Z9 15 U1 2 U2 13 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 DEC PY 2013 VL 34 IS 12 BP 2835 EP 2842 DI 10.1016/j.neurobiolaging.2013.05.030 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 247XQ UT WOS:000326657800015 PM 23859610 ER PT J AU Jawad, S Liu, BY Agron, E Nussenblatt, RB Sen, HN AF Jawad, Shayma Liu, Baoying Agron, Elvira Nussenblatt, Robert B. Sen, H. Nida TI Elevated Serum Levels of Interleukin-17A in Uveitis Patients SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE Cytokine; interleukin 17; serum; Th17; uveitis ID 1ST INTERNATIONAL WORKSHOP; BEHCETS-DISEASE; ANKYLOSING-SPONDYLITIS; T-CELLS; EXPRESSION; IL-17; CYTOKINE; IL-23; AUTOIMMUNITY; ASSOCIATION AB Purpose: T helper 17 cells (Th17) are one of the main pathogenic effectors in autoimmune uveitis, and IL-17A is the signature cytokine of Th17 cells. This study aims to assess serum IL-17A levels in patients with autoimmune uveitis and evaluate associations between IL-17A levels and disease characteristics. Methods: Serum IL-17A levels from 87 autoimmune uveitis patients and 60 healthy controls were assessed using an enzyme-linked immunosorbent assay. Among this cohort, 9 patients were followed longitudinally for IL-17A levels during active and inactive stages of their disease. Results: Median serum IL-17A levels were higher among uveitis patients compared to controls (p<0.0001). Moreover, IL-17A levels were elevated among uveitis patients with active disease compared to those with inactive disease (p = 0.0202). Among the 9 patients followed longitudinally, IL-17A levels were elevated during active disease compared to the inactive stage (p = 0.0078). Conclusions: Serum IL-17A levels are elevated in uveitis patients, particularly in active uveitis. C1 [Jawad, Shayma; Liu, Baoying; Nussenblatt, Robert B.; Sen, H. Nida] NEI, Clin Immunol Lab, NIH, Bethesda, MD 20892 USA. [Agron, Elvira] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), Immunol Lab, Bldg 10,Room 10N109,10 Ctr Dr, Bethesda, MD 20814 USA. EM hatice.sen@nih.gov FU Laboratory of Immunology; National Eye Institute FX We would like to thank the Laboratory of Immunology and National Eye Institute Intramural Research Program for their support. NR 33 TC 8 Z9 8 U1 1 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0927-3948 EI 1744-5078 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD DEC PY 2013 VL 21 IS 6 BP 434 EP 439 DI 10.3109/09273948.2013.815786 PG 6 WC Ophthalmology SC Ophthalmology GA 252EG UT WOS:000326987300003 PM 23957503 ER PT J AU Cesta, MF Hard, GC Boyce, JT Ryan, MJ Chan, PC Sills, RC AF Cesta, Mark F. Hard, Gordon C. Boyce, John T. Ryan, Michael J. Chan, Po C. Sills, Robert C. TI Complex Histopathologic Response in Rat Kidney to Oral beta-myrcene: An Unusual Dose-related Nephrosis and Low-dose Alpha2u-Globulin Nephropathy SO TOXICOLOGIC PATHOLOGY LA English DT Article DE kidney; nephropathy; beta-myrcene; alpha2u-globulin; rat ID HYALINE DROPLET NEPHROPATHY; ALPHA-2U-GLOBULIN; ASSOCIATION; CPN AB Oral gavage studies with -myrcene in male F344 rats showed a complex renal pathology comprising both alpha2u-globulin (2u-g) nephropathy, an unusual nephrosis involving the outer stripe of outer medulla (OSOM), and an increased incidence of renal tubule tumors by 2 years. In the 90-day and 2-year studies, respectively, 2u-g nephropathy and linear papillary mineralization were observed in males at the two lower doses but were absent from the high dose. Nephrosis was characterized by dilation of the S3 tubules, nuclear enlargement (including karyomegaly), and luminal pyknotic cells, all in the outermost OSOM. Nephrosis was minimal at the higher doses in the 90-day study, but progressed to a severe grade in males dosed with 1,000 mg/kg for 2 years. Renal tubule tumors developed in treated groups with incidences up to 30% in the 250 and 500 mg/kg male dose groups. Tumors at the lower doses in males may have been associated with 2u-g nephropathy, while those at higher doses in both sexes may have been due to the nephrosis. Because -myrcene induced a complex spectrum of renal pathology, the 2u-g nephropathy mechanism cannot be the sole mechanism of carcinogenesis in these rats. C1 [Cesta, Mark F.; Chan, Po C.; Sills, Robert C.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Boyce, John T.] Beechy Ridge Toxpath, Clay, WV USA. [Ryan, Michael J.] Battelle Columbus, Columbus, OH USA. RP Cesta, MF (reprint author), NIEHS, Natl Toxicol Program, 111 TW Alexander Dr,Rm B337,POB 12233,MD B3-06, Res Triangle Pk, NC 27709 USA. EM cesta@niehs.nih.gov FU Division of the National Toxicology Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC; NIEHS, NIH [NO1-ES-95435] FX This work was supported by the Division of the National Toxicology Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC. However, the statements, opinions, or conclusions contained herein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the U. S. Government. Dr Hard's efforts in this project were supported, in part, by Federal funds from the NIEHS, NIH, under contract NO1-ES-95435 to Experimental Pathology Laboratories Inc., Research Triangle Park, NC. The authors wish to thank Ms. Natasha Clayton and Mr. David Olson for preparing the immunohistochemical stains, and Drs. David Malarkey and Kyathanahalli Janardhan for their review of this article. NR 16 TC 2 Z9 2 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD DEC PY 2013 VL 41 IS 8 BP 1068 EP 1077 DI 10.1177/0192623313482057 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA 248CI UT WOS:000326670900003 PM 23531794 ER PT J AU Sanford, BJ Emerson, SU Purcell, RH Engle, RE Dryman, BA Cecere, TE Buechner-Maxwell, V Sponenberg, DP Meng, XJ AF Sanford, B. J. Emerson, S. U. Purcell, R. H. Engle, R. E. Dryman, B. A. Cecere, T. E. Buechner-Maxwell, V. Sponenberg, D. P. Meng, X. J. TI Serological Evidence for a Hepatitis E Virus-Related Agent in Goats in the United States SO TRANSBOUNDARY AND EMERGING DISEASES LA English DT Article DE hepatitis E virus; animal reservoir; goat; prospective study; experimental infection; neutralizing antibodies ID CROSS-SPECIES INFECTION; ANTI-HEV ANTIBODIES; TRANSPLANT RECIPIENTS; ZOONOTIC TRANSMISSION; NEUROLOGIC DISORDERS; DOMESTIC-ANIMALS; RHESUS-MONKEYS; BLOOD-DONORS; PIG-LIVER; WILD RATS AB Hepatitis E virus (HEV) causes an important public health disease in many developing countries and is also endemic in some industrialized countries. In addition to humans, strains of HEV have been genetically identified from pig, chicken, rat, mongoose, deer, rabbit and fish. While the genotypes 1 and 2 HEV are restricted to humans, the genotypes 3 and 4 HEV are zoonotic and infect humans and other animal species. As a part of our ongoing efforts to search for potential animal reservoirs for HEV, we tested goats from Virginia for evidence of HEV infection and showed that 16% (13/80) of goat sera from Virginia herds were positive for IgG anti-HEV. Importantly, we demonstrated that neutralizing antibodies to HEV were present in selected IgG anti-HEV positive goat sera. Subsequently, in an attempt to genetically identify the HEV-related agent from goats, we conducted a prospective study in a closed goat herd with known anti-HEV seropositivity and monitored a total of 11 kids from the time of birth until 14weeks of age for evidence of HEV infection. Seroconversion to IgG anti-HEV was detected in seven of the 11 kids, although repeated attempts to detect HEV RNA by a broad-spectrum nested RT-PCR from the faecal and serum samples of the goats that had seroconverted were unsuccessful. In addition, we also attempted to experimentally infect laboratory goats with three well-characterized mammalian strains of HEV but with no success. The results indicate that a HEV-related agent is circulating and maintained in the goat population in Virginia and that the goat HEV is likely genetically very divergent from the known HEV strains. C1 [Sanford, B. J.; Dryman, B. A.; Cecere, T. E.; Buechner-Maxwell, V.; Sponenberg, D. P.; Meng, X. J.] Virginia Tech, Coll Vet Med, Dept Biomed Sci & Pathobiol, Ctr Mol Med & Infect Dis,Virginia Polytech Inst &, Blacksburg, VA USA. [Emerson, S. U.; Purcell, R. H.; Engle, R. E.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Meng, XJ (reprint author), Virginia Polytech Inst & State Univ, Coll Vet Med, Dept Biomed Sci & Pathobiol, 1981 Kraft Dr, Blacksburg, VA 24060 USA. EM xjmeng@vt.edu RI Meng, X.J./B-8769-2009; Cecere, Thomas/N-9266-2016 OI Meng, X.J./0000-0002-2739-1334; FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; NIH intramural contract [HHSN272200800962P]; NIH [AI065546, AI050611] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases and by a NIH intramural contract (HHSN272200800962P) and in part by extramural grants from NIH (AI065546 and AI050611). We thank Pete Jobst, Marlice Vonck, Pam Mohr and Shannon Viers at the Virginia Tech Animal Facility for their assistance. NR 61 TC 10 Z9 10 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1865-1674 EI 1865-1682 J9 TRANSBOUND EMERG DIS JI Transbound. Emerg. Dis. PD DEC PY 2013 VL 60 IS 6 BP 538 EP 545 DI 10.1111/tbed.12001 PG 8 WC Infectious Diseases; Veterinary Sciences SC Infectious Diseases; Veterinary Sciences GA 248JU UT WOS:000326696500006 PM 22909079 ER PT J AU Shi, M Lemey, P Brar, MS Suchard, MA Murtaugh, MP Carman, S D'Allaire, S Delisle, B Lambert, ME Gagnon, CA Ge, L Qu, YH Yoo, D Holmes, EC Leung, FCC AF Shi, Mang Lemey, Philippe Brar, Manreetpal Singh Suchard, Marc A. Murtaugh, Michael P. Carman, Susy D'Allaire, Sylvie Delisle, Benjamin Lambert, Marie-Eve Gagnon, Carl A. Ge, Li Qu, Yihan Yoo, Dongwan Holmes, Edward C. Leung, Frederick Chi-Ching TI The spread of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) in North America: A phylogeographic approach SO VIROLOGY LA English DT Article DE Phylogeography; PRRSV; Evolution; Recombination; Molecular epidemiology ID RECOMBINATION; SEQUENCES; EVOLUTIONARY; PHYLOGENIES; MODELS AB The emergence and spread of Type 2 Porcine Reproductive and Respiratory Syndrome virus (Type 2 PRRSV) in North America is heavily influenced by the multiple site production system used in the hog industry. However, it is unclear how anthropogenic factors such has this have shaped the current spatial distribution of PRRSV genotypes. We employed Bayesian phylogeographic analyses of 7040 ORF5 sequences to reveal the recent geographical spread of Type 2 PRRSV in North America. The directions and intensities in our inferred virus traffic network closely mirror the hog transportation. Most notably, we reveal multiple viral introductions from Canada into the United States causing a major shift in virus genetic composition in the Midwest USA that went unnoticed by the regular surveillance and field epidemiological studies. Overall, these findings provide important insights into the dynamics of Type 2 PRRSV evolution and spread that will facilitate programs for control and prevention. (C) 2013 Elsevier Inc. All rights reserved. C1 [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Lemey, Philippe] Katholieke Univ Leuven, Rega Inst, Dept Microbiol & Immunol, B-3000 Louvain, Belgium. [Brar, Manreetpal Singh; Leung, Frederick Chi-Ching] Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China. [Suchard, Marc A.] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Murtaugh, Michael P.] Univ Minnesota, Dept Vet & Biomed Sci, St Paul, MN 55108 USA. [Carman, Susy; Ge, Li] Univ Guelph, Lab Serv Div, Hlth Anim Lab, Guelph, ON N1H 6R8, Canada. [D'Allaire, Sylvie; Delisle, Benjamin; Lambert, Marie-Eve; Gagnon, Carl A.] Univ Montreal, Fac Med Vet, St Hyacinthe, PQ J2S 7C6, Canada. [Qu, Yihan] Univ Sydney, Fac Agr & Environm, Sydney, NSW 2006, Australia. [Yoo, Dongwan] Univ Illinois, Coll Vet Med, Urbana, IL 61801 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Leung, Frederick Chi-Ching] Nanjing Agr Univ, Bioinformat Ctr, Nanjing, Jiangsu, Peoples R China. RP Leung, FCC (reprint author), Univ Hong Kong, Sch Biol Sci, Hong Kong, Hong Kong, Peoples R China. EM fcleung@hkucc.hku.hk RI Gagnon, Carl/A-9239-2015; OI Holmes, Edward/0000-0001-9596-3552 FU Research Grant Council of the Hong Kong Government [GRF770612]; HKU Strategic Research Theme of Infection and Immunology; European Community's Seventh Framework Programme [278433]; ERC [260864]; International Postgraduate Research Scholarship from the University of Sydney; NHMRC Australia FX This work was supported by grants from the Research Grant Council of the Hong Kong Government (GRF770612) and HKU Strategic Research Theme of Infection and Immunology to FCL and from the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement no. 278433 and ERC (Grant agreement no. 260864) to PL. MS is supported by an International Postgraduate Research Scholarship from the University of Sydney, while ECH is supported by an NHMRC Australia Fellowship. Special thanks are given to Kay Faaberg, National Animal Disease Center, Ames, IA, and Trevor Wennblom, University of Minnesota, Minneapolis, MN, for database maintenance. NR 27 TC 13 Z9 13 U1 2 U2 18 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 DEC PY 2013 VL 447 IS 1-2 BP 146 EP 154 DI 10.1016/j.virol.2013.08.028 PG 9 WC Virology SC Virology GA 246QF UT WOS:000326553500016 PM 24210109 ER PT J AU Cortes-Malagon, EM Bonilla-Delgado, J Diaz-Chavez, J Hidalgo-Miranda, A Romero-Cordoba, S Uren, A Celik, H McCormick, M Munguia-Moreno, JA Ibarra-Sierra, E Escobar-Herrera, J Lambert, PF Mendoza-Villanueva, D Bermudez-Cruz, RM Gariglio, P AF Cortes-Malagon, Enoc M. Bonilla-Delgado, Jose Diaz-Chavez, Jose Hidalgo-Miranda, Alfredo Romero-Cordoba, Sandra Ueren, Aykut Celik, Haydar McCormick, Matthew Munguia-Moreno, Jose A. Ibarra-Sierra, Eloisa Escobar-Herrera, Jaime Lambert, Paul F. Mendoza-Villanueva, Daniel Bermudez-Cruz, Rosa M. Gariglio, Patricio TI Gene expression profile regulated by the HPV16 E7 oncoprotein and estradiol in cervical tissue SO VIROLOGY LA English DT Article DE HPV16 E7; 17 beta-estradiol; Microarrays; Cervix; Carcinogenesis; K14E7 ID HUMAN-PAPILLOMAVIRUS TYPE-16; ESTROGEN-RECEPTOR-ALPHA; SQUAMOUS-CELL CARCINOMA; TRANSGENIC MOUSE MODEL; INTRAEPITHELIAL NEOPLASIA; EPITHELIAL-CELLS; HUMAN KERATINOCYTES; DIAGNOSTIC MARKERS; PERIPHERAL-BLOOD; UP-REGULATION AB The HPV16 E7 oncoprotein and 17 beta-estradiol are important factors for the induction of premalignant lesions and cervical cancer. The study of these factors is crucial for a better understanding of cervical tumorigenesis. Here, we assessed the global gene expression profiles induced by the HPV16 E7 oncoprotein and/or 17 beta-estradiol in cervical tissue of FvB and K14E7 transgenic mice. We found that the most dramatic changes in gene expression occurred in K14E7 and FvB groups treated with 17 beta-estradiol. A large number of differentially expressed genes involved in the immune response were observed in 17 beta-estradiol treated groups. The E7 oncoprotein mainly affected the expression of genes involved in cellular metabolism. Our microarray data also identified differentially expressed genes that have not previously been reported in cervical cancer. The identification of genes regulated by E7 and 17 beta-estradiol, provides the basis for further studies on their role in cervical carcinogenesis. (C) 2013 Elsevier Inc. All rights reserved. C1 [Cortes-Malagon, Enoc M.; Munguia-Moreno, Jose A.; Bermudez-Cruz, Rosa M.; Gariglio, Patricio] Ctr Invest & Estudios Avanzados Cinvestav, Dept Genet & Mol Biol, Mexico City 07360, DF, Mexico. [Escobar-Herrera, Jaime] Ctr Invest & Estudios Avanzados Cinvestav, Dept Cell Biol, Mexico City 07360, DF, Mexico. [Cortes-Malagon, Enoc M.; Bonilla-Delgado, Jose] Hosp Juarez Mexico, Res Unit, Mexico City 07760, DF, Mexico. [Diaz-Chavez, Jose] UNAM Inst Nacl Cancerol INCan, Unit Biomed Res Canc, Mexico City 14080, DF, Mexico. [Hidalgo-Miranda, Alfredo; Romero-Cordoba, Sandra] Inst Nacl Med Genom INMEGEN, Oncogen Dept, Mexico City 14610, DF, Mexico. [Ueren, Aykut; Celik, Haydar; McCormick, Matthew] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC 20057 USA. [Ibarra-Sierra, Eloisa] Inst Estatal Cancerol, Res Lab, Acapulco 39570, Guerrero, Mexico. [Lambert, Paul F.] Univ Wisconsin, McArdle Lab Canc Res, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Mendoza-Villanueva, Daniel] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Gariglio, P (reprint author), Ctr Invest & Estudios Avanzados Cinvestav, Dept Genet & Mol Biol, Av Inst Politecn Nacl 2508, Mexico City 07360, DF, Mexico. EM enoc.cortes@salud.gob.mx; jose.bonilla@salud.gob.mx; josediaz030178@hotmail.com; ahidalgo@inmegen.gob.mx; sromero_cordoba@hotmail.com; au26@georgetown.edu; hc547@georgetown.edu; mjm444@georgetown.edu; antoniomgeminis@yahoo.com.mx; eibarra@cinvestav.mx; moemras@yahoo.com; plambert@wisc.edu; daniel.mendozavillanueva@nih.gov; roberm@cinvestav.mx; vidal@cinvestav.mx RI Hidalgo-Miranda, Alfredo/B-2123-2010; Romero-Cordoba, Sandra Lorena/A-2246-2014 OI Hidalgo-Miranda, Alfredo/0000-0003-2315-3977; Romero-Cordoba, Sandra Lorena/0000-0002-5591-696X FU Intramural Research Program of the NIH; NCI; CONACYT; NIH [R01CA120847, P01CA022443]; [ICYT326/11] FX The authors would like to thank to Raul Mojica (INMEGEN), Laura Uribe Figueroa (INMEGEN), Enrique Garcia Villa, Elizabeth Alvarez Rios, Rodolfo Ocadiz Delgado and Lauro Macias Gonzales for technical support. P.G. was supported by grants from the ICYT326/11 to perform this work. This research was supported in part by the Intramural Research Program of the NIH, NCI and CONACYT (D.M.V.). P.F.L. was supported by grants from the NIH: R01CA120847 and P01CA022443. This study was performed in partial fulfillment of the requirement for the doctoral degree of E.M.C.M. in Biomedical Sciences at Universidad Nacional Autonoma de Mexico. NR 76 TC 11 Z9 12 U1 1 U2 17 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 DEC PY 2013 VL 447 IS 1-2 BP 155 EP 165 DI 10.1016/j.virol.2013.08.036 PG 11 WC Virology SC Virology GA 246QF UT WOS:000326553500017 PM 24210110 ER PT J AU Song, HF Sidney, J Wiseman, RW Josleyn, N Cohen, M Blaney, JE Jahrling, PB Sette, A AF Song, Haifeng Sidney, John Wiseman, Roger W. Josleyn, Nicole Cohen, Melanie Blaney, Joseph E. Jahrling, Peter B. Sette, Alessandro TI Characterizing monkeypox virus specific CD8+T cell epitopes in rhesus macaques SO VIROLOGY LA English DT Article DE Monkeypox virus; Rhesus; T cell epitopes; CD8+T cells; Bioinformatics analysis; Peptides; Elispot ID SIMIAN IMMUNODEFICIENCY VIRUS; I MOLECULE MAMU-A-ASTERISK-01; VACCINIA VIRUS; LETHAL MONKEYPOX; SMALLPOX VACCINE; IMMUNE-RESPONSE; PEPTIDE BINDING; INFECTION; CHALLENGE; PROTECTS AB To characterize T cell epitopes in monkeypox virus (MPXV) infected rhesus macaques, we utilized IFN gamma Elispot assay to screen 400 predicted peptides from 20 MPXV proteins. Two peptides from the F8L protein, an analog of E9L protein in vaccinia, were found to elicit CD8+ T cell responses. Prediction and in vitro MHC binding analyses suggest that one is restricted by Mamu-A1*001 and another by Mamu-A1*002. The Mamu-A1*002 epitope is completely identical in all reported sequences for variola, vaccinia, cowpox and MPXV. The Mamu-A1*001 epitope is conserved in MPXV and vaccinia, and has one residue substitution (V6 > I) in some cowpox sequences and all variola sequences. Given CD8(+) T-cell epitopes from E9L were also identified in humans and mice, our data suggested that F8L/E9L may be a dominant pox viral protein for CD8+ T cell responses, and may be considered as a target when designing vaccines that target pox-specific T cell responses. (C) 2013 Elsevier Inc. All rights reserved. C1 [Song, Haifeng; Josleyn, Nicole; Cohen, Melanie; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. [Sidney, John; Sette, Alessandro] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. [Wiseman, Roger W.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Blaney, Joseph E.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. RP Song, HF (reprint author), NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. EM songhai@mail.nih.gov; alex@liai.org FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [HHSN272200700016I]; PHS HHS [HHSN272200700016I] NR 34 TC 0 Z9 0 U1 0 U2 4 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 DEC PY 2013 VL 447 IS 1-2 BP 181 EP 186 DI 10.1016/j.virol.2013.09.003 PG 6 WC Virology SC Virology GA 246QF UT WOS:000326553500020 PM 24210113 ER PT J AU Gill, RB Bowman, JJ Krogmann, T Wollenberg, K Asher, DM Cohen, JI AF Gill, Rachel B. Bowman, J. Jason Krogmann, Tammy Wollenberg, Kurt Asher, David M. Cohen, Jeffrey I. TI Coding potential of UL/b ' from the initial source of rhesus cytomegalovirus Strain 68-1 SO VIROLOGY LA English DT Article DE Human cytomegalovirus; Rhesus cytomegalovirus; Cercopithecine herpesvirus: macacine herpesvirus 3; Cynomolgus macaque cytomegalovirus; UL/b ' ID ENDOTHELIAL-CELLS; ANTIBODY-RESPONSE; IN-VITRO; MACAQUES; COMPLEX; INFECTION; ENCODES; GENES; REPLICATION; CHEMOKINE AB Rhesus cytomegalovirus (RhCMV) 68-1 is the prototypic strain of RhCMV that has been used for pathogenesis and vaccine development. We determined the complete sequence of the RhCMV 68-1 UL/b' region directly from the original urine from which RhCMV 68-1 was isolated in 1968, and compared it to other RhCMVs. The laboratory passaged RhCMV 68-1 has inversions, deletions, and stop codons in UL/b' that are absent in the original isolate and other low passage RhCMV isolates. Fourteen of the 17 open reading frames (ORFs) in 68-1 UL/b' in the original isolate share >95% amino acid identity with low passage RhCMV. The original isolate retains 6 ORFs that encode alpha-chemokine-like proteins, including RhUL146 and RhUL146b that share only 92% and 81% amino acid identity, respectively, with a contemporary low passage RhCMV isolate. Identification of the original RhCMV 68-1 UL/b' sequence is important for using RhCMV 68-1 in pathogenesis and vaccine studies. (C) 2013 Elsevier Inc. All rights reserved. C1 [Gill, Rachel B.; Bowman, J. Jason; Krogmann, Tammy; Cohen, Jeffrey I.] NIH, Med Virol Sect, Infect Dis Lab, Bethesda, MD 20892 USA. [Wollenberg, Kurt] NIH, Bioinformat & Computat Biosci Branch, Bethesda, MD 20892 USA. [Asher, David M.] US FDA, Lab Bacterial & Transmissible Spongiform Encephal, Div Emerging & Transfus Transmitted Dis, Rockville, MD 20852 USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, Bldg 50,Rm 6134,50 South Dr,MSC1807, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This study was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. We thank Anita Mora and Heather Murphy of Rocky Mountain Laboratories (NIAID) for their assistance with artwork, Yanmei Wang for assistance with viral DNA quantification, and Peter Barry for advice with sequencing. NR 44 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC PY 2013 VL 447 IS 1-2 BP 208 EP 212 DI 10.1016/j.virol.2013.08.026 PG 5 WC Virology SC Virology GA 246QF UT WOS:000326553500023 PM 24210116 ER PT J AU Yang, ZL Maruri-Avidal, L Sisler, J Stuart, CA Moss, B AF Yang, Zhilong Maruri-Avidal, Liliana Sisler, Jerry Stuart, Carey A. Moss, Bernard TI Cascade regulation of vaccinia virus gene expression is modulated by multistage promoters SO VIROLOGY LA English DT Article DE Poxvirus transcription; mRNA Synthesis; Consensus promoter sequence; Regulation of gene expression ID EARLY TRANSCRIPTION FACTOR; INTERMEDIATE-STAGE GENES; GENOME-WIDE ANALYSIS; PROTEIN INTERACTIONS; MUTATIONAL ANALYSIS; DNA-REPLICATION; BINDING PROTEIN; IN-VITRO; H5R GENE; PURIFICATION AB Vaccinia virus contains similar to 200 genes classified temporally as early, intermediate or late. We analyzed 53 intermediate promoters to determine whether any have dual late promoter activity. Our strategy involved (i) construction of a cell line that stably expressed the three late transcription factors, (ii) infection with a vaccinia virus mutant that expresses RNA polymerase but neither intermediate nor late transcription factors, and (iii) transfection with plasmids containing a luciferase reporter regulated by an intermediate promoter. After confirming the specificity of the system for late promoters, we found that many intermediate promoters had late promoter activity, the strength of which correlated with a TAAAT at the initiator site and T-content from positions -12 to -8 of the coding strand. In contrast, intermediate promoter activity correlated with the A-content from positions -22 to -14. The sequence correlations were confirmed by altering the specificities of strict intermediate and late promoters. Published by Elsevier Inc. C1 [Yang, Zhilong; Maruri-Avidal, Liliana; Sisler, Jerry; Stuart, Carey A.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX We thank Catherine Cotter for maintenance of cell cultures, Yan Xiang for antibody to the A14 protein, members of our laboratory for helpful discussions, and the NIAID Biological Imaging Section for help with confocal microscopy. Research support was provided by the Division of Intramural Research, NIAID, NIH. NR 33 TC 3 Z9 4 U1 2 U2 9 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 DEC PY 2013 VL 447 IS 1-2 BP 213 EP 220 DI 10.1016/j.virol.2013.09.007 PG 8 WC Virology SC Virology GA 246QF UT WOS:000326553500024 PM 24210117 ER PT J AU Vargas-Inchaustegui, DA Xiao, P Hogg, AE Demberg, T McKinnon, K Venzon, D Brocca-Cofano, E DiPasquale, J Lee, EM Hudacik, L Pal, R Sui, YJ Berzofsky, JA Liu, LD Langermann, S Robert-Guroff, M AF Vargas-Inchaustegui, Diego A. Xiao, Peng Hogg, Alison E. Demberg, Thorsten McKinnon, Katherine Venzon, David Brocca-Cofano, Egidio DiPasquale, Janet Lee, Eun M. Hudacik, Lauren Pal, Ranajit Sui, Yongjun Berzofsky, Jay A. Liu, Linda Langermann, Solomon Robert-Guroff, Marjorie TI Immune targeting of PD-1(hi) expressing cells during and after antiretroviral therapy in SIV-infected rhesus macaques SO VIROLOGY LA English DT Article DE PD-1; Treg; ART; Immunomodulation; Viremia ID CHRONIC VIRAL-INFECTION; CD8(+) T-CELLS; SIMIAN IMMUNODEFICIENCY; HIV-INFECTION; FOLLICULAR HELPER; TREG CELLS; BLOCKADE; RESPONSES; VACCINATION; CD4(+) AB High-level T cell expression of PD-1 during Sly infection is correlated with impaired proliferation and function. We evaluated the phenotype and distribution of T cells and Tregs during antiretroviral therapy plus PD-1 modulation (using a B7-DC-Ig fusion protein) and post-ART. Chronically Sly-infected rhesus macaques received: 11 weeks of ART (Group A); 11 weeks of ART plus B7-DC-Ig (Group B); 11 weeks of ART plus B7-DC-Ig, then 12 weeks of B7-DC-Ig alone (Group C). Continuous B7-DC-Ig treatment (Group C) decreased rebound viremia post-ART compared to pre-ART levels, associated with decreased PD-1(hi) expressing T cells and Tregs in PBMCs, and PD-1(hi) Tregs in lymph nodes. It transiently decreased expression of Ki67 and alpha(4)beta(7) in PBMC CD4(+) and CD8(+) Tregs for up to 8 weeks post-ART and maintained Ag-specific T-cell responses at low levels. Continued immune modulation targeting PD-1(hi) cells during and post-ART helps maintain lower viremia, keeps a favorable T cell/Treg repertoire and modulates antigen-specific responses. Published by Elsevier Inc. C1 [Vargas-Inchaustegui, Diego A.; Xiao, Peng; Hogg, Alison E.; Demberg, Thorsten; McKinnon, Katherine; Brocca-Cofano, Egidio; DiPasquale, Janet; Sui, Yongjun; Berzofsky, Jay A.; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Lee, Eun M.; Hudacik, Lauren; Pal, Ranajit] Adv Biosci Labs Inc, Rockville, MD 20850 USA. [Liu, Linda] Amplimmune Inc, Gaithersburg, MD 20878 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute FX We gratefully acknowledge the animal caretakers at Advanced BioScience Laboratories, Inc., for their expert care of our rhesus macaques and collection of serial samples. The following reagents were obtained through the NIH Nonhuman Primate Reagent Resource: Alpha-4/beta-7-APC and CD4-Qdot 655. The following reagent was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: SIVmac239 Gag peptides, Complete Set. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 68 TC 6 Z9 6 U1 0 U2 10 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 DEC PY 2013 VL 447 IS 1-2 BP 274 EP 284 DI 10.1016/j.virol.2013.09.015 PG 11 WC Virology SC Virology GA 246QF UT WOS:000326553500031 PM 24210124 ER PT J AU Zhang, LM Alter, HJ Wang, HP Jia, SZ Wang, E Marincola, FM Shih, JWK Wang, RY AF Zhang, Lumin Alter, Harvey J. Wang, Haiping Jia, Shuaizheng Wang, Ena Marincola, Francesco M. Shih, James W. -K. Wang, Richard Y. TI The modulation of hepatitis C virus 1a replication by PKR is dependent on NF-kB mediated interferon beta response in Huh7.5.1 cells (vol 438, pg 28, 2013) SO VIROLOGY LA English DT Correction C1 [Zhang, Lumin; Alter, Harvey J.; Wang, Ena; Marincola, Francesco M.; Wang, Richard Y.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Wang, Haiping] Acad Mil Med Sci, Affiliated Hosp, Dept Transfus Med, Beijing, Peoples R China. [Jia, Shuaizheng] Beijing Inst Transfus Med, Beijing, Peoples R China. [Shih, James W. -K.] Xiamen Univ, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen, Peoples R China. RP Wang, RY (reprint author), NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM rwang@cc.nih.gov RI zhang, lumin/R-3456-2016 NR 1 TC 0 Z9 0 U1 0 U2 7 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 DEC PY 2013 VL 447 IS 1-2 BP 339 EP 339 DI 10.1016/j.virol.2013.08.007 PG 1 WC Virology SC Virology GA 246QF UT WOS:000326553500038 ER PT J AU Robert, V Vu, D Amor, AB van de Wiele, N Brouwer, C Jabas, B Szoke, S Dridi, A Triki, M ben Daoud, S Chouchen, O Vaas, L de Cock, A Stalpers, JA Stalpers, D Verkley, GJM Groenewald, M dos Santos, FB Stegehuis, G Li, W Wu, LH Zhang, R Ma, JC Zhou, MM Gorjon, SP Eurwilaichitr, L Ingsriswang, S Hansen, K Schoch, C Robbertse, B Irinyi, L Meyer, W Cardinali, G Hawksworth, DL Taylor, JW Crous, PW AF Robert, Vincent Duong Vu Amor, Ammar Ben Hadj van de Wiele, Nathalie Brouwer, Carlo Jabas, Bernard Szoke, Szaniszlo Dridi, Ahmed Triki, Maher ben Daoud, Samy Chouchen, Oussema Vaas, Lea de Cock, Arthur Stalpers, Joost A. Stalpers, Dora Verkley, Gerard J. M. Groenewald, Marizeth dos Santos, Felipe Borges Stegehuis, Gerrit Li, Wei Wu, Linhuan Zhang, Run Ma, Juncai Zhou, Miaomiao Gorjon, Sergio Perez Eurwilaichitr, Lily Ingsriswang, Supawadee Hansen, Karen Schoch, Conrad Robbertse, Barbara Irinyi, Laszlo Meyer, Wieland Cardinali, Gianluigi Hawksworth, David L. Taylor, John W. Crous, Pedro W. TI MycoBank gearing up for new horizons SO IMA FUNGUS LA English DT Article DE MycoBank; EUBOLD identification services; Forum; Fungi; International Nucleotide Sequence Database Collaboration; Next Generation Sequencing; Nomenclature; Registration; Repositories; Typification AB MycoBank, a registration system for fungi established in 2004 to capture all taxonomic novelties, acts as a coordination hub between repositories such as Index Fungorum and Fungal Names. Since January 2013, registration of fungal names is a mandatory requirement for valid publication under the International Code of Nomenclature for algae, fungi and plants (ICN). This review explains the database innovations that have been implemented over the past few years, and discusses new features such as advanced queries, registration of typification events (MBT numbers for lecto, epi- and neotypes), the multi-lingual database interface, the nomenclature discussion forum, annotation system, and web services with links to third parties. MycoBank has also introduced novel identification services, linking DNA sequence data to numerous related databases to enable intelligent search queries. Although MycoBank fills an important void for taxon registration, challenges for the future remain to improve links between taxonomic names and DNA data, and to also introduce a formal system for naming fungi known from DNA sequence data only. To further improve the quality of MycoBank data, remote access will now allow registered mycologists to act as MycoBank curators, using Citrix software. C1 [Robert, Vincent; Duong Vu; Amor, Ammar Ben Hadj; van de Wiele, Nathalie; Brouwer, Carlo; Jabas, Bernard; Szoke, Szaniszlo; Dridi, Ahmed; Triki, Maher; ben Daoud, Samy; Chouchen, Oussema; Vaas, Lea; de Cock, Arthur; Stalpers, Joost A.; Stalpers, Dora; Verkley, Gerard J. M.; Groenewald, Marizeth; dos Santos, Felipe Borges; Stegehuis, Gerrit; Zhou, Miaomiao] CBS KNAW Fungal Biodivers Ctr, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Li, Wei; Wu, Linhuan; Zhang, Run; Ma, Juncai] Chinese Acad Sci, Inst Microbiol, Beijing 100101, Peoples R China. [Gorjon, Sergio Perez] Univ Salamanca, Salamanca 37007, Spain. [Eurwilaichitr, Lily; Ingsriswang, Supawadee] Natl Ctr Genet Engn & Biotechnol BIOTEC, Klongluang 12120, Pathumthani, Thailand. [Hansen, Karen] Swedish Museum Nat Hist S, Dept Cryptogam Bot, S-10405 Stockholm, Sweden. [Schoch, Conrad; Robbertse, Barbara] NIH, Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Irinyi, Laszlo; Meyer, Wieland] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Res Lab,Ctr Infect Dis & Microbiol,Westmead Hosp, Westmead Millennium Inst,Sydney Med Sch, Sydney, NSW, Australia. [Irinyi, Laszlo; Meyer, Wieland] Westmead Hosp, Sydney, NSW, Australia. [Cardinali, Gianluigi] Univ Perugia, Dip Biol Appl, I-06121 Perugia, Italy. [Hawksworth, David L.] Univ Complutense Madrid, Fac Farm, Dept Biol Vegetal 2, E-28040 Madrid, Spain. [Hawksworth, David L.] Nat Hist Museum, Dept Life Sci, London SW7 5BD, England. [Hawksworth, David L.] Royal Bot Gardens, Mycol Sect, Richmond TW9 3DS, Surrey, England. [Taylor, John W.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA. RP Robert, V (reprint author), CBS KNAW Fungal Biodivers Ctr, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. EM v.robert@cbs.knaw.nl RI Crous, Pedro/H-1489-2012; Groenewald, Marizeth/G-4976-2012; OI Crous, Pedro/0000-0001-9085-8825; Groenewald, Marizeth/0000-0003-0835-5925; Meyer, Wieland/0000-0001-9933-8340 FU European Commission's Seventh Framework Program for Research and Technological Development; "Fonds Economische Structuurversterking" (FES) of the Dutch Ministry of Education, Culture and Science (OCW); Australian NH MRC [APP1031952]; Intramural Research Program of the NIH, National Library of Medicine FX The MycoBank software developments were partially made within the framework of the Indexing for Life (i4Life) project, a European e-Infrastructure project co-funded by the European Commission's Seventh Framework Program for Research and Technological Development.; Some data entries were made possible thanks to the EMbaRC project also supported by the European Commission's Seventh Framework Program for Research and Technological Development; Parts of the developments were done in the framework of the "Inversteringproject NCB" supported by the "Fonds Economische Structuurversterking" (FES) of the Dutch Ministry of Education, Culture and Science (OCW).; Parts of the developments were also done in the framework of the "DNA barcoding of pathogenic fungi as the basis for the development of novel standardized diagnostic", Australian NH& MRC grant # APP1031952 to WM and VR.; CLS acknowledges support from the Intramural Research Program of the NIH, National Library of Medicine. NR 16 TC 13 Z9 13 U1 0 U2 7 PU INT MYCOLOGICAL ASSOC PI BERKELEY PA C/O J TAYLOR, DEPT PLANT & MICROBIAL BIOLOGY, BERKELEY, CA 94720 USA SN 2210-6340 EI 2210-6359 J9 IMA FUNGUS JI IMA Fungus PD DEC PY 2013 VL 4 IS 2 BP 371 EP 379 DI 10.5598/imafungus.2013.04.02.16 PG 9 WC Mycology SC Mycology GA V46UH UT WOS:000209908600035 PM 24563843 ER PT J AU Reid, BC AF Reid, Britt C. TI Visual Screening for Oral Cancer May Reduce Oral Cancer Mortality in High-risk Adult Populations Through Early Diagnosis and Treatment SO JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE LA English DT Editorial Material C1 NCI, Modifiable Risk Factors Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Reid, BC (reprint author), NCI, Modifiable Risk Factors Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E128, Bethesda, MD 20892 USA. EM reidbr@mail.nih.gov NR 9 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-3382 J9 J EVID-BASED DENT PR JI J. Evid.-Based Dent. Pract. PD DEC PY 2013 VL 13 IS 4 BP 174 EP 176 DI 10.1016/j.jebdp.2013.10.013 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V37RY UT WOS:000209294100013 PM 24237744 ER PT J AU Pavlova, O Ieva, R Bernstein, HD AF Pavlova, Olga Ieva, Raffaele Bernstein, Harris D. TI Monitoring the Assembly of a Secreted Bacterial Virulence Factor Using Site-specific Crosslinking SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 82; Autotransporters; Bam complex; Molecular chaperones; protein-protein interactions; Site-specific photocrosslinking AB This article describes a method to detect and analyze dynamic interactions between a protein of interest and other factors in vivo. Our method is based on the amber suppression technology that was originally developed by Peter Schultz and colleagues(1). An amber mutation is first introduced at a specific codon of the gene encoding the protein of interest. The amber mutant is then expressed in E. coli together with genes encoding an amber suppressor tRNA and an amino acyl-tRNA synthetase derived from Methanococcus jannaschii. Using this system, the photo activatable amino acid analog p-benzoylphenylalanine (Bpa) is incorporated at the amber codon. Cells are then irradiated with ultraviolet light to covalently link the Bpa residue to proteins that are located within 3-8 angstrom. Photocrosslinking is performed in combination with pulse-chase labeling and immunoprecipitation of the protein of interest in order to monitor changes in protein-protein interactions that occur over a time scale of seconds to minutes. We optimized the procedure to study the assembly of a bacterial virulence factor that consists of two independent domains, a domain that is integrated into the outer membrane and a domain that is translocated into the extracellular space, but the method can be used to study many different assembly processes and biological pathways in both prokaryotic and eukaryotic cells. In principle interacting factors and even specific residues of interacting factors that bind to a protein of interest can be identified by mass spectrometry. C1 [Pavlova, Olga; Ieva, Raffaele; 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 RI Ieva, Raffaele/J-9207-2014 OI Ieva, Raffaele/0000-0002-3405-0650 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. NR 17 TC 0 Z9 0 U1 2 U2 3 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD DEC PY 2013 IS 82 AR UNSP e51217 DI 10.3791/51217 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RR UT WOS:000209229000068 PM 24378574 ER PT J AU Tacher, V Lin, M Bhagat, N Jaoudeh, NA Radaelli, A Noordhoek, N Carelsen, B Wood, BJ Geschwind, JF AF Tacher, Vania Lin, MingDe Bhagat, Nikhil Jaoudeh, Nadine Abi Radaelli, Alessandro Noordhoek, Niels Carelsen, Bart Wood, Bradford J. Geschwind, Jean-Francois TI Dual-phase Cone-beam Computed Tomography to See, Reach, and Treat Hepatocellular Carcinoma during Drug-eluting Beads Transarterial Chemoembolization SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 82; Carcinoma; Hepatocellular; Tomography; X-Ray Computed; Surgical Procedures; Minimally Invasive; Digestive System Diseases; Diagnosis; Therapeutics; Surgical Procedures; Operative; Equipment and Supplies; Transarterial chemo-embolization; Hepatocellular carcinoma; Dual-phase cone-beam computed tomography; 3D roadmap; Drug-Eluting Beads AB The advent of cone-beam computed tomography (CBCT) in the angiography suite has been revolutionary in interventional radiology. CBCT offers 3 dimensional (3D) diagnostic imaging in the interventional suite and can enhance minimally-invasive therapy beyond the limitations of 2D angiography alone. The role of CBCT has been recognized in transarterial chemo-embolization (TACE) treatment of hepatocellular carcinoma (HCC). The recent introduction of a CBCT technique: dual-phase CBCT (DP-CBCT) improves intra-arterial HCC treatment with drug-eluting beads (DEB-TACE). DP-CBCT can be used to localize liver tumors with the diagnostic accuracy of multi-phasic multidetector computed tomography (M-MDCT) and contrast enhanced magnetic resonance imaging (CE-MRI) (See the tumor), to guide intra-arterially guidewire and microcatheter to the desired location for selective therapy (Reach the tumor), and to evaluate treatment success during the procedure (Treat the tumor). The purpose of this manuscript is to illustrate how DP-CBCT is used in DEB-TACE to see, reach, and treat HCC. C1 [Tacher, Vania; Bhagat, Nikhil; Geschwind, Jean-Francois] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Div Vasc & Intervent Radiol, Baltimore, MD 21287 USA. [Lin, MingDe] Philips Res North Amer, CIITS, Andover, MA 01810 USA. [Jaoudeh, Nadine Abi; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Intervent Radiol Sect, Bethesda, MD USA. RP Lin, M (reprint author), Philips Res North Amer, CIITS, Andover, MA 01810 USA. EM ming.lin@philips.com FU NIH/NCI [R01 CA160771, P30 CA006973]; Philips Research North America, Briarcliff Manor, NY, USA; French Society of Radiology (SFR) FX The authors wish to acknowledge the financial support of NIH/NCI R01 CA160771, P30 CA006973, Philips Research North America, Briarcliff Manor, NY, USA and the French Society of Radiology (SFR). NR 26 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD DEC PY 2013 IS 82 AR UNSP e50795 DI 10.3791/50795 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RR UT WOS:000209229000024 ER PT J AU Amara, SG AF Amara, Susan G. TI The Activation of Intracellular Signaling Systems by Amphetamines: A Potential Role for Trace Amine Receptors SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Amara, Susan G.] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 6.3 BP S11 EP S11 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100022 ER PT J AU Augier, E Damadzic, R Singley, E Pincus, A Heilig, M AF Augier, Eric Damadzic, Ruslan Singley, Erick Pincus, Alexandra Heilig, Markus TI Reduced Motivation to Consume Alcohol after an Extended Access SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE alcohol; addiction; self-administration; extended access; amygdala C1 [Augier, Eric; Damadzic, Ruslan; Singley, Erick; Pincus, Alexandra; Heilig, Markus] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T68 BP S312 EP S313 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100512 ER PT J AU Baker, MB Lindell, S Yuan, QP Zhou, ZF Higley, JD Suomi, S Barr, C AF Baker, Maggie B. Lindell, Stephen Yuan, Qiaoping Zhou, Zhifeng Higley, J. Dee Suomi, Stephen Barr, Christina TI Disruption of Early Maternal Care Results in Epigenetic Regulation of the Oxytocin Receptor (OXTR) Gene in Rhesus Macaques SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE oxytocin; stress; epigenetic; macaque; Chip-SEQ C1 [Baker, Maggie B.; Lindell, Stephen; Yuan, Qiaoping; Zhou, Zhifeng; Higley, J. Dee; Suomi, Stephen; Barr, Christina] NIAAA, NIH, Bethesda, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T210 BP S414 EP S414 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100653 ER PT J AU Barbier, E Tapocik, J Johnstone, AL Schank, J Zhou, ZF Yuan, QP Goldman, D Wahlestedt, C Heilig, M AF Barbier, Estelle Tapocik, Jenica Johnstone, Andrea L. Schank, Jesse Zhou, Zhifeng Yuan, Qiaoping Goldman, David Wahlestedt, Claes Heilig, Markus TI The Methyltransferase PRDM2 Regulates Escalated Alcohol Consumption SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE alcohol dependence; epigenetic; histone methyltransferase C1 [Barbier, Estelle; Tapocik, Jenica; Johnstone, Andrea L.; Schank, Jesse; Zhou, Zhifeng; Yuan, Qiaoping; Goldman, David; Wahlestedt, Claes; Heilig, Markus] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2013 VL 38 SU 2 MA T95 BP S330 EP S330 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100539 ER PT J AU Baumann, MH AF Baumann, Michael H. TI Effects of Newly-emerging Synthetic Cathinone Derivatives on Monoamine Transporter Function in Rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Baumann, Michael H.] NIDA, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2013 VL 38 SU 2 MA 16.2 BP S23 EP S23 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100044 ER PT J AU Berman, RA McAdams, H Greenstein, D Gogtay, N Rapoport, JL AF Berman, Rebecca A. McAdams, Harrison Greenstein, Deanna Gogtay, Nitin Rapoport, Judith L. TI Distinct Patterns of Functional Connectivity in Patients with Childhood-Onset Schizophrenia, Their Unaffected Siblings, and Healthy Controls SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE fMRI; resting-state; psychosis; cortex C1 [Berman, Rebecca A.; McAdams, Harrison; Greenstein, Deanna; Gogtay, Nitin; Rapoport, Judith L.] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M110 BP S181 EP S182 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100320 ER PT J AU Bossert, JM AF Bossert, Jennifer M. TI Role of Ventral Medial Prefrontal Cortex (mPFC) and Its Projections to Accumbens Shell on Context-induced Reinstatement of Heroin Seeking in Rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Bossert, Jennifer M.] NIDA, NIH, Baltimore, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 45.4 BP S77 EP S78 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100155 ER PT J AU Brotman, MA Deveney, CM Thomas, LA Hinton, K Yi, J Pine, DS Leibenluft, E AF Brotman, Melissa A. Deveney, Christen M. Thomas, Laura A. Hinton, Kendra Yi, Jennifer Pine, Daniel S. Leibenluft, Ellen TI Parametric Modulation of Neural Activity during Face Emotion Processing in Unaffected Youth at Familial Risk for Bipolar Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE fMRI; bipolar disorder; youth at familial risk; face emotion C1 [Brotman, Melissa A.; Deveney, Christen M.; Thomas, Laura A.; Hinton, Kendra; Yi, Jennifer; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Bethesda, MD 20892 USA. RI Brotman, Melissa/H-7409-2013 NR 0 TC 1 Z9 1 U1 0 U2 0 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 DEC PY 2013 VL 38 SU 2 MA M39 BP S132 EP S133 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100249 ER PT J AU Colvis, C AF Colvis, Christine TI NCATS/NIH-Industry Pilot Program on Drug Repositioning SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Colvis, Christine] Natl Ctr Adv Translat Sci, Bethesda, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 44.2 BP S75 EP S75 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100149 ER PT J AU Dickinson, D Straub, R Trampush, JW Gao, Y Feng, NP Ursini, G Bigos, K Kolachana, B Hashimoto, R Takeda, M Rujescu, D Callicott, JH Hyde, TM Berman, KF Kleinman, JE Weinberger, DR AF Dickinson, Dwight Straub, Richard Trampush, Joey W. Gao, Yuan Feng, Ningping Ursini, Gianluca Bigos, Kristin Kolachana, Bhaskar Hashimoto, Ryota Takeda, Masatoshi Rujescu, Dan Callicott, Joseph H. Hyde, Thomas M. Berman, Karen F. Kleinman, Joel E. Weinberger, Daniel R. TI Association of SCN2A Variants with Cognitive Ability in Schizophrenia, and Additional Support from Analyses of Unaffected Siblings, Independent Schizophrenia Samples, fMRI, and mRNA Expression in Brain SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE SCN2A; schizophrenia; cognition; GWAS; fMRI; RNA sequencing C1 [Dickinson, Dwight; Straub, Richard; Trampush, Joey W.; Gao, Yuan; Feng, Ningping; Ursini, Gianluca; Bigos, Kristin; Kolachana, Bhaskar; Hashimoto, Ryota; Takeda, Masatoshi; Rujescu, Dan; Callicott, Joseph H.; Hyde, Thomas M.; Berman, Karen F.; Kleinman, Joel E.; Weinberger, Daniel R.] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W80 BP S486 EP S487 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100756 ER PT J AU Driver, DI Greenstein, D Farmer, M Rapoport, JL Gogtay, N AF Driver, David I. Greenstein, Deanna Farmer, Madison Rapoport, Judith L. Gogtay, Nitin TI Premorbid Impairments in Childhood-onset Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE childhood-onset schizophrenia; premorbid impairments C1 [Driver, David I.; Greenstein, Deanna; Farmer, Madison; Rapoport, Judith L.; Gogtay, Nitin] NIMH, Washington, DC USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T188 BP S399 EP S400 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100631 ER PT J AU Eisenberg, DP Masdeu, JC Kohn, P Kolachana, BS Weinberger, DR Berman, KF AF Eisenberg, Daniel P. Masdeu, Joseph C. Kohn, Philip Kolachana, Bhaskar S. Weinberger, Daniel R. Berman, Karen F. TI Impact of DOPA Decarboxylase Genetic Variation on Its In Vivo Enzymatic Activity in Humans SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE DOPA decarboxylase; DDC; dopamine; gene; PET C1 [Eisenberg, Daniel P.; Masdeu, Joseph C.; Kohn, Philip; Kolachana, Bhaskar S.; Weinberger, Daniel R.; Berman, Karen F.] NIMH, Bethesda, MD 20892 USA. RI Eisenberg, Daniel/S-4342-2016 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M32 BP S127 EP S128 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100242 ER PT J AU Enoch, MA Hodgkinson, CA Gorodetsky, E Marietta, C Roy, A Goldman, D AF Enoch, Mary-Anne Hodgkinson, Colin A. Gorodetsky, Elena Marietta, Cheryl Roy, Alec Goldman, David TI Haplotype and SNP Variation in Genes Implicated in GABA Synthesis, Synaptic Transmission and Re-uptake are Predictors for Alcoholism SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE GABA; GAD1; GPHN; GABBR1; SLC6A1 C1 [Enoch, Mary-Anne; Hodgkinson, Colin A.; Gorodetsky, Elena; Marietta, Cheryl; Roy, Alec; Goldman, David] NIAAA, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2013 VL 38 SU 2 MA W55 BP S470 EP S470 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100733 ER PT J AU Furey, ML Szczepanik, J Nugent, AC Brutsche, N Luckenbaugh, D Zarate, CA AF Furey, Maura L. Szczepanik, Joanna Nugent, Allison C. Brutsche, Nancy Luckenbaugh, David Zarate, Carlos A. TI Neural Response in Visual Cortex to Emotional Stimuli Predicts Clinical Outcome Across Rapid Antidepressant Agents SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE ketamine; scopolamine; biomarker C1 [Furey, Maura L.; Szczepanik, Joanna; Nugent, Allison C.; Brutsche, Nancy; Luckenbaugh, David; Zarate, Carlos A.] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T181 BP S395 EP S396 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100624 ER PT J AU Gogtay, N AF Gogtay, Nitin TI Vulnerability or Resilience? Brain Developmental Studies in Non-Psychotic Siblings of Childhood Onset Schizophrenia Patients SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Gogtay, Nitin] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 7.4 BP S13 EP S13 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100027 ER PT J AU Goswami, S Mishra, S Hoon, M Mannes, A Iadarola, M AF Goswami, Samridhi Mishra, Santosh Hoon, Mark Mannes, Andrew Iadarola, Michael TI Analysis of the Pain Transcriptome Using RNA-Seq SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE gene expression transcriptome RNA Seq pain analgesia C1 [Goswami, Samridhi; Mishra, Santosh; Hoon, Mark; Mannes, Andrew; Iadarola, Michael] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T127 BP S352 EP S352 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100571 ER PT J AU Gregory, MD Kippenhan, JS Mervis, C Sottile, M Czarapata, J Roe, K Xiao, E Tong, YX Kolachana, BS Weinberger, DR Mattay, VS Berman, KF AF Gregory, Michael D. Kippenhan, J. Shane. Mervis, Carolyn Sottile, Melanie Czarapata, Jasmin Roe, Katherine Xiao, Ena Tong, Yunxia Kolachana, Bhaskar S. Weinberger, Daniel R. Mattay, Venkata S. Berman, Karen F. TI Functional Connectivity of the Intraparietal Sulcus Is Affected by Both Copy Number and Sequence Variation of the Williams Syndrome Gene LIMK1 SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE Williams syndrome; LIMK1; intraparietal sulcus; fMRI; connectivity C1 [Gregory, Michael D.; Kippenhan, J. Shane.; Mervis, Carolyn; Sottile, Melanie; Czarapata, Jasmin; Roe, Katherine; Xiao, Ena; Tong, Yunxia; Kolachana, Bhaskar S.; Weinberger, Daniel R.; Mattay, Venkata S.; Berman, Karen F.] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M144 BP S206 EP S207 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100354 ER PT J AU Grodin, EN Momenan, R AF Grodin, Erica N. Momenan, Reza TI Morphometric and Volumetric Subcortical Differences in Alcoholics with and without Comorbid Drug Use Disorders SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE subcortical; morphometry; substance-abuse; alcoholism C1 [Grodin, Erica N.; Momenan, Reza] NIAAA, Bethesda, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M116 BP S185 EP S186 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100326 ER PT J AU Guerrieri, G Ben Dor, R Smith, L Thompson, K Martinez, P Rubinow, D Schmidt, P AF Guerrieri, Gioia Ben Dor, Rivka Smith, Leslie Thompson, Karla Martinez, Pedro Rubinow, David Schmidt, Peter TI The Hypothalamic-Pituitary-Adrenal Axis, Reproductive Aging, and Depression: Results of Cortisol and ACTH Response to Dex/CRH testing in Women with and without Perimenopause-related Depression SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE perimenopause; depression; HPA-axis; cortisol; ACTH C1 [Guerrieri, Gioia; Ben Dor, Rivka; Smith, Leslie; Thompson, Karla; Martinez, Pedro; Rubinow, David; Schmidt, Peter] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T195 BP S404 EP S405 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100638 ER PT J AU Hall, FS Houston-Ludlam, A Lin, ZC Uhl, G AF Hall, Frank S. Houston-Ludlam, Alexandra Lin, Zhicheng Uhl, George TI The Effects of Gene Knockout of the Vesicular Monoamine Transporter 2 (VMAT2; SLC18A2) and the Dopamine Transporter (DAT; SLC3A6) on Ethanol Consumption and Escalation in Mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE alcoholism; pharmacogenetics; dopamine transporter; vesicular monoamine transporter; escalation C1 [Hall, Frank S.; Houston-Ludlam, Alexandra; Lin, Zhicheng; Uhl, George] NIDA, Baltimore, MD USA. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W193 BP S565 EP S565 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100868 ER PT J AU Huang, MC Schwandt, ML Chester, JA Kirchhoff, AM Kao, CF Liang, TB Tapocik, J Ramchandani, VA George, DT Hodgkinson, CA Goldman, D Heilig, M AF Huang, Ming-Chyi Schwandt, Melanie L. Chester, Julie A. Kirchhoff, Aaron M. Kao, Chung-Feng Liang, Tiebing Tapocik, Jenica Ramchandani, Vijay A. George, David T. Hodgkinson, Colin A. Goldman, David Heilig, Markus TI FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE FKBP5 gene; alcohol withdrawal severity; HPA axis; humans; mice C1 [Huang, Ming-Chyi; Schwandt, Melanie L.; Chester, Julie A.; Kirchhoff, Aaron M.; Kao, Chung-Feng; Liang, Tiebing; Tapocik, Jenica; Ramchandani, Vijay A.; George, David T.; Hodgkinson, Colin A.; Goldman, David; Heilig, Markus] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W54 BP S469 EP S470 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100732 ER PT J AU Innis, R AF Innis, Robert TI Binding of 11C-(R)-rolipram to Phosphodiesterase 4 is Downregulated in Major Depressive Disorder and Normalized with Antidepressant Treatment SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Innis, Robert] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 DEC PY 2013 VL 38 SU 2 MA 54.1 BP S95 EP S95 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100188 ER PT J AU Jabbi, M Chen, Q Turner, N White, M Kippenhan, JS Kohn, P Dickinson, D Kolachana, B Mattay, V Weinberger, DR Berman, K AF Jabbi, Mbemba Chen, Qiang Turner, Nicholas White, Michael Kippenhan, J. Shane Kohn, Philip Dickinson, Dwight Kolachana, Bhaskar Mattay, Venkata Weinberger, Daniel R. Berman, Karen TI Variation in the Williams Syndrome GTF2i Gene and Anxiety-proneness Interactively Predict DLPFC Response to Aversive Social Stimuli in Humans SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE genetics; anxiety proneness; GTF2i; DLPFC response C1 [Jabbi, Mbemba; Chen, Qiang; Turner, Nicholas; White, Michael; Kippenhan, J. Shane; Kohn, Philip; Dickinson, Dwight; Kolachana, Bhaskar; Mattay, Venkata; Weinberger, Daniel R.; Berman, Karen] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W81 BP S487 EP S487 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100757 ER PT J AU Johanna, JM Davis, M Leibenluft, E Fox, N Shechner, T Pine, DS Nelson, E AF Johanna, Jarcho M. Davis, Megan Leibenluft, Ellen Fox, Nathan Shechner, Tomer Pine, Daniel S. Nelson, Eric TI Dysregulated Neural Response to Social Evaluation in Bullied Adolescents: A Potential Mechanism that Promotes Risk for Social Anxiety Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE fMRI; peer victimization; adolescence; social evaluation C1 [Johanna, Jarcho M.; Davis, Megan; Leibenluft, Ellen; Fox, Nathan; Shechner, Tomer; Pine, Daniel S.; Nelson, Eric] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 4 U2 6 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 DEC PY 2013 VL 38 SU 2 MA M48 BP S139 EP S139 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100258 ER PT J AU Kim, SW Fowler, J Skolnick, P Kang, Y Kim, D Volkow, ND AF Kim, Sung Won Fowler, Joanna Skolnick, Phil Kang, Yeona Kim, Dohyun Volkow, Nora D. TI Buspirone Blocks Dopamine D3 Receptors in the Non-human Primate Brain when Administered Orally SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE addiction; treatment; striatum; pallidum; buspirone; D3 receptors C1 [Kim, Sung Won; Fowler, Joanna; Skolnick, Phil; Kang, Yeona; Kim, Dohyun; Volkow, Nora D.] NIDA, Rockville, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M139 BP S203 EP S203 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100349 ER PT J AU Kopin, IJ Sullivan, P Goldstein, DS AF Kopin, Irwin J. Sullivan, Patti Goldstein, David S. TI Key Role of Decreased Vesicular Uptake in the Profound Myocardial Norepinephrine Depletion in Parkinson's Disease SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE Norepinephrine; Dopamine; VMAT; myocardium; MAO C1 [Kopin, Irwin J.; Sullivan, Patti; Goldstein, David S.] NINDS, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M23 BP S121 EP S122 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100233 ER PT J AU Kunii, Y Hyde, TM Deep-Soboslay, A Weinberger, DR Kleinman, JE Lipska, B AF Kunii, Yasuto Hyde, Thomas M. Deep-Soboslay, Amy Weinberger, Daniel R. Kleinman, Joel E. Lipska, Barbara TI Expression of CHRNA7 and the Chimeric Gene CHRFAM7A are Altered in the Postmortem Dorsolateral Prefrontal Cortex in Major Psychiatric Disorders SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE prefrontal cortex; human; nicotinic receptor; postmortem; SNP; genetic C1 [Kunii, Yasuto; Hyde, Thomas M.; Deep-Soboslay, Amy; Weinberger, Daniel R.; Kleinman, Joel E.; Lipska, Barbara] NIMH, Bethesda, MD 20892 USA. RI Lipska, Barbara/E-4569-2017 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M28 BP S125 EP S125 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100238 ER PT J AU Leggio, L Schwandt, ML Oot, EN Dias, AA Ramchandani, VA AF Leggio, Lorenzo Schwandt, Melanie L. Oot, Emily N. Dias, Alexandra A. Ramchandani, Vijay A. TI Fasting-induced Increase in Plasma Ghrelin is Blunted by Intravenous Alcohol Administration: A Within-subject Placebo-controlled Study SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE alcohol; ghrelin; insulin; GLP-1; PYY; intravenous alcohol administration C1 [Leggio, Lorenzo; Schwandt, Melanie L.; Oot, Emily N.; Dias, Alexandra A.; Ramchandani, Vijay A.] NIDA, NIAAA, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T200 BP S407 EP S408 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100643 ER PT J AU Lehmann, M Herkenham, M AF Lehmann, Michael Herkenham, Miles TI Acute but Not Chronic Psychosocial Stress Alters the Density and Immune-phenotype of Microglia in Mouse Stress-responsive Brain Regions SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE microglia; mouse; psychosocial-stress; immune; cytokines; prefrontal cortex C1 [Lehmann, Michael; Herkenham, Miles] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T87 BP S325 EP S325 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100531 ER PT J AU Leibenluft, E AF Leibenluft, Ellen TI Neural Mechanisms of Frustration in Chronically Irritable Youth SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Leibenluft, Ellen] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 14.3 BP S20 EP S21 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100039 ER PT J AU Lovinger, D AF Lovinger, David TI Chronic Ethanol Exposure Increases Output from the Sensorimotor Striatum in Mouse and Monkey Models via Changes in Neuronal Excitability and Synaptic Transmission SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Lovinger, David] NIAAA, Bethesda, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 47.3 BP S81 EP S82 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100162 ER PT J AU Mann, C Durkee, C Grodin, EN Ramchandani, VA Momenan, R AF Mann, Claire Durkee, Caitlin Grodin, Erica N. Ramchandani, Vijay A. Momenan, Reza TI Measuring the Effects of Acute Alcohol Infusion on Human Brain Metabolites: An MR Spectroscopy Study SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE MRS; ethanol; glutamate; alcoholism C1 [Mann, Claire; Durkee, Caitlin; Grodin, Erica N.; Ramchandani, Vijay A.; Momenan, Reza] NIAAA, Bethesda, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M30 BP S126 EP S127 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100240 ER PT J AU Marenco, S Zhang, Y Slagle, A Kuo, S Meyer, C Sethi, A Barnett, AS Shen, J Weinberger, DR Berman, KF AF Marenco, Stefano Zhang, Yan Slagle, Anna Kuo, Susie Meyer, Christian Sethi, Adhiraaj Barnett, Alan S. Shen, Jun Weinberger, Daniel R. Berman, Karen F. TI Glutamate Levels Determined with Magnetic Resonance Spectroscopy (MRS) in the Medial Prefrontal Cortex of Patients with Psychosis as Compared to Healthy Volunteers SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE glutamate; MRS; schizophrenia; aging C1 [Marenco, Stefano; Zhang, Yan; Slagle, Anna; Kuo, Susie; Meyer, Christian; Sethi, Adhiraaj; Barnett, Alan S.; Shen, Jun; Weinberger, Daniel R.; Berman, Karen F.] NIMH, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M94 BP S171 EP S172 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100304 ER PT J AU Martinez, P Nieman, LK Morrow, L Cintron, D Thompson, K Rubinow, D Schmidt, P AF Martinez, Pedro Nieman, Lynnette K. Morrow, Leslie Cintron, Dahima Thompson, Karla Rubinow, David Schmidt, Peter TI Therapeutic Benefits of Dutasteride, a 5 Alpha-reductase Type I Inhibitor, in PMDD: Results of a Pilot Study SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE premenstrual mood disorders (PMDD); 5-alpha reductase; allopregnanolone; progesterone; dutasteride C1 [Martinez, Pedro; Nieman, Lynnette K.; Morrow, Leslie; Cintron, Dahima; Thompson, Karla; Rubinow, David; Schmidt, Peter] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T194 BP S403 EP S404 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100637 ER PT J AU McHugh, MJ Catherine, D Jacquelyn, B Salmeron, BJ Devous, MD Briggs, RW Walker, NR Adinoff, B Stein, EA AF McHugh, Meredith J. Catherine, Demers Jacquelyn, Braud Salmeron, Betty J. Devous, Michael D. Briggs, Richard W. Walker, N. Robrina Adinoff, Bryon Stein, Elliot A. TI Cortico-amygdala Coupling as a Marker of Early Relapse Risk in Cocaine-addicted Individuals SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE cocaine addiction; amygdala; connectivity; relapse C1 [McHugh, Meredith J.; Catherine, Demers; Jacquelyn, Braud; Salmeron, Betty J.; Devous, Michael D.; Briggs, Richard W.; Walker, N. Robrina; Adinoff, Bryon; Stein, Elliot A.] NIDA IRP, Baltimore, MD USA. RI Salmeron, Betty Jo/M-1793-2016 OI Salmeron, Betty Jo/0000-0003-1699-9333 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M131 BP S196 EP S197 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100341 ER PT J AU Merikangas, KR AF Merikangas, Kathleen Ries TI Comorbidity of Medical and Psychiatric Disorders in the Neurodevelopmental Genomics Cohort Study SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Merikangas, Kathleen Ries] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 49.3 BP S86 EP S86 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100170 ER PT J AU Phillip, S Sharp, W Rapoport, JL AF Phillip, Shaw Sharp, Wendy Rapoport, Judith L. TI Abnormalities in Striato-pallidal-thalamic Surface Morphology as an Endophenotype for Obsessive-Compulsive Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE Obsesssive-Compulsive Disorder; Striatum; Thalamus; Systems Neuroscience; Endophenotype C1 [Phillip, Shaw; Sharp, Wendy; Rapoport, Judith L.] NHGRI, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M207 BP S250 EP S251 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100416 ER PT J AU Prabhakaran, R Rasetti, R Xiao, E Kolachana, BS Weinberger, DR Mattay, VS Berman, KF AF Prabhakaran, Ranjani Rasetti, Roberta Xiao, Ena Kolachana, Bhaskar S. Weinberger, Daniel R. Mattay, Venkata S. Berman, Karen F. TI Variation in Serotonin Transporter Gene Predicts Neural Activation in a Response Inhibition Task SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE serotonin transporter gene; response inhibition; fMRI; flanker task; individual differences C1 [Prabhakaran, Ranjani; Rasetti, Roberta; Xiao, Ena; Kolachana, Bhaskar S.; Weinberger, Daniel R.; Mattay, Venkata S.; Berman, Karen F.] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W39 BP S459 EP S460 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100717 ER PT J AU Qin, HD Samuels, J Wang, Y Nestadt, G Yao, Y AF Qin, Haide Samuels, Jack Wang, Ying Nestadt, Gerald Yao, Yin TI New Insight into Genetic Mechanism Underlying the Treatment Effect of Obsessive-Compulsive Disorder Using SSRIs SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE selective serotonin reuptake inhibitors (SSRIs) obsessive-compulsive disorder (OCD) pharmacogenomics GWAS study family-based design C1 [Qin, Haide; Samuels, Jack; Wang, Ying; Nestadt, Gerald; Yao, Yin] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W83 BP S488 EP S488 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100759 ER PT J AU Raznahan, A Phillip, S Liv, C Greenstein, D Lerch, J Chakravarty, M Giedd, J AF Raznahan, Armin Phillip, Shaw Liv, Clasen Greenstein, Deanna Lerch, Jason Chakravarty, Mallar Giedd, Jay TI The Spatiotempotal Organization of Subcortical Anatomy in Human Development SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE Development; MRI; subcortex; WGCNA C1 [Raznahan, Armin; Phillip, Shaw; Liv, Clasen; Greenstein, Deanna; Lerch, Jason; Chakravarty, Mallar; Giedd, Jay] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-2002-8978 NR 0 TC 0 Z9 0 U1 0 U2 1 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 DEC PY 2013 VL 38 SU 2 MA M38 BP S132 EP S132 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100248 ER PT J AU Resnick, SM Bilgel, M An, Y Thambisetty, M Kraut, M Zhou, Y Wong, DF AF Resnick, Susan M. Bilgel, Murat An, Yang Thambisetty, Madhav Kraut, Michael Zhou, Yun Wong, Dean F. TI Longitudinal Change in Amyloid Deposition, Measured by PET and 11-C-PiB, in Older Adults SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE amyloid imaging; PET-PiB; preclinical Alzheimer's disease; aging; longitudinal studies C1 [Resnick, Susan M.; Bilgel, Murat; An, Yang; Thambisetty, Madhav; Kraut, Michael; Zhou, Yun; Wong, Dean F.] NIA, Baltimore, MD 21224 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M119 BP S188 EP S188 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100329 ER PT J AU Robinson, OJ AF Robinson, Oliver J. TI The Impact of Induced Anxiety on Ventral Striatal Response to Aversive and Appetitive Prediction Error Signals SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Robinson, Oliver J.] NIMH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 19.4 BP S29 EP S29 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100056 ER PT J AU Rubinstein, D Eisenberg, DP Carver, FW Weinberger, DR Coppola, R Berman, KF AF Rubinstein, Dani Eisenberg, Daniel P. Carver, Frederick W. Weinberger, Daniel R. Coppola, Richard Berman, Karen F. TI Reduced Prefrontal Gamma Band Power in Patients with Schizophrenia Studied with MEG During Working Memory SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE Magnetoencephalography; Working; memory; Schizophrenia Gamma C1 [Rubinstein, Dani; Eisenberg, Daniel P.; Carver, Frederick W.; Weinberger, Daniel R.; Coppola, Richard; Berman, Karen F.] NIMH, Bethesda, MD 20892 USA. RI Eisenberg, Daniel/S-4342-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 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 DEC PY 2013 VL 38 SU 2 MA M156 BP S214 EP S215 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100366 ER PT J AU Schank, JR King, C Cheng, KJ Rice, KC Weinshenker, D Schroeder, JP Heilig, M AF Schank, Jesse R. King, Courtney Cheng, Kejun Rice, Kenner C. Weinshenker, David Schroeder, Jason P. Heilig, Markus TI The Neurokinin-1 Receptor Mediates Stress-induced Reinstatement to Alcohol and Cocaine Seeking SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE stress; reinstatement; neurokinin; cocaine; alcohol C1 [Schank, Jesse R.; King, Courtney; Cheng, Kejun; Rice, Kenner C.; Weinshenker, David; Schroeder, Jason P.; Heilig, Markus] NIAAA, NIH, Bethesda, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W154 BP S539 EP S540 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100829 ER PT J AU Sibley, DR Free, RB Chun, LN Moritz, A Miller, B Doyle, T Conroy, J Padron, A Meade, J Xiao, JB Han, Y Duan, LH Ferrer, M Javitch, J Southall, N Marugan, J AF Sibley, David R. Free, R. Benjamin Chun, Lani Moritz, Amy Miller, Brittney Doyle, Trevor Conroy, Jennie Padron, Adrian Meade, Julie Xiao, Jingbo Han, Yang Duan, Lihua Ferrer, Marc Javitch, Jonathan Southall, Noel Marugan, Juan TI Discovery and Characterization of a G Protein-biased Agonist That Inhibits beta-arrestin Recruitment to the D2 Dopamine Receptor SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE dopamine receptor; functional-selectivity; biased-agonism; cAMP; beta-arrestin D2 C1 [Sibley, David R.; Free, R. Benjamin; Chun, Lani; Moritz, Amy; Miller, Brittney; Doyle, Trevor; Conroy, Jennie; Padron, Adrian; Meade, Julie; Xiao, Jingbo; Han, Yang; Duan, Lihua; Ferrer, Marc; Javitch, Jonathan; Southall, Noel; Marugan, Juan] NINDS, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W163 BP S545 EP S546 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100838 ER PT J AU Spagnolo, P Kwako, L Momenan, R Schwandt, ML Ramchandani, VA Hommer, DW George, DT Heilig, M AF Spagnolo, Primavera Kwako, Laura Momenan, Reza Schwandt, Melanie L. Ramchandani, Vijay A. Hommer, Daniel W. George, David T. Heilig, Markus TI Effects of Neurokinin 1 Receptor Antagonism on Brain Response to Emotional Visual Stimuli in Comorbid Alcohol Dependence and Posttraumatic Stress Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE PTSD; alcoholism; NK1 antagonism; vmPFC C1 [Spagnolo, Primavera; Kwako, Laura; Momenan, Reza; Schwandt, Melanie L.; Ramchandani, Vijay A.; Hommer, Daniel W.; George, David T.; Heilig, Markus] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T165 BP S383 EP S384 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100608 ER PT J AU Stangl, BL Schwandt, ML Kwako, LE Yan, J Zametkin, M Ramchandani, VA AF Stangl, Bethany L. Schwandt, Melanie L. Kwako, Laura E. Yan, Jia Zametkin, Molly Ramchandani, Vijay A. TI Adverse Childhood Experiences Predict Heavier Drinking and Greater Alcohol Intake During Intravenous (IV) Alcohol Self-Administration in Non-Dependent Drinkers SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE childhood trauma; CTQ; IV alcohol; CASE; self-administration C1 [Stangl, Bethany L.; Schwandt, Melanie L.; Kwako, Laura E.; Yan, Jia; Zametkin, Molly; Ramchandani, Vijay A.] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W133 BP S524 EP S525 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100809 ER PT J AU Tapocik, J Schank, JR Mayo, C King, C Koenig, J Heilig, M Elmer, GI AF Tapocik, Jenica Schank, Jesse R. Mayo, Cheryl King, Courtney Koenig, Jim Heilig, Markus Elmer, Greg I. TI Comorbidity of PTSD and Alcoholism: A Rat Model of PTSD Leads to Escalated Ethanol Consumption SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE PTSD; alcoholism; predator exposure; two bottle choice; learned helplessness C1 [Tapocik, Jenica; Schank, Jesse R.; Mayo, Cheryl; King, Courtney; Koenig, Jim; Heilig, Markus; Elmer, Greg I.] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T14 BP S280 EP S281 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100460 ER PT J AU Tomasi, D Wang, GJ Caparelli, E Volkow, ND AF Tomasi, Dardo Wang, Gene-Jack Caparelli, Elisabeth Volkow, Nora D. TI Brain Activation to Natural Cues and Drug Cues and Dopamine Receptors in Cocaine Addicts SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE Addiction; fMRI; cocaine; PET; dopamine C1 [Tomasi, Dardo; Wang, Gene-Jack; Caparelli, Elisabeth; Volkow, Nora D.] NIH, Fulton, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M36 BP S130 EP S131 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100246 ER PT J AU Tseng, WL Deveney, CM Guyer, AE Yi, J Espy, K Wakschlag, L Towbin, K Leibenluft, E Brotman, MA AF Tseng, Wan-Ling Deveney, Christen M. Guyer, Amanda E. Yi, Jennifer Espy, Kimberly Wakschlag, Lauren Towbin, Kenneth Leibenluft, Ellen Brotman, Melissa A. TI Responses to Blocked Goal Attainment in Preschoolers at Risk for Bipolar Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE Bipolar disorder; Risk factor; Irritability; Preschoolers; Frustration C1 [Tseng, Wan-Ling; Deveney, Christen M.; Guyer, Amanda E.; Yi, Jennifer; Espy, Kimberly; Wakschlag, Lauren; Towbin, Kenneth; Leibenluft, Ellen; Brotman, Melissa A.] NIMH, NIH, Bethesda, MD 20892 USA. RI Brotman, Melissa/H-7409-2013 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M194 BP S241 EP S242 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100403 ER PT J AU Nguyen, TV Schmidt, P Kippenhan, JS Sottile, M Ekuta, V Kolachana, BS Verchinski, BA Mattay, VS Kleinman, JE Lipska, B Weinberger, DR Berman, KF AF Tuong-Vi Nguyen Schmidt, Peter Kippenhan, J. Shane Sottile, Melanie Ekuta, Victor Kolachana, Bhaskar S. Verchinski, Beth A. Mattay, Venkata S. Kleinman, Joel E. Lipska, Barbara Weinberger, Daniel R. Berman, Karen F. TI Sex Steroid Receptor Gene Expression Correlates with the Expression of Neurodevelopmental Genes and Modulates Gray Matter Volume in the Human Brain SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE estrogen receptor; progesterone receptor; estradiol; progesterone; development C1 [Tuong-Vi Nguyen; Schmidt, Peter; Kippenhan, J. Shane; Sottile, Melanie; Ekuta, Victor; Kolachana, Bhaskar S.; Verchinski, Beth A.; Mattay, Venkata S.; Kleinman, Joel E.; Lipska, Barbara; Weinberger, Daniel R.; Berman, Karen F.] NIH, Bethesda, MD 20892 USA. RI Lipska, Barbara/E-4569-2017 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA T209 BP S413 EP S414 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100652 ER PT J AU Uhl, G Hall, FS Ranscht, B Uetani, N Drgonova, J AF Uhl, George Hall, Frank S. Ranscht, Barbara Uetani, Noriko Drgonova, Jana TI Genes Harboring Addiction-related Variants Alter Dose-response Relationships for Stimulant Reward SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE cocaine; amphetamine; knockout mouse; translational reserach; polygenic disorder C1 [Uhl, George; Hall, Frank S.; Ranscht, Barbara; Uetani, Noriko; Drgonova, Jana] NIDA, Baltimore, MD USA. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M16 BP S116 EP S117 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100226 ER PT J AU Umhau, JC Zhou, WY Thada, S Herscovitch, P Salem, N Hibbeln, JR Hirvonen, J Rapoport, S AF Umhau, John C. Zhou, Weiyin Thada, Shantalaxmi Herscovitch, Peter Salem, Norman, Jr. Hibbeln, Joseph R. Hirvonen, Jussi Rapoport, Stanley TI Non-smoking Chronic Alcoholics Following Withdrawal Show Increased Cerebral Blood Flow and Altered Brain Docosahexaenoic (DHA) Metabolism on Partial Volume Error-corrected PET SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE chronic alcoholism; positron emission tomography; cerebral blood flow; docosahexaenoic acid; brain C1 [Umhau, John C.; Zhou, Weiyin; Thada, Shantalaxmi; Herscovitch, Peter; Salem, Norman, Jr.; Hibbeln, Joseph R.; Hirvonen, Jussi; Rapoport, Stanley] NIA, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M40 BP S133 EP S134 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100250 ER PT J AU Volkow, ND AF Volkow, Nora D. TI Unmotivated? Signatures of Blunted Dopaminergic Responsiveness in Chronic Marijuana Abuse SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 [Volkow, Nora D.] NIDA, Rockville, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA 39.4 BP S67 EP S67 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100131 ER PT J AU Yan, J Stangl, BL Reimers, MA Schwandt, ML Sun, H Hodgkinson, CA Goldman, D Hommer, DW George, DT Kendler, KS Heilig, M Ramchandani, VA AF Yan, Jia Stangl, Bethany L. Reimers, Mark A. Schwandt, Melanie L. Sun, Hui Hodgkinson, Colin A. Goldman, David Hommer, Daniel W. George, David T. Kendler, Kenneth S. Heilig, Markus Ramchandani, Vijay A. TI Genetic Pathway Analyses of the Endocannabinoid System in a Sample of Social Drinkers and Treatment-Seeking Alcoholics SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE alcohol dependence; pathway analysis; endocannabinoid system; genetics C1 [Yan, Jia; Stangl, Bethany L.; Reimers, Mark A.; Schwandt, Melanie L.; Sun, Hui; Hodgkinson, Colin A.; Goldman, David; Hommer, Daniel W.; George, David T.; Kendler, Kenneth S.; Heilig, Markus; Ramchandani, Vijay A.] NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W97 BP S498 EP S499 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100773 ER PT J AU Yao, Y Xu, MY Murphy, E Wang, H McMahon, FJ AF Yao, Yin Xu, Mengyuan Murphy, Eleanor Wang, Harold McMahon, Francis J. TI A Mixture Model Estimate of Time to Antidepressant Drug-Effect in Association with Covariates Using the STAR(star)D Sample SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE drug effect; drug onset; major depression; anxiety; association C1 [Yao, Yin; Xu, Mengyuan; Murphy, Eleanor; Wang, Harold; McMahon, Francis J.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA M193 BP S241 EP S241 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100402 ER PT J AU Yuan, QP Yeo, S Zhou, ZF Hodgkinson, CA Goldman, D AF Yuan, Qiaoping Yeo, Seungeun Zhou, Zhifeng Hodgkinson, Colin A. Goldman, David TI Differential Allelic Expression and cis-Regulatory Sites at Human Neuronal Genes SO NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract DE human; expression; regulation; genetics C1 [Yuan, Qiaoping; Yeo, Seungeun; Zhou, Zhifeng; Hodgkinson, Colin A.; Goldman, David] NIAAA, Bethesda, MD USA. NR 0 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2013 VL 38 SU 2 MA W67 BP S477 EP S478 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA V40KI UT WOS:000209477100744 ER PT J AU Sanchez, MA Rabin, BA Gaglio, B Henton, M Elzarrad, MK Purcell, P Glasgow, RE AF Sanchez, Michael A. Rabin, Borsika A. Gaglio, Bridget Henton, Michelle Elzarrad, M. Khair Purcell, Peyton Glasgow, Russell E. TI A systematic review of eHealth cancer prevention and control interventions: new technology, same methods and designs? SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Review DE eHealth; Pragmatic trials; Systematic review; Design; PRECIS; External validity; RE-AIM framework AB There has been a recent surge of eHealth programs in cancer and other content areas, but few reviews have focused on the methodologies and designs employed in these studies. We conducted a systematic review of studies on eHealth interventions on cancer prevention and control published between 2001 and 2010 applying the Pragmatic Explanatory Continuum Indicator Summary (PRECIS) criteria and external validity components from the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. We identified 113 studies that focused on cancer prevention and control of eHealth interventions. Most studies fell midway along the explanatory/pragmatic trial continuum, but few reported on various practical feasibility criteria for translation. Despite vast interest in cancer eHealth and the applied nature of this field, few studies considered key external validity issues. There is a need for use of alternative pragmatic study designs and transparent reporting of external validity components to produce more rapid and generalizable results. C1 [Sanchez, Michael A.; Elzarrad, M. Khair] NCI, Bethesda, MD 20892 USA. [Rabin, Borsika A.; Henton, Michelle] Kaiser Permanente Colorado, CRN Canc Commun Res Ctr, Denver, CO USA. [Gaglio, Bridget] Kaiser Permanente Midatlantic States, Midatlantic Permanente Res Inst, Rockville, MD USA. [Elzarrad, M. Khair] NCI, US FDA, Interagency Oncol Task Force IOTF Fellowship Canc, Bethesda, MD 20892 USA. [Purcell, Peyton] SAIC Frederick Inc, CMRP, Clin Res Directorate, Natl Lab Canc Res, Frederick, MD USA. RP Sanchez, MA (reprint author), NCI, Bethesda, MD 20892 USA. EM sanchezgarciama@mail.nih.gov FU National Cancer Institute Centers of Excellence in Cancer Communication Research [P20CA137219]; National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX The preparation of this manuscript was partially funded through the National Cancer Institute Centers of Excellence in Cancer Communication Research (award number P20CA137219). This project has been funded, in whole or in part, with federal funds from the National Cancer Institute, the 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 it mention of trade names, commercial products, or organizations implying endorsement by the US government. The opinions expressed are those of the authors and do not necessarily reflect those of the National Cancer Institute. NR 31 TC 8 Z9 8 U1 3 U2 6 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 DEC PY 2013 VL 3 IS 4 BP 392 EP 401 DI 10.1007/s13142-013-0224-1 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V39LR UT WOS:000209413000008 PM 24294327 ER PT J AU Michino, M Donthamsetti, P Beuming, T Banala, A Duan, LH Roux, T Han, Y Trinquet, E Newman, AH Javitch, JA Shi, L AF Michino, Mayako Donthamsetti, Prashant Beuming, Thijs Banala, Ashwini Duan, Lihua Roux, Thomas Han, Yang Trinquet, Eric Newman, Amy Hauck Javitch, Jonathan A. Shi, Lei TI A Single Glycine in Extracellular Loop 1 Is the Critical Determinant for Pharmacological Specificity of Dopamine D2 and D3 Receptors SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; FUNCTIONALIZED LINKING CHAINS; EXCHANGE MOLECULAR-DYNAMICS; BINDING-SITE CREVICE; TRANSMEMBRANE SEGMENT; STRUCTURAL BIOLOGY; CRYSTAL-STRUCTURES; LIGAND-BINDING; BETA-HAIRPIN; SELECTIVITY AB Subtype-selective agents for the dopamine D3 receptor (D3R) have been considered as potential medications for drug addiction and other neuropsychiatric disorders. Medicinal chemistry efforts have led to the discovery of 4-phenylpiperazine derivatives that are >100-fold selective for the dopamine D3 receptor over dopamine D2 receptor (D2R), despite high sequence identity (78% in the transmembrane domain). Based on the recent crystal structure of D3R, we demonstrated that the 4-phenylpiperazine moiety in this class of D3R-selective compounds binds to the conserved orthosteric binding site, whereas the extended aryl amide moiety is oriented toward a divergent secondary binding pocket (SBP). In an effort to further characterize molecular determinants of the selectivity of these compounds, we modeled their binding modes in D3R and D2R by comparative ligand docking and molecular dynamics simulations. We found that the aryl amide moiety in the SBP differentially induces conformational changes in transmembrane segment 2 and extracellular loop 1 (EL1), which amplify the divergence of the SBP in D3R and D2R. Receptor chimera and site-directed mutagenesis studies were used to validate these binding modes and to identify a divergent glycine in EL1 as critical to D3R over D2R subtype selectivity. A better understanding of drug-dependent receptor conformations such as these is key to the rational design of compounds targeting a specific receptor among closely related homologs, and may also lead to discovery of novel chemotypes that exploit subtle differences in protein conformations. C1 [Michino, Mayako; Shi, Lei] Cornell Univ, Weill Med Coll, Inst Computat Biomed, Dept Physiol & Biophys, New York, NY 10021 USA. [Donthamsetti, Prashant; Duan, Lihua; Han, Yang; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Donthamsetti, Prashant; Duan, Lihua; Han, Yang; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. [Donthamsetti, Prashant; Duan, Lihua; Han, Yang; Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Beuming, Thijs] Schrodinger Inc, New York, NY USA. [Banala, Ashwini; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD USA. [Roux, Thomas; Trinquet, Eric] Cisbio Bioassays, Codolet, France. RP Shi, L (reprint author), Weill Cornell Med Coll, Dept Physiol & Biophys, 1300 York Ave,Box 75, New York, NY 10065 USA. EM jaj2@columbia.edu; les2007@med.cornell.edu FU Ranger at the Texas Advanced Computing Center [TG-MCB090022] FX Computations were performed on the Ranger at the Texas Advanced Computing Center [Project Number TG-MCB090022]. NR 47 TC 23 Z9 23 U1 0 U2 15 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 DEC PY 2013 VL 84 IS 6 BP 854 EP 864 DI 10.1124/mol.113.087833 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 248GX UT WOS:000326687200007 PM 24061855 ER PT J AU Leddy, MA Anderson, BL Schulkin, J AF Leddy, Meaghan A. Anderson, Britta L. Schulkin, Jay TI Cognitive-behavioral therapy and decision science SO NEW IDEAS IN PSYCHOLOGY LA English DT Article DE Cognitive-behavioral therapy; Decision science; Judgment; Decision making; Biases ID GENERALIZED ANXIETY DISORDER; RANDOMIZED CONTROLLED-TRIAL; MOOD-CONGRUENT JUDGMENT; FOLLOW-UP; ANTIDEPRESSANT MEDICATION; PSYCHOLOGICAL TREATMENTS; DEPRESSED-PATIENTS; MAJOR DEPRESSION; RATIONAL CHOICE; HINDSIGHT BIAS AB In recent decades cognitive-behavioral therapy (CBT) and decision science (DS) have emerged within the field of psychological science. Though these are two vastly different areas of study, they are similar in that they address human information processing, cognition, behavior, and the link between them. In this article, we provide brief summaries of CBT and decision science, discuss their similarities and differences, and discuss how future research can identify ways in which these fields can inform each other. Several CBT techniques that might be of use to the efforts of the decision science field to prevent cognitive biases are suggested. Research that integrates these two fields may lead to the improvement of both. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Leddy, Meaghan A.; Anderson, Britta L.] VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Leddy, Meaghan A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. [Schulkin, Jay] Amer Coll Obstetricians & Gynecologists, Res Dept, Washington, DC 20024 USA. [Schulkin, Jay] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. [Schulkin, Jay] NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. RP Schulkin, J (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, 3970 Reservoir Rd NW, Washington, DC 20007 USA. EM anderson.britta.l@gmail.com; jschulkin@acog.org NR 91 TC 1 Z9 1 U1 3 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0732-118X EI 1873-3522 J9 NEW IDEAS PSYCHOL JI New Ideas Psychol. PD DEC PY 2013 VL 31 IS 3 BP 173 EP 183 DI 10.1016/j.newideapsych.2013.01.001 PG 11 WC Psychology, Multidisciplinary; Psychology, Experimental SC Psychology GA 244AI UT WOS:000326359100001 ER PT J AU Hall, FS Drgonova, J Jain, S Uhl, GR AF Hall, F. Scott Drgonova, Jana Jain, Siddharth Uhl, George R. TI Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong? SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Addiction; Drug abuse; Genome-wide association study; Linkage; Transgenic; Knockout; Genetics ID MU-OPIOID-RECEPTOR; TRANSPORTER KNOCKOUT MICE; D-2 DOPAMINE-RECEPTOR; PREPULSE INHIBITION DEFICITS; CONDITIONED PLACE PREFERENCE; SMOKING-CESSATION SUCCESS; SINGLE-NUCLEOTIDE POLYMORPHISMS; AND/OR SEROTONIN TRANSPORTERS; SUBSTANCE USE DISORDERS; ALCOHOL DEPENDENCE AB Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS. Published by Elsevier Inc. C1 [Hall, F. Scott; Drgonova, Jana; Jain, Siddharth; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Hall, FS (reprint author), NIDA, Mol Neurobiol Branch, 333 Cassell Dr, Baltimore, MD 21224 USA. EM shall@intra.nida.nih.gov RI Hall, Frank/C-3036-2013; OI Hall, Frank/0000-0002-0822-4063; Drgonova, Jana/0000-0002-4623-8466 FU National Institute on Drug Abuse FX This work was supported by intramural funding from the National Institute on Drug Abuse. NR 184 TC 11 Z9 13 U1 7 U2 55 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD DEC PY 2013 VL 140 IS 3 BP 267 EP 279 DI 10.1016/j.pharmthera.2013.07.006 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 244WZ UT WOS:000326422200005 PM 23872493 ER PT J AU Camfield, L Masae, A McGregor, JA Promphaking, B AF Camfield, Laura Masae, Awae McGregor, J. Allister Promphaking, Buapun TI Cultures of Aspiration and Poverty? Aspirational Inequalities in Northeast and Southern Thailand SO SOCIAL INDICATORS RESEARCH LA English DT Article DE Aspirations; Subjective wellbeing; Thailand; Inequality; Adaptation; Poverty ID CONSUMPTION; WOMEN; HAPPINESS AB The paper provides micro-level evidence of rising inequality in Thailand, using data from an intensive study of seven communities in Northeast and Southern Thailand. This inequality affects participants' material and subjective wellbeing, their aspirations, and the extent to which they feel these are realised. The paper argues that adaptation, expressed as reduced aspirations, could explain why the effect of material poverty on people's satisfaction with their lives is small. The reduction in attainment of aspirations linked to socio-economic status suggests that a small, but constant group of people are being excluded from a shift in the societal consensus over what constitutes a good life. C1 [Camfield, Laura] Univ E Anglia, Dept Int Dev, Norwich NR4 7TJ, Norfolk, England. [Masae, Awae] NIDA, Sch Social & Environm Dev, Bangkok, Thailand. [Promphaking, Buapun] Khon Kaen Univ, Khon Kaen, Thailand. RP Camfield, L (reprint author), Univ E Anglia, Dept Int Dev, Norwich NR4 7TJ, Norfolk, England. EM l.camfield@uea.ac.uk OI Camfield, Laura/0000-0002-0165-9857 NR 58 TC 1 Z9 1 U1 1 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0303-8300 EI 1573-0921 J9 SOC INDIC RES JI Soc. Indic. Res. PD DEC PY 2013 VL 114 IS 3 BP 1049 EP 1072 DI 10.1007/s11205-012-0189-3 PG 24 WC Social Sciences, Interdisciplinary; Sociology SC Social Sciences - Other Topics; Sociology GA 244QZ UT WOS:000326405800017 ER PT J AU Kuo, CC Moon, K Thayer, KA Navas-Acien, A AF Kuo, Chin-Chi Moon, Katherine Thayer, Kristina A. Navas-Acien, Ana TI Environmental Chemicals and Type 2 Diabetes: An Updated Systematic Review of the Epidemiologic Evidence SO CURRENT DIABETES REPORTS LA English DT Review DE Systematic review; Environmental chemicals; Diabetes; Arsenic; Cadmium; Mercury; Persistent organic pollutants; Bisphenol A; Phthalates; Type 2 diabetes; Epidemiology ID PERSISTENT ORGANIC POLLUTANTS; POLYCHLORINATED BIPHENYL EXPOSURE; URINARY PHTHALATE METABOLITES; CAPACITOR MANUFACTURING PLANT; BISPHENOL-A CONCENTRATIONS; OPERATION RANCH HAND; ARSENIC EXPOSURE; INSULIN-RESISTANCE; NATIONAL-HEALTH; ENDOCRINE DISRUPTOR AB The burden of diabetes is increasing globally. Identifying novel preventable risk factors is an urgent need. In 2011, the U.S. National Toxicological Program (NTP) conducted a workshop to evaluate the epidemiologic and experimental evidence on the relationship of environmental chemicals with obesity, diabetes, and metabolic syndrome. Although the evidence was insufficient to establish causality, the NTP workshop review identified an overall positive association between some environmental chemicals and diabetes. In the present systematic review, our objective was to summarize the epidemiological research published since the NTP workshop. We identified a total of 29 articles (7 on arsenic, 3 on cadmium, 2 on mercury, 11 on persistent organic pollutants, 3 on phthalates, and 4 on bisphenol A), including 7 prospective studies. Considering consistency, temporality, strength, dose-response relationship, and biological plausibility (confounding), we concluded that the evidence is suggestive but not sufficient for a relationship between arsenic and persistent organic pollutants and is insufficient for mercury, phthalates, and bisphenol A. For cadmium, the epidemiologic evidence does not seem to suggest an association with diabetes. Important research questions include the need for additional prospective studies and the evaluation of the dose-response relationship, the role of joint exposures, and effect modification with other comorbidities and genetic variants. C1 [Kuo, Chin-Chi; Moon, Katherine; Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Kuo, Chin-Chi; Moon, Katherine; Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Kuo, Chin-Chi; Moon, Katherine; Navas-Acien, Ana] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Thayer, Kristina A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Kuo, CC (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. EM ckuo@jhsph.edu; kmoon@jhsph.edu; thayer@niehs.nih.gov; anavas@jhsph.edu RI Tuomisto, Jouko/J-7450-2012 FU National Institute of Environmental Health Sciences [R01ES021367, P30ES03819]; National Heart Lung and Blood Institute [R01HL090863] FX Supported by grants from the National Institute of Environmental Health Sciences (R01ES021367, P30ES03819) and the National Heart Lung and Blood Institute (R01HL090863). NR 123 TC 60 Z9 63 U1 6 U2 74 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD DEC PY 2013 VL 13 IS 6 BP 831 EP 849 DI 10.1007/s11892-013-0432-6 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 241SR UT WOS:000326188500009 PM 24114039 ER PT J AU Ramakrishnan, B Moncrief, AJ Davis, TA Holland, LA Qasba, PK AF Ramakrishnan, Boopathy Moncrief, Anthony J. Davis, Tyler A. Holland, Lisa A. Qasba, Pradman K. TI Investigations on beta 1,4-galactosyltransferase I using 6-sulfo-GlcNAc as an acceptor sugar substrate SO GLYCOCONJUGATE JOURNAL LA English DT Article DE beta 1,4-galactosyltransferase; Acceptor specificity; 6-sulfo-GlcNAc; Crystal structure; Capillary electrophoresis ID ALPHA-LACTALBUMIN; CRYSTAL-STRUCTURE; N-ACETYLGLUCOSAMINE; LACTOSE SYNTHETASE; GALACTOSYLTRANSFERASE; GLYCOSYLTRANSFERASES; REVEALS; COMPLEX; PROTEIN; MUTANT AB 6-sulfate modified N-acetylglucosamine (6-sulfo-GlcNAc) is often found as part of many biologically important carbohydrate epitopes such as 6-sulfo-Le(X). In these epitopes, the 6-sulfo-GlcNAc moiety is extended by a galactose sugar in a beta 1-4 linkage. The beta 4GalT1 enzyme transfers galactose (Gal) from UDP-Gal to N-acetylglucosamine (GlcNAc) in the presence of manganese. Here we report that the beta 4GalT1 enzyme transfers Gal to the 6-sulfo-GlcNAc and 4-methylumbelliferyl-6-sulfo-N-acetyl-beta-D-glucosaminide (6-sulfo-beta GlcNAc-MU) acceptor substrates, although with very low efficiency. To understand the effect that the 6-sulfate group on the GlcNAc acceptor has on the catalytic activity of the beta 4GalT1 molecule, we have determined the crystal structure of the catalytic domain of bovine beta 4GalT1 mutant enzyme M344H-beta 4GalT1 complex with the 6-sulfo-GlcNAc molecule. In the crystal structure, the 6-sulfo-GlcNAc is bound to the protein in a way that is similar to the GlcNAc molecule. However, the 6-sulfate group engages in additional interactions with the hydrophobic region, residues 276-285, of the protein molecule, and this group is found wedged between the aromatic side chains of Phe-280 and Trp314 residues. Since the side chain of the Trp314 residue undergoes conformational changes during the catalytic cycle of the enzyme, molecular interaction between Trp314 and the 6-sulfate group might hinder this conformational change. Therefore, the lack of a favorable binding environment, together with hindrance to the conformational changes, might be responsible for the poor catalytic activity. C1 [Ramakrishnan, Boopathy; Qasba, Pradman K.] NCI, Struct Glycobiol Sect, Basic Sci Lab, Frederick, MD 21702 USA. [Ramakrishnan, Boopathy] SAIC Frederick Inc, Basic Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Moncrief, Anthony J.; Davis, Tyler A.; Holland, Lisa A.] W Virginia Univ, C Eugene Bennett Dept Chem, Morgantown, WV 26506 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, Basic Sci Lab, POB B, Frederick, MD 21702 USA. EM qasbapr@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Science Foundation [1003907]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. We acknowledge support for T. A. D. from the National Science Foundation (Cooperative Agreement 1003907). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 32 TC 1 Z9 1 U1 4 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0282-0080 EI 1573-4986 J9 GLYCOCONJUGATE J JI Glycoconjugate J. PD DEC PY 2013 VL 30 IS 9 BP 835 EP 842 DI 10.1007/s10719-013-9488-4 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 241TB UT WOS:000326189600003 PM 23942731 ER PT J AU Ftacek, P Nelson, V Szu, SC AF Ftacek, Peter Nelson, Victor Szu, Shousun C. TI Immunochemical characterization of synthetic hexa-, octa- and decasaccharide conjugate vaccines for Vibrio cholerae O:1 Serotype Ogawa with emphasis on antigenic density and chain length SO GLYCOCONJUGATE JOURNAL LA English DT Article DE Neoglyco conjugate; Cholera vaccine; Immunogenicity; Vibriocidal ID SHIGELLA-DYSENTERIAE TYPE-1; ORAL CHOLERA; BACTERICIDAL ANTIBODIES; IMMUNE-RESPONSES; FAMILY CONTACTS; PROTEIN CARRIER; EAST PAKISTAN; FIELD-TRIAL; LIPOPOLYSACCHARIDE; POLYSACCHARIDE AB Cholera remains to be a global health problem without suitable vaccines for endemic control or outbreak relief. Here we describe a new parenteral vaccine based on neoglyco-conjugate of synthetic fragments of O-specific polysaccharide (O-SP) of Vibrio cholerae O1, serotype Ogawa. Hexa-, octa- and decasaccharides of the O-SP with carboxylic acid at the reducing end were chemically synthesized and conjugated to tetanus toxoid (TT). The conjugates prepared by a novel linking scheme consisted of 17-atom linker of hydrazide and alkyl bonds elicited robust serum IgG anti-LPS responses with vibriocidal activities in mice. There is a length dependence in immune response with decasaccharide conjugates elicited the highest anti-LPS IgG. There seems to be an indication that regardless of the carbohydrate chain length, a molar ratio of 230 +/- 10 monosaccharide units per TT induced high antibody response. The conjugates also elicited cross-reactive antibodies to serotype Inaba. The formulation of the proposed cholera conjugate vaccine, similar to other licensed polysaccharide vaccine, is suitable for children immunization. A parenteral cholera vaccine could overcome the diminishing immunogenicity in most of oral vaccines due to the gastrointestinal complexity and environmental enteropathy in children living in impoverished environment and could be considered for global cholera immunization. C1 [Ftacek, Peter; Nelson, Victor; Szu, Shousun C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Szu, SC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bldg 6,Room 1A06,9000 Rockville Pike, Bethesda, MD 20892 USA. EM szunih@gmail.com FU Intramural Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported fully by the Intramural Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors have no conflict interest to disclose. NR 72 TC 1 Z9 1 U1 1 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0282-0080 EI 1573-4986 J9 GLYCOCONJUGATE J JI Glycoconjugate J. PD DEC PY 2013 VL 30 IS 9 BP 871 EP 880 DI 10.1007/s10719-013-9491-9 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 241TB UT WOS:000326189600006 PM 23955520 ER PT J AU Staats, KA Van Helleputte, L Jones, AR Bento-Abreu, A Van Hoecke, A Shatunov, A Simpson, CL Lemmens, R Jaspers, T Fukami, K Nakamura, Y Brown, RH Van Damme, P Liston, A Robberecht, W Al-Chalabi, A Van Den Bosch, L AF Staats, Kim A. Van Helleputte, Lawrence Jones, Ashley R. Bento-Abreu, Andre Van Hoecke, Annelies Shatunov, Aleksey Simpson, Claire L. Lemmens, Robin Jaspers, Tom Fukami, Kiyoko Nakamura, Yoshikazu Brown, Robert H., Jr. Van Damme, Philip Liston, Adrian Robberecht, Wim Al-Chalabi, Ammar Van Den Bosch, Ludo TI Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Amyotrophic lateral sclerosis; Phospholipase C delta 1; Neurogenetics; SOD1-G93A mice; Excitotoxicity; Motor neuron disease; Nuclear shrinkage ID AMYOTROPHIC-LATERAL-SCLEROSIS; GENOME-WIDE ASSOCIATION; MOTOR-NEURON DEGENERATION; TRANSGENIC MOUSE MODEL; HEXANUCLEOTIDE REPEAT; MUTATIONS; SUSCEPTIBILITY; DISEASE; C-DELTA-1; ALS AB Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease, resulting in selective motor neuron degeneration and paralysis. Patients die approximately 3-5 years after diagnosis. Disease pathophysiology is multifactorial, including excitotoxicity, but is not yet fully understood. Genetic analysis has proven fruitful in the past to further understand genes modulating the disease and increase knowledge of disease mechanisms. Here, we revisit a previously performed microsatellite analysis in ALS and focus on another hit, PLCD1, encoding phospholipase C delta 1 (PLC delta 1), to investigate its role in ALS. PLC delta 1 may contribute to excitotoxicity as it increases inositol 1,4,5-trisphosphate (IP3) formation, which releases calcium from the endoplasmic reticulum through IP3 receptors. We find that expression of PLC delta 1 is increased in ALS mouse spinal cord and in neurons from ALS mice. Furthermore, genetic ablation of this protein in ALS mice significantly increases survival, but does not affect astrogliosis, microgliosis, aggregation or the amount of motor neurons at end stage compared to ALS mice with PLC delta 1. Interestingly, genetic ablation of PLC delta 1 prevents nuclear shrinkage of motor neurons in ALS mice at end stage. These results indicate that PLCD1 contributes to ALS and that PLC delta 1 may be a new target for future studies. (C) 2013 Elsevier Inc. All rights reserved. C1 [Jones, Ashley R.; Shatunov, Aleksey; Al-Chalabi, Ammar] Kings Coll London, Inst Psychiat, Dept Clin Neurosci, London, England. [Simpson, Claire L.] NHGRI, Inherited Dis Res Branch, US Natl Inst Hlth, Baltimore, MD USA. [Fukami, Kiyoko; Nakamura, Yoshikazu] Tokyo Univ Pharm & Life Sci, Lab Genome & Biosignal, Hachioji, Tokyo 19203, Japan. [Brown, Robert H., Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Liston, Adrian] VIB, Autoimmune Genet Lab, Louvain, Belgium. [Liston, Adrian] Katholieke Univ Leuven, Dept Microbiol & Immunol, Louvain, Belgium. EM kim.staats@vib-kuleuven.be; Lawrence.vanhelleputte@vib-kuleuven.be; ashley.ajones@kcl.ac.uk; Andre.BentoAbreu@vib-kuleuven.be; avanhoecke@neuro.mpg.de; aleksey.shatunov@kcLac.uk; claire.simpson@nih.gov; robin.lemmens@vib-kuleuven.be; tom.jaspers@vib-kuleuven.be; kfukami@ls.toyaku.ac.jp; ynakamur@toyaku.ac.jp; robertbrown@umassmed.edu; philip.vandamme@vib-kuleuven.be; adriandiston@vib-kuleuven.be; wim.robberecht@vib-kuleuven.be; ammar.al-chalabi@kcl.ac.uk; ludo.vandenbosch@vib-kuleuven.be RI Al-Chalabi, Ammar/E-5361-2010; Van Damme, Philip/A-6464-2009; Liston, Adrian/G-8606-2013 OI Al-Chalabi, Ammar/0000-0002-4924-7712; Van Damme, Philip/0000-0001-6384-0611; Liston, Adrian/0000-0002-6272-4085 FU ALS Association; Motor Neurone Disease Association of England, Wales and Northern Ireland; NIHR Dementia Biomedical Research Unit at South London; Maudsley NHS Foundation Trust; King's College London; "Fund for Scientific Research Flanders" (FWO-Vlaanderen); University of Leuven (KU Leuven); Belgian Government (Interuniversity Attraction Poles, programme of the Belgian Federal Science Policy Office) [P7/16]; ALS Therapy Alliance; Angel Fund; European Community [259867]; National Human Genome Research Institute, National Institutes of Health FX MC thanks the ALS Association and Motor Neurone Disease Association of England, Wales and Northern Ireland for support. He receives salary support from the NIHR Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. This work was supported by grants from the "Fund for Scientific Research Flanders" (FWO-Vlaanderen), the University of Leuven (KU Leuven), the Belgian Government (Interuniversity Attraction Poles, programme P7/16 of the Belgian Federal Science Policy Office), the ALS Therapy Alliance, the Angel Fund and the European Community's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867). PVD and RL hold a clinical investigatorship of the FWO-Vlaanderen. WR is supported through the E von Behring Chair for Neuromuscular and Neurodegenerative Disorders. CLS is funded by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. NR 48 TC 6 Z9 7 U1 2 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 DEC PY 2013 VL 60 BP 11 EP 17 DI 10.1016/j.nbd.2013.08.006 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 239ZO UT WOS:000326064700002 PM 23969236 ER PT J AU Lopez-Dominguez, JA Khraiwesh, H Gonzalez-Reyes, JA Lopez-Lluch, G Navas, P Ramsey, JJ de Cabo, R Buron, MI Villalba, JM AF Alberto Lopez-Dominguez, Jose Khraiwesh, Husam Antonio Gonzalez-Reyes, Jose Lopez-Lluch, Guillermo Navas, Placido Ramsey, Jon Jay de Cabo, Rafael Buron, Maria Isabel Villalba, Jose M. TI Dietary fat modifies mitochondrial and plasma membrane apoptotic signaling in skeletal muscle of calorie-restricted mice SO AGE LA English DT Article DE Apoptotic signaling; Calorie restriction; Dietary fat; Sarcopenia; Skeletal muscle ID AGE-RELATED ALTERATIONS; COENZYME-Q; OXIDATIVE STRESS; ACID-COMPOSITION; LIFE-SPAN; EICOSAPENTAENOIC ACID; GASTROCNEMIUS-MUSCLE; REGULATORY PROTEINS; ANTIOXIDANT SYSTEM; PLANTARIS MUSCLE AB Calorie restriction decreases skeletal muscle apoptosis, and this phenomenon has been mechanistically linked to its protective action against sarcopenia of aging. Alterations in lipid composition of membranes have been related with the beneficial effects of calorie restriction. However, no study has been designed to date to elucidate if different dietary fat sources with calorie restriction modify apoptotic signaling in skeletal muscle. We show that a 6-month calorie restriction decreased the activity of the plasma membrane neutral sphingomyelinase, although caspase-8/10 activity was not altered, in young adult mice. Lipid hydroperoxides, Bax levels, and cytochrome c and AIF release/accumulation into the cytosol were also decreased, although caspase-9 activity was unchanged. No alterations in caspase-3 and apoptotic index (DNA fragmentation) were observed, but calorie restriction improved structural features of gastrocnemius fibers by increasing cross-sectional area and decreasing circularity of fibers in cross sections. Changing dietary fat with calorie restriction produced substantial alterations of apoptotic signaling. Fish oil augmented the protective effect of calorie restriction decreasing plasma membrane neutral sphingomyelinase, Bax levels, caspase-8/10, and -9 activities, while increasing levels of the antioxidant coenzyme Q at the plasma membrane, and potentiating the increase of cross-sectional area and the decrease of fiber circularity in cross sections. Many of these changes were not found when we used lard. Our data support that dietary fish oil with calorie restriction produces a cellular anti-apoptotic environment in skeletal muscle with a downregulation of components involved in the initial stages of apoptosis engagement, both at the plasma membrane and the mitochondria. C1 [Alberto Lopez-Dominguez, Jose; Khraiwesh, Husam; Antonio Gonzalez-Reyes, Jose; Buron, Maria Isabel; Villalba, Jose M.] Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Cordoba 14014, Spain. [Lopez-Lluch, Guillermo; Navas, Placido] Univ Pablo Olavide CSIC, CABD, Seville, Spain. [Lopez-Lluch, Guillermo; Navas, Placido] CIBERER Inst Salud Carlos III, Seville, Spain. [Ramsey, Jon Jay] Univ Calif Davis, VM Mol Biosci, Davis, CA 95616 USA. [de Cabo, Rafael] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Villalba, JM (reprint author), Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Campus Excelencia Agroalimentario CeiA3,Edificio, Cordoba 14014, Spain. EM jmvillalba@uco.es RI Gonzalez-Reyes, Jose A/K-1367-2014; Lopez-Lluch, Guillermo/N-4742-2014; de Cabo, Rafael/J-5230-2016; OI Gonzalez-Reyes, Jose A/0000-0003-1918-5490; Lopez-Lluch, Guillermo/0000-0001-9830-8502; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIH [1R01AG028125-01A1]; Ministerio de Economia y Competitividad [BFU2011-23578]; Junta de Andalucia Proyectos de Excelencia [P09-CVI-4887]; Junta de Andalucia Proyectos Internacionales grant; Junta de Andalucia [BIO-276]; University of Cordoba [BIO-276]; Spanish Ministerio de Educacion; Agencia Espanola de Cooperacion Internacional al Desarrollo FX This work was supported by NIH grant 1R01AG028125-01A1 (to JJR, PN and JMV), Ministerio de Economia y Competitividad BFU2011-23578 (to JMV), Junta de Andalucia Proyectos de Excelencia grant P09-CVI-4887 (to JMV), Junta de Andalucia Proyectos Internacionales grant (to JMV), and BIO-276 (Junta de Andalucia and the University of Cordoba, to JMV). JALD was funded by a predoctoral fellowship of the Spanish Ministerio de Educacion. HK was funded by a predoctoral fellowship of the Agencia Espanola de Cooperacion Internacional al Desarrollo. NR 60 TC 7 Z9 7 U1 0 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD DEC PY 2013 VL 35 IS 6 BP 2027 EP 2044 DI 10.1007/s11357-012-9492-9 PG 18 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 240MK UT WOS:000326100600001 PM 23179253 ER PT J AU Pizzarelli, F Maas, R Dattolo, P Tripepi, G Michelassi, S D'Arrigo, G Mieth, M Bandinelli, S Ferrucci, L Zoccali, C AF Pizzarelli, Francesco Maas, Renke Dattolo, Pietro Tripepi, Giovanni Michelassi, Stefano D'Arrigo, Graziella Mieth, Maren Bandinelli, Stefania Ferrucci, Luigi Zoccali, Carmine TI Asymmetric dimethylarginine predicts survival in the elderly SO AGE LA English DT Article DE ADMA; Elderly; Cardiovascular risk factor; Survival; Population study ID NITRIC-OXIDE SYNTHASE; CORONARY-HEART-DISEASE; L-ARGININE PARADOX; CARDIOVASCULAR RISK; ENDOTHELIAL DYSFUNCTION; CELL SENESCENCE; ADMA; HUMANS; MORTALITY; PLASMA AB Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase implicated in several age-related biological mechanisms such as telomere shortening and cell senescence. We tested the hypothesis that ADMA blood level is an independent predictor of mortality in elderly. This is a longitudinal population-based cohort study. Participants are a representative cohort of 1,025 men and women (age range 65-102 years) living in Chianti area, Tuscany, Italy. The plasma ADMA was measured by liquid chromatography-tandem mass spectrometry. During the follow-up (95 +/- 32 months), 384 individuals died, of whom 141 (37 %) died of cardiovascular (CV) causes. In adjusted analyses, the plasma ADMA was the strongest predictor of all-cause mortality (HR (0.1 mu Mol/L) 1.26, 95 % CI 1.10-1.44, P < 0.001) with a non-significant trend for CV mortality (HR 1.22, P = 0.07). The predictive effect of the ADMA level on mortality was statistically significant among participants with low to low-normal l-arginine levels (a parts per thousand currency sign60 mu Mol/L), but not in those with l-arginine > 60 mu Mol/L. Notwithstanding the association of ADMA with all-cause mortality was robust, this biomarker failed to add predictive power to a simple model based on the risk factors in the elderly (area under the ROC curve 0.85 +/- 0.01 vs. 0.84 +/- 0.01). ADMA is a strong independent predictor of mortality in the older population, and l-arginine modifies the effect of ADMA on survival. The mechanisms for this association should be targeted by future studies. C1 [Pizzarelli, Francesco; Dattolo, Pietro; Michelassi, Stefano] SM Annunziata Hosp, Nephrol Unit, I-50011 Florence, Italy. [Maas, Renke; Mieth, Maren] Univ Erlangen Nurnberg, Inst Expt & Klin Pharmakol & Toxikol, D-91054 Erlangen, Germany. [Tripepi, Giovanni; D'Arrigo, Graziella; Zoccali, Carmine] Osped Riuniti Reggio Calabria, CNR, IBIM, Reggio Di Calabria, Italy. [Tripepi, Giovanni; D'Arrigo, Graziella; Zoccali, Carmine] Osped Riuniti Reggio Calabria, Nephrol Transplant Unit, Reggio Di Calabria, Italy. [Bandinelli, Stefania] SM Annunziata Hosp, Geriatr Unit, I-50011 Florence, Italy. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Pizzarelli, F (reprint author), SM Annunziata Hosp, Nephrol Unit, Via Antella 58, I-50011 Florence, Italy. EM fpizzarelli@yahoo.com; pierodattolo@tin.it OI Zoccali, Carmine/0000-0002-6616-1996 NR 32 TC 14 Z9 14 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD DEC PY 2013 VL 35 IS 6 BP 2465 EP 2475 DI 10.1007/s11357-013-9523-1 PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 240MK UT WOS:000326100600036 PM 23584888 ER PT J AU Liyanage, NPM Dassanayake, RP Kuszynski, CA Duhamel, GE AF Liyanage, Namal P. M. Dassanayake, Rohana P. Kuszynski, Charles A. Duhamel, Gerald E. TI Contribution of Helicobacter hepaticus Cytolethal Distending Toxin Subunits to Human Epithelial Cell Cycle Arrest and Apoptotic Death in vitro SO HELICOBACTER LA English DT Article DE apoptosis; CDT; cell cycle arrest; Helicobacter hepaticus ID HUMAN T-CELLS; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; HAEMOPHILUS-DUCREYI; ESCHERICHIA-COLI; CAMPYLOBACTER-JEJUNI; BACTERIAL GENOTOXIN; B6C3F(1) MICE; G(2) ARREST; DNA-DAMAGE; ANNEXIN-V AB BackgroundCytolethal distending toxin (CDT) is the only known virulence factor found in H.hepaticus, the cause of chronic typhlocolitis and hepatitis leading to colonic and hepatocellular carcinomas in mice. Interaction of the tripartite polypeptide CdtA, CdtB, and CdtC subunits produced by H.hepaticus CDT (HhepCDT) causes cell cycle arrest and apoptotic death of cultured cells; however, the contribution of individual subunit to these processes has not been investigated. Materials and MethodsThe temporal relationship between cell cycle and apoptotic death of human epithelial HeLa and INT407 cells intoxicated with HhepCDT holotoxin or reconstituted recombinant HhepCDT was compared by flow cytometry. The genotoxic activity of individual and combinations of recombinant HhepCDT protein subunits or increasing concentrations of individual recombinant HhepCDT protein subunits transfected into HeLa cells was assessed at 72hours post-treatment by flow cytometry. ResultsSimilar time course of HhepCDT-induced G(2)/M cell cycle arrest and apoptotic death was found with both cell lines which reached a maximum at 72hours. The presence of all three HhepCDT subunits was required for maximum cell cycle arrest and apoptosis of both cell lines. Transfection of HeLa cells with HhepCdtB, but not with HhepCdtA or HhepCdtC, resulted in a dose-dependent G(2)/M arrest and apoptotic death. ConclusionAll three subunits of HhepCDT are required for maximum epithelial cell cycle arrest and progression to apoptotic death, and HhepCdtB subunit alone is necessary and sufficient for epithelial cell genotoxicity. C1 [Liyanage, Namal P. M.; Dassanayake, Rohana P.; Duhamel, Gerald E.] Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE USA. [Kuszynski, Charles A.] Univ Nebraska Med Ctr, Coll Med, Dept Pathol & Microbiol, Omaha, NE USA. [Liyanage, Namal P. M.] NCI, Vaccine Branch, Bethesda, MD 20892 USA. [Dassanayake, Rohana P.] Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. RP Duhamel, GE (reprint author), Cornell Univ, Dept Biomed Sci, Coll Vet Med, T4 012A Vet Res Tower, Ithaca, NY 14850 USA. EM ged36@cornell.edu FU NIH/NIAID [RO3 AI059532] FX We thank ShiHong Gill in the School of Veterinary Medicine and Biomedical Sciences at the University of Nebraska-Lincoln for her excellent technical assistance with flow cytometry. This study was funded in part by the NIH/NIAID grant RO3 AI059532 to GED. NR 67 TC 6 Z9 7 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD DEC PY 2013 VL 18 IS 6 BP 433 EP 443 DI 10.1111/hel.12084 PG 11 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA 238YK UT WOS:000325988100005 PM 23895367 ER PT J AU Zou, QH Ross, TJ Gu, H Geng, XJ Zuo, XN Hong, LE Gao, JH Stein, EA Zang, YF Yang, YH AF Zou, Qihong Ross, Thomas J. Gu, Hong Geng, Xiujuan Zuo, Xi-Nian Hong, L. Elliot Gao, Jia-Hong Stein, Elliot A. Zang, Yu-Feng Yang, Yihong TI Intrinsic Resting-State Activity Predicts Working Memory Brain Activation and Behavioral Performance SO HUMAN BRAIN MAPPING LA English DT Article DE resting-state fMRI; ALFF; N-back working memory; load dependency; behavior ID FUNCTIONAL CONNECTIVITY; VISUAL-CORTEX; INTERINDIVIDUAL DIFFERENCES; PREFRONTAL CORTEX; MOTOR CORTEX; DEFAULT MODE; TASK; FMRI; MRI; VARIABILITY AB Although resting-state brain activity has been demonstrated to correspond with task-evoked brain activation, the relationship between intrinsic and evoked brain activity has not been fully characterized. For example, it is unclear whether intrinsic activity can also predict task-evoked deactivation and whether the rest-task relationship is dependent on task load. In this study, we addressed these issues on 40 healthy control subjects using resting-state and task-driven [N-back working memory (WM) task] functional magnetic resonance imaging data collected in the same session. Using amplitude of low-frequency fluctuation (ALFF) as an index of intrinsic resting-state activity, we found that ALFF in the middle frontal gyrus and inferior/superior parietal lobules was positively correlated with WM task-evoked activation, while ALFF in the medial prefrontal cortex, posterior cingulate cortex, superior frontal gyrus, superior temporal gyrus, and fusiform gyrus was negatively correlated with WM task-evoked deactivation. Further, the relationship between the intrinsic resting-state activity and task-evoked activation in lateral/superior frontal gyri, inferior/superior parietal lobules, superior temporal gyrus, and midline regions was stronger at higher WM task loads. In addition, both resting-state activity and the task-evoked activation in the superior parietal lobule/precuneus were significantly correlated with the WM task behavioral performance, explaining similar portions of intersubject performance variance. Together, these findings suggest that intrinsic resting-state activity facilitates or is permissive of specific brain circuit engagement to perform a cognitive task, and that resting activity can predict subsequent task-evoked brain responses and behavioral performance. Hum Brain Mapp 34:3204-3215, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Zou, Qihong; Ross, Thomas J.; Gu, Hong; Geng, Xiujuan; Stein, Elliot A.; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Zou, Qihong; Gao, Jia-Hong] Peking Univ, MRI Res Ctr, Beijing 100871, Peoples R China. [Zou, Qihong; Gao, Jia-Hong] Peking Univ, Beijing City Key Lab Med Phys & Engn, Beijing 100871, Peoples R China. [Zou, Qihong; Zang, Yu-Feng] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. [Zuo, Xi-Nian] Chinese Acad Sci, Inst Psychol, Lab Funct Connectome & Dev, Key Lab Behav Sci, Beijing 100101, Peoples R China. [Zuo, Xi-Nian] Chinese Acad Sci, Inst Psychol, Magnet Resonance Imaging Res Ctr, Beijing 100101, Peoples R China. [Hong, L. Elliot] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Gao, Jia-Hong] Univ Chicago, Brain Res Imaging Ctr, Chicago, IL 60637 USA. [Zang, Yu-Feng] Hangzhou Normal Univ, Affiliated Hosp, Ctr Cognit & Brain Disorders, Hangzhou, Zhejiang, Peoples R China. RP Yang, YH (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM zangyf@gmail.com; yihongyang@intra.nida.nih.gov RI ZANG, Yu-Feng/J-1558-2012; OI ZANG, Yu-Feng/0000-0003-1833-8010; Ross, Thomas/0000-0002-7745-3572; Zuo, Xi-Nian/0000-0001-9110-585X FU Intramural Research Program of the National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH); Natural Science Foundation of China [81020108022]; China's National Strategic Basic Research Program (973) [2012CB720700] FX Contract grant sponsors: Intramural Research Program of the National Institute on Drug Abuse (NIDA) and National Institutes of Health (NIH); Contract grant sponsor: Natural Science Foundation of China; Contract grant number: 81020108022; Contract grant sponsor: China's National Strategic Basic Research Program (973); Contract grant number: 2012CB720700. NR 52 TC 56 Z9 58 U1 3 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD DEC PY 2013 VL 34 IS 12 BP 3204 EP 3215 DI 10.1002/hbm.22136 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 240BC UT WOS:000326068700008 PM 22711376 ER PT J AU Montalvo, V Quigley, L Vistica, BP Boelte, KC Nugent, LF Takai, T McVicar, DW Gery, I AF Montalvo, Vanessa Quigley, Laura Vistica, Barbara P. Boelte, Kimberly C. Nugent, Lindsey F. Takai, Toshiyuki McVicar, Daniel W. Gery, Igal TI Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes SO IMMUNOLOGY LA English DT Article DE cytokines; lymphoid cells; ocular inflammation; TREM-2 ID EXPERIMENTAL AUTOIMMUNE UVEITIS; MYELOID CELLS (TREM)-2; TOLL-LIKE RECEPTOR; INFLAMMATORY RESPONSES; AMPLIFIES INFLAMMATION; DAP12-DEFICIENT MICE; CUTTING EDGE; FCR-GAMMA; ACTIVATION; DISEASE AB DNAX-activation protein 12 (DAP12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT-PCR detected in normal mouse eyes considerable levels of DAP12 and multiple DAP12-coupled receptors, in particular TREM-1, Clec5a and SIRPb1. The role of DAP12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid-binding protein (IRBP), and to develop experimental autoimmune uveitis (EAU). Surprisingly, sequential analysis of EAU in mice deficient in DAP12 in two different animal facilities at first revealed enhanced disease as compared with wild-type mice, but when these mice were re-derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulated in vitro with IRBP, lymphocytes from the DAP12-deficient mice housed in the two facilities proliferated and produced opposite profiles of pro-inflammatory and anti-inflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP12 deficiency on development of autoimmune disease are dramatically affected by environmental factors. C1 [Montalvo, Vanessa; Vistica, Barbara P.; Nugent, Lindsey F.; Gery, Igal] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Quigley, Laura; Boelte, Kimberly C.; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Takai, Toshiyuki] Tohoku Univ, Inst Dev Aging & Canc, Dept Expt Immunol, Sendai, Miyagi 980, Japan. RP Gery, I (reprint author), NEI, NIH, Bldg 10,Room 10N208, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov RI McVicar, Daniel/G-1970-2015 FU Intramural Research Programs of the National Eye Institute; Intramural Research Program of the Center for Cancer Research of the National Cancer Institute FX This work was supported by the Intramural Research Programs of the National Eye Institute and the Intramural Research Program of the Center for Cancer Research of the National Cancer Institute. The authors are grateful to Dr Wayne Yokoyama of Washington University, St Louis, for the gift of DAP12-deficient mice on the C57BL/6 background. We thank Dr Robert Fariss, Biological Imagining Core, NEI, for digitized microscopy and Mehak K. Aziz and Osato Ogbeifun for superb professional help. V.M, L.Q., B.P.V., K.C.B. and L.F.N. performed the experimental work and contributed to the interpretation of data and preparation of the manuscript. T.T. generated the DAP12-deficient mice. D.W.M. and I.G. designed the experiments, contributed to data interpretation and wrote the paper. NR 37 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD DEC PY 2013 VL 140 IS 4 BP 475 EP 482 DI 10.1111/imm.12158 PG 8 WC Immunology SC Immunology GA 240GB UT WOS:000326081900009 PM 23906311 ER PT J AU Lee, JH Cheng, KT Malinin, V Li, ZL Yao, ZS Lee, SJ Gould, CM Olivier, KN Chen, C Perkins, WR Paik, CH AF Lee, Jae-Ho Cheng, Kenneth T. Malinin, Vladimir Li, Zhili Yao, Zhengsheng Lee, Sung-Jin Gould, Christine M. Olivier, Kenneth N. Chen, Clara Perkins, Walter R. Paik, Chang H. TI Tc-99m-labeled therapeutic inhaled amikacin loaded liposomes SO JOURNAL OF LIPOSOME RESEARCH LA English DT Article DE Tc-99m-labeled liposome-encapsulated amikacin; radiolabeling; size exclusion analysis ID GEL EXCLUSION CHROMATOGRAPHY; CYSTIC-FIBROSIS PATIENTS; PSEUDOMONAS-AERUGINOSA; GAMMA-SCINTIGRAPHY; LUNG DEPOSITION; IN-VITRO; CLEARANCE; PERFORMANCE; VOLUNTEERS; TOBRAMYCIN AB The radiolabeling of the liposome surface can be a useful tool for in vivo tracking of therapeutic drug loaded liposomes. We investigated radiolabeling therapeutic drug (i.e. an antibiotic, amikacin) loaded liposomes with Tc-99m, nebulization properties of Tc-99m-labeled liposomal amikacin for inhalation (Tc-99m-LAI), and its stability by size exclusion low-pressure liquid chromatography (LPLC). LAI was reacted with Tc-99m using SnCl2 dissolved in ascorbic acid as a reducing agent for 10 min at room temperature. The labeled products were then purified by anion exchange resin. The purified Tc-99m-LAI in 1.5% NaCl solution was incubated at 4 degrees C to assess its stability by LPLC. The purified Tc-99m-LAI was subjected to studies with a clinically used nebulizer (PARI eFlow (R)) and the Anderson Cascade Impactor (ACI). The use of ascorbic acid at 0.91 mM resulted in a quantitative labeling efficiency. The LPLC profile showed that the liposomal peak of LAI detected by a UV monitor at both 200 nm and 254 nm overlapped with the radioactivity peak of Tc-99m-LAI, indicating that Tc-99m-LAI is suitable for tracing LAI. The ACI study demonstrated that the aerosol droplet size distribution determined gravimetrically was similar to that determined by radioactivity. The liposome surface labeling method using SnCl2 in 0.91 mM ascorbic acid produced Tc-99m-LAI with a high labeling efficiency and stability that are adequate to evaluate the deposition and clearance of inhaled LAI in the lung by gamma scintigraphy. C1 [Lee, Jae-Ho; Cheng, Kenneth T.; Yao, Zhengsheng; Lee, Sung-Jin; Chen, Clara; Paik, Chang H.] NIH, Radiopharmaceut Lab, Div Nucl Med, Dept Radiol & Imaging Sci,Warren G Magnuson Clin, Bethesda, MD 20892 USA. [Malinin, Vladimir; Li, Zhili; Perkins, Walter R.] Insmed Inc, Monmouth Jct, NJ 08852 USA. [Gould, Christine M.; Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lee, JH (reprint author), NIH, Radiopharmaceut Lab, Div Nucl Med, Dept Radiol & Imaging Sci,Warren G Magnuson Clin, Bldg 10, Bethesda, MD 20892 USA. EM leejaeho@mail.nih.gov FU National Institute of Allergy and Infectious Diseases; Clinical Center of the NIH FX This research was supported in part by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the Clinical Center of the NIH. NR 33 TC 4 Z9 4 U1 0 U2 13 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0898-2104 EI 1532-2394 J9 J LIPOSOME RES JI J. Liposome Res. PD DEC PY 2013 VL 23 IS 4 BP 336 EP 342 DI 10.3109/08982104.2013.819889 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 232VM UT WOS:000325522500009 PM 23879241 ER PT J AU Koethe, Y Widemann, BC Hajjar, F Wood, BJ Venkatesan, AM AF Koethe, Yilun Widemann, Brigitte C. Hajjar, Fouad Wood, Bradford J. Venkatesan, Aradhana M. TI PET-Guided Biopsy With Needle Navigation Facilitates Diagnosis of Angiosarcoma in Neurofibromatosis Type 1 SO PEDIATRIC BLOOD & CANCER LA English DT Article DE FDG-PET; image guided biopsy; malignant peripheral neural sheath tumor; neurofibromatosis type 1; plexiform neurofibroma ID NERVE SHEATH TUMORS; TOMOGRAPHY FDG-PET AB Malignant degeneration frequently arises from preexisting plexiform neurofibroma in patients with neurofibromatosis type 1 (NF1). Image guided biopsy for diagnostic purposes, such as with CT guidance, can be technically challenging in these patients, as CT cannot distinguish malignant from benign areas within the same tumor. Navigation with multi-modality (PET, CT, and ultrasound) image fusion facilitated the successful biopsy and diagnosis of angiosarcoma arising from a pelvic neurofibroma in a patient with NF1. Successful targeting assisted treatment selection in this case. This novel navigation technique may facilitate the otherwise difficult diagnosis of malignancy in patients with NF1. Pediatr Blood Cancer 2013;60:E166-E169. (c) 2013 Wiley Periodicals, Inc. C1 [Koethe, Yilun; Wood, Bradford J.; Venkatesan, Aradhana M.] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Koethe, Yilun; Wood, Bradford J.; Venkatesan, Aradhana M.] NIH, Bethesda, MD 20892 USA. [Koethe, Yilun] Duke Univ, Sch Med, Durham, NC USA. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Hajjar, Fouad] Florida Hosp, Childrens Ctr Canc & Blood Dis, Orlando, FL USA. RP Venkatesan, AM (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, 10 Ctr Dr,Bldg 10 CRC,Room 1C369,MSC 1182, Bethesda, MD 20892 USA. EM venkatesana@cc.nih.gov FU Intramural Research program of the NIH; NIH Clinical Center; National Cancer Institute FX This research was supported in part by the Intramural Research program of the NIH, by the NIH Clinical Center and by the National Cancer Institute. NR 9 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2013 VL 60 IS 12 BP E166 EP E169 DI 10.1002/pbc.24668 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 232HX UT WOS:000325484900005 PM 23922330 ER PT J AU Ghirlando, R Felsenfeld, G AF Ghirlando, Rodolfo Felsenfeld, Gary TI Physical Chemistry of Nucleic Acids and Their Complexes SO BIOPOLYMERS LA English DT Review DE DNA; chromatin; polynucleotide structures ID RICH HISTONE KERNEL; CHROMATIN-STRUCTURE; NEUTRAL PH; TRANSCRIBING POLYMERASE; POLYRIBOADENYLIC ACID; NUCLEOSOME STRUCTURE; RNA-POLYMERASE; TRANSCRIPTION; DNA; CONFORMATION AB Studies of the physical properties of nucleic acids began almost immediately following the discovery of the DNA structure. Early investigations focused on the stability and specificity of multi-strand polynucleotide complexes, then gradually on their interaction with other molecules, particularly proteins. As molecular and structural biology expanded to provide detailed information about biochemical mechanisms, physical studies eventually acquired the additional constraint that they should be relevant to functioning biological systems. We describe work in our laboratory that began with investigations of relatively simple questions about the role of electrostatic interactions in the stabilization of multi-strand nucleic acid structures, and evolved to studies of chromatin structure in vitro and within the nucleus. Published 2013 Wiley Periodicals, Inc*. Biopolymers 99: 910-915, 2013. C1 [Ghirlando, Rodolfo; Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases FX Contract grant sponsor: Intramural Research Program, National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases NR 46 TC 3 Z9 3 U1 2 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD DEC PY 2013 VL 99 IS 12 SI SI BP 910 EP 915 DI 10.1002/bip.22311 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 227DS UT WOS:000325089800002 PM 23765314 ER PT J AU Lynch, SM Major, JM Cawthon, R Weinstein, SJ Virtamo, J Lan, Q Rothman, N Albanes, D Stolzenberg-Solomon, RZ AF Lynch, Shannon M. Major, Jacqueline M. Cawthon, Richard Weinstein, Stephanie J. Virtamo, Jarmo Lan, Qing Rothman, Nathaniel Albanes, Demetrius Stolzenberg-Solomon, Rachael Z. TI A prospective analysis of telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer (ATBC) prevention study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; telomere length; biomarker; epidemiology ID COHORT-CONSORTIUM PANSCAN; MULTIPLEX QUANTITATIVE PCR; BODY-MASS INDEX; POOLED-ANALYSIS; INTRAEPITHELIAL NEOPLASIA; CIGARETTE-SMOKING; ALCOHOL INTAKE; MALE SMOKERS; RISK; CELLS AB Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR = 1.26 95% CI = 1.09-1.46; highest quartile compared to lowest, OR = 1.57, 95% CI = 1.01-2.43, p-trend = 0.007). This association remained for subjects diagnosed within the first five years of blood draw (continuous OR = 1.46, 95% CI = 1.19-1.79 highest quartile OR = 2.92, 95% CI = 1.47-5.77, p-trend = 0.002), but not those diagnosed greater than five years after blood draw (continuous OR = 1.03, 95% CI = 0.85-1.22; highest quartile OR = 1.04, 95% CI = 0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk. What's new? This is the first prospective study to examine the association between blood leukocyte telomere length and pancreatic cancer. In tumor, longer telomeres have been observed in advanced pancreatic cancer and risk factors for pancreatic cancer (cigarette smoke and diabetes) are known to affect telomere length. Based on a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, here the authors found that longer blood leukocyte telomeres were significantly associated with increased pancreatic cancer risk. The results add insight into the role of telomeres in pancreatic cancer, a disease that can benefit from the identification of early detection markers. C1 [Lynch, Shannon M.; Major, Jacqueline M.; Weinstein, Stephanie J.; Albanes, Demetrius; Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lynch, Shannon M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Ctr Genet & Complex Traits, Philadelphia, PA 19104 USA. [Cawthon, Richard] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Lan, Qing; Rothman, Nathaniel] NCI, Ocupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Lynch, SM (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, Ctr Genet & Complex Traits, Philadelphia, PA 19104 USA. EM lynchsh@mail.med.upenn.edu RI Albanes, Demetrius/B-9749-2015 NR 54 TC 22 Z9 22 U1 1 U2 38 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 DEC 1 PY 2013 VL 133 IS 11 BP 2672 EP 2680 DI 10.1002/ijc.28272 PG 9 WC Oncology SC Oncology GA 227DA UT WOS:000325087600017 PM 23674344 ER PT J AU Rosenberg, AS Roivainen, M Hovi, T Liu, Q Murphy, PM AF Rosenberg, A. S. Roivainen, M. Hovi, T. Liu, Q. Murphy, P. M. TI CCR5 Deficiency and Severe Polio Infection in the 1984 Outbreak in Finland SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE poliovirus; CCR5delta32; neuropathology ID NILE-VIRUS-INFECTION; CHEMOKINE RECEPTORS; POLIOMYELITIS AB CCR5, a leukocyte chemoattractant receptor for chemokines CCL3, CCL4, and CCL5, promotes innate and adaptive immune responses by mediating leukocyte trafficking within lymph nodes and to peripheral tissues and is also known as a co-receptor for HIV cell entry. Homozygous inheritance of a complete loss-of-function mutation in CCR5 (CCR532/CCR532) is associated with symptomatic neuroinflammatory disease in humans with West Nile and Tickborne Encephalitis flavivirus infections. This study sought to establish whether CCR5 deficiency could also be a determinant of clinical outcome after infection by poliovirus which results in central nervous system damage in only a small proportion of cases. We analyzed serum samples from seven patients and 79 controls, collected during the 1984-1985 polio outbreak in Finland, where CCR532 is relatively common in the general population. The results excluded CCR5 deficiency as the sole determinant of severe neurologic disease after poliovirus infection in this population. J. Med. Virol. 85:2139-2140, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Rosenberg, A. S.] US FDA, Div Therapeut Prot, Off Biotechnol Prod, CDER, Silver Spring, MD USA. [Roivainen, M.; Hovi, T.] Natl Inst Hlth & Welf THL, Dept Infect Dis Surveillance & Control, Virol Unit, Helsinki, Finland. [Liu, Q.; Murphy, P. M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Rosenberg, AS (reprint author), US FDA, Div Therapeut Prot, Off Biotechnol Prod, CDER, Silver Spring, MD USA. EM amy.rosenberg@fda.hhs.gov NR 10 TC 0 Z9 0 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD DEC PY 2013 VL 85 IS 12 BP 2139 EP 2140 DI 10.1002/jmv.23739 PG 2 WC Virology SC Virology GA 227ZE UT WOS:000325153400012 PM 24037958 ER PT J AU Shen, XP Liu, YX Zhang, EZ Bhamidipati, P AF Shen, Xipeng Liu, Yixun Zhang, Eddy Z. Bhamidipati, Poornima TI An Infrastructure for Tackling Input-Sensitivity of GPU Program Optimizations SO INTERNATIONAL JOURNAL OF PARALLEL PROGRAMMING LA English DT Article DE GPU; Program Optimizations; Empirical Search; CUDA; G-ADAPT; Cross-input Adaptation ID GENERATION; FEEDBACK AB Graphic processing units (GPU) have become increasingly adopted for the enhancement of computing throughput. However, the development of a high-quality GPU application is challenging, due to the large optimization space and complex unpredictable effects of optimizations on GPU program performance. Many recent efforts have been employing empirical search-based auto-tuners to tackle the problem, but few of them have concentrated on the influence of program inputs on the optimizations. In this paper, based on a set of CUDA and OpenCL kernels, we report some evidences on the importance for auto-tuners to adapt to program input changes, and present a framework, G-ADAPT+, to address the influence by constructing cross-input predictive models for automatically predicting the (near-)optimal configurations for an arbitrary input to a GPU program. G-ADAPT+ is based on source-to-source compilers, specifically, Cetus and ROSE. It supports the optimizations of both CUDA and OpenCL programs. C1 [Shen, Xipeng] Coll William & Mary, Dept Comp Sci, Williamsburg, VA 23185 USA. [Liu, Yixun] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Zhang, Eddy Z.] Rutgers State Univ, Dept Comp Sci, New Brunswick, NJ 08901 USA. [Bhamidipati, Poornima] Capital One, Williamsburg, VA 23185 USA. RP Shen, XP (reprint author), Coll William & Mary, Dept Comp Sci, Williamsburg, VA 23185 USA. EM xshen@cs.wm.edu; yixun.liu@nih.gov; eddy.zhengzhang@cs.rutgers.edu; poornimabhamidipati@gmail.com FU National Science Foundation [0720499, 0811791, CAREER 0954015]; Department of Energy FX This material is based upon work supported by the National Science Foundation under Grant No. 0720499 and 0811791 and CAREER 0954015, along with the Early Career Grant from the Department of Energy. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation or the Department of Energy. NR 31 TC 2 Z9 2 U1 0 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7458 J9 INT J PARALLEL PROG JI Int. J. Parallel Program. PD DEC PY 2013 VL 41 IS 6 SI SI BP 855 EP 869 DI 10.1007/s10766-012-0236-3 PG 15 WC Computer Science, Theory & Methods SC Computer Science GA 195TK UT WOS:000322726300007 ER PT J AU Frierson, GM Howard, EN DeFina, LF Powell-Wiley, TM Willis, BL AF Frierson, Georita M. Howard, Erica N. DeFina, Laura F. Powell-Wiley, Tiffany M. Willis, Benjamin L. TI EFFECT OF RACE AND SOCIOECONOMIC STATUS ON CARDIOVASCULAR RISK FACTOR BURDEN: THE COOPER CENTER LONGITUDINAL STUDY SO ETHNICITY & DISEASE LA English DT Article DE Socioeconomic Status; Racial/ethnic Minorities; Preventive Medicine; Cardiovascular Risk Factors ID ALL-CAUSE MORTALITY; RACIAL DISPARITIES; AFRICAN-AMERICANS; PHYSICAL-FITNESS; CARDIORESPIRATORY FITNESS; INCOME INEQUALITY; HEALTH; MEN; PREVALENCE; STRESS AB Objectives: This study examines the prevalence of cardiovascular risk factors and chronic disease burden among African Americans compared to Caucasians in a population of higher socioeconomic status. Design: The current study is a cross-sectional, secondary data analysis of the Cooper Center Longitudinal Study. Setting: Patients with a medical examination from 1970-2010 at the Cooper Clinic. Participants: 762 African Americans and 40,051 Caucasians who met the criteria. Outcome Measures: Racial differences in cardiovascular risk factors/burden of disease between African Americans and Caucasians. Results: African Americans had higher prevalence of evaluated cardiovascular risk factors than did Caucasians after controlling for obesity, tobacco use, and physical fitness. Caucasians had greater likelihood of no risk factors while African Americans were more likely to have all three risk factors. Race was typically predictive of cardiovascular risk factors in African Americans compared to Caucasians. Conclusions: Findings suggest that health differences persist despite greater socioeconomic status, and further investigations of biopsychosocial causes are warranted. (Ethn Dis. 2013;23[1]:35-42) C1 [Frierson, Georita M.] Howard Univ, Dept Psychol, Washington, DC 20059 USA. [Howard, Erica N.; DeFina, Laura F.; Willis, Benjamin L.] Cooper Inst, Dallas, TX USA. [Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Frierson, GM (reprint author), Howard Univ, Dept Psychol, CB Powell Bldg, Washington, DC 20059 USA. EM georitafrierson@gmail.com FU Intramural NIH HHS [Z99 HL999999] NR 58 TC 5 Z9 5 U1 1 U2 249 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD WIN PY 2013 VL 23 IS 1 BP 35 EP 42 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 069VH UT WOS:000313464700007 PM 23495620 ER PT J AU Holland, RJ Paulisch, R Cao, Z Keefer, LK Saavedra, JE Donzelli, S AF Holland, Ryan J. Paulisch, Rika Cao, Zhao Keefer, Larry K. Saavedra, Joseph E. Donzelli, Sonia TI Enzymatic generation of the NO/HNO-releasing IPA/NO anion at controlled rates in physiological media using beta-galactosidase SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE IPA/NO; Prodrug; Nitroxyl; Diazeniumdiolate; Gal-IPA/NO; beta-Galactosidase ID NITROXYL HNO DONORS; NITRIC-OXIDE; DIAZENIUMDIOLATE; CHEMISTRY; NO; PRODRUGS AB We introduce a strategy for generating mixtures of nitric oxide (NO) and nitroxyl (HNO) at tunable rates in physiological media. The approach involves converting a spontaneously HNO/NO-generating ion to a caged (prodrug) form that is essentially stable in neutral media, but that can be activated for HNO/NO release by adding an enzyme capable of efficiently opening the cage to regenerate the ion. By judiciously choosing the enzyme, substrate, and reaction conditions, unwanted scavenging of the HNO and NO by the protein can be minimised and the catalytic efficiency of the enzyme can be maintained. We illustrate this approach with a proof-of-concept study wherein the prodrug is Gal-IPA/NO, a diazeniumdiolate of structure iPrHN-N(O)=NOR, with R = beta-D-galactosyl. Escherichia coli-derived beta-D-galactosidase at concentrations of 1.9-15 nM hydrolysed 56 mu M substrate with half-lives of 140-19 mm, respectively, producing the IPA/NO anion (iPrHN-N(O)=NO-, half-life similar to 3 mm), which in turn spontaneously hydrolysed to mixtures of HNO with NO. Using saturating substrate concentrations furnished IPA/NO generation rates that were directly proportional to enzyme concentration. Consistent with these data, the enzyme/substrate combination applied to ventricular myocytes isolated from wild-type mouse hearts resulted not only in a significant positive inotropic effect, but also rescued the cells from the negative inotropy, hypercontractions, and occasional cell death seen with the enzyme alone. This mechanism represents an alternate approach for achieving controlled fluxes of NO/HNO to investigate their biological actions. (C) 2013 Published by Elsevier Inc. C1 [Holland, Ryan J.; Keefer, Larry K.] NCI, Biol Chem Lab, Drug Design Sect, Frederick, MD 21702 USA. [Paulisch, Rika; Donzelli, Sonia] Univ Med Ctr Hamburg Eppendorf, Dept Expt Pharmacol & Toxicol, D-20246 Hamburg, Germany. [Cao, Zhao; Saavedra, Joseph E.] Frederick Natl Lab Canc Res, SAIC Frederick, Basic Res Program, Ft Detrick, MD 21702 USA. RP Holland, RJ (reprint author), NCI, Biol Chem Lab, Drug Design Sect, Frederick, MD 21702 USA. EM hollandrj@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and with Federal funds from the National Cancer Institute under Contract HHSN261200800001E to SAIC. We thank Dr. Sergey Tarasov and Ms. Marzena A. Dyba of the Biophysics Resource in the Structural Biophysics Laboratory, NCI-Frederick, for assistance with the high resolution mass spectrometry studies. We gratefully acknowledge Mr. John Klose for assistance with the NMR experiments. NR 28 TC 3 Z9 3 U1 3 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 30 PY 2013 VL 35 BP 131 EP 136 DI 10.1016/j.niox.2013.10.003 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 270IP UT WOS:000328312400017 PM 24126017 ER PT J AU Salunke, S Brandys, B Giacoia, G Tuleu, C AF Salunke, Smita Brandys, Barbara Giacoia, George Tuleu, Catherine TI The STEP (Safety and Toxicity of Excipients for Paediatrics) database: Part 2-The pilot version SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Excipients; Children; Database; Toxicity; Adverse effects; Chemicals ID PROPYLENE-GLYCOL; EXPOSURE; MEDICINES AB The screening and careful selection of excipients is a critical step in paediatric formulation development as certain excipients acceptable in adult formulations, may not be appropriate for paediatric use. While there is extensive toxicity data that could help in better understanding and highlighting the gaps in toxicity studies, the data are often scattered around the information sources and saddled with incompatible data types and formats. This paper is the second in a series that presents the update on the Safety and Toxicity of Excipients for Paediatrics ("STEP") database being developed by Eu-US PFIs, and describes the architecture data fields and functions of the database. The STEP database is a user designed resource that compiles the safety and toxicity data of excipients that is scattered over various sources and presents it in one freely accessible source. Currently, in the pilot database data from over 2000 references/10 excipients presenting preclinical, clinical, regulatory information and toxicological reviews, with references and source links. The STEP database allows searching "FOR" excipients and "BY" excipients. This dual nature of the STEP database, in which toxicity and safety information can be searched in both directions, makes it unique from existing sources. If the pilot is successful, the aim is to increase the number of excipients in the existing database so that a database large enough to be of practical research use will be available. It is anticipated that this source will prove to be a useful platform for data management and data exchange of excipient safety information. (C) 2013 Elsevier B. V. All rights reserved. C1 [Salunke, Smita; Tuleu, Catherine] UCL Sch Pharm, Dept Pharmaceut, London WC1N 1AX, England. [Salunke, Smita; Tuleu, Catherine] UCL Sch Pharm, Ctr Paediat Pharm Res, London WC1N 1AX, England. [Brandys, Barbara] NIH, Natl Inst Hlth NIH Lib, Div Lib Serv, Off Res Serv, Bethesda, MD 20892 USA. [Giacoia, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, OPPB, NIH, Bethesda, MD USA. RP Salunke, S (reprint author), UCL Sch Pharm, Dept Pharmaceut, 29-39 Brunswick Sq, London WC1N 1AX, England. EM S.Salunke@ucl.ac.uk OI tuleu, catherine/0000-0001-8384-357X FU European Union [261060] FX The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. 261060. NR 27 TC 19 Z9 20 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD NOV 30 PY 2013 VL 457 IS 1 BP 310 EP 322 DI 10.1016/j.ijpharm.2013.09.013 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 248FU UT WOS:000326681800033 PM 24070789 ER PT J AU Chen, BJ Qin, J AF Chen, Baojiang Qin, Jing TI A new estimation with minimum trace of asymptotic covariance matrix for incomplete longitudinal data with a surrogate process SO STATISTICS IN MEDICINE LA English DT Article DE longitudinal data; missing data; optimal; surrogate outcome ID DOUBLY ROBUST ESTIMATION; MISSING DATA; END-POINTS; REGRESSION-MODELS; INFERENCE; IMPUTATION; TRIALS AB Missing data is a very common problem in medical and social studies, especially when data are collected longitudinally. It is a challenging problem to utilize observed data effectively. Many papers on missing data problems can be found in statistical literature. It is well known that the inverse weighted estimation is neither efficient nor robust. On the other hand, the doubly robust (DR) method can improve the efficiency and robustness. As is known, the DR estimation requires a missing data model (i.e., a model for the probability that data are observed) and a working regression model (i.e., a model for the outcome variable given covariates and surrogate variables). Because the DR estimating function has mean zero for any parameters in the working regression model when the missing data model is correctly specified, in this paper, we derive a formula for the estimator of the parameters of the working regression model that yields the optimally efficient estimator of the marginal mean model (the parameters of interest) when the missing data model is correctly specified. Furthermore, the proposed method also inherits the DR property. Simulation studies demonstrate the greater efficiency of the proposed method compared with the standard DR method. A longitudinal dementia data set is used for illustration. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Chen, Baojiang] Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE 68198 USA. [Qin, Jing] NIAID, NIH, Bethesda, MD 20892 USA. RP Chen, BJ (reprint author), Univ Nebraska Med Ctr, Dept Biostat, Omaha, NE 68198 USA. EM baojiang.chen@unmc.edu FU National Institute on Aging [U01AG016976] FX Dr. Chen were supported in part by the National Institute on Aging grant U01AG016976. This paper presents the findings and conclusions of the authors. NR 28 TC 0 Z9 0 U1 0 U2 3 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 NOV 30 PY 2013 VL 32 IS 27 BP 4763 EP 4780 DI 10.1002/sim.5875 PG 18 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 238QT UT WOS:000325963300006 PM 23744541 ER PT J AU Hu, JX Hu, K Liu, T Stern, MK Mistry, R Challiss, RAJ Costanzi, S Wess, J AF Hu, Jianxin Hu, Kelly Liu, Tong Stern, Matthew K. Mistry, Rajendra Challiss, R. A. John Costanzi, Stefano Wess, Juergen TI Novel Structural and Functional Insights into M-3 Muscarinic Receptor Dimer/Oligomer Formation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Cholinergic Receptor; G Protein-coupled Receptors (GPCR); Neurotransmitter Receptors; Receptor Structure-function; Site-directed Mutagenesis ID PROTEIN-COUPLED RECEPTOR; CRYSTAL-STRUCTURE; ACETYLCHOLINE-RECEPTORS; OPIOID RECEPTOR; NATIVE MEMBRANES; MOLECULAR-BASIS; DRUG DISCOVERY; RHODOPSIN; ACTIVATION; TRANSDUCIN AB Background: G protein-coupled receptors (GPCRs) exist in dimeric/oligomeric arrays but the structural basis underling this phenomenon is not well understood. Results: The M-3 muscarinic receptor, a prototypic GPCR, can form multiple, structurally distinct dimeric species. Conclusion: GPCRs may exist in a dynamic equilibrium of multiple dimers or oligomers. Significance: Our findings may facilitate efforts to target GPCR dimers for therapeutic purposes. Class A G protein-coupled receptors (GPCRs) are able to form homodimers and/or oligomeric arrays. We recently proposed, based on bioluminescence resonance energy transfer studies with the M-3 muscarinic receptor (M3R), a prototypic class A GPCR, that the M3R is able to form multiple, structurally distinct dimers that are probably transient in nature (McMillin, S. M., Heusel, M., Liu, T., Costanzi, S., and Wess, J. (2011) J. Biol. Chem. 286, 28584-28598). To provide more direct experimental support for this concept, we employed a disulfide cross-linking strategy to trap various M3R dimeric species present in a native lipid environment (transfected COS-7 cells). Disulfide cross-linking studies were carried out with many mutant M3Rs containing single cysteine (Cys) substitutions within two distinct cytoplasmic M3R regions, the C-terminal portion of the second intracellular loop (i2) and helix H8 (H8). The pattern of cross-links that we obtained, in combination with molecular modeling studies, was consistent with the existence of two structurally distinct M3R dimer interfaces, one involving i2/i2 contacts (TM4-TM5-i2 interface) and the other one characterized by H8-H8 interactions (TM1-TM2-H8 interface). Specific H8-H8 disulfide cross-links led to significant impairments in M3R-mediated G protein activation, suggesting that changes in the structural orientation or mobility of H8 are critical for efficient receptor-G protein coupling. Our findings provide novel structural and functional insights into the mechanisms involved in M3R dimerization (oligomerization). Because the M3R shows a high degree of sequence similarity with many other class A GPCRs, our findings should be of considerable general interest. C1 [Hu, Jianxin; Hu, Kelly; Liu, Tong; Stern, Matthew K.; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Mistry, Rajendra; Challiss, R. A. John] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England. [Costanzi, Stefano] Amer Univ, Dept Chem, Washington, DC 20016 USA. [Costanzi, Stefano] Amer Univ, Ctr Behav Neurosci, Washington, DC 20016 USA. RP Wess, J (reprint author), Bldg 8A,Rm B1A-05,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov OI Costanzi, Stefano/0000-0003-3183-7332; Challiss, John/0000-0001-5506-2848 FU National Institutes of Health, NIDDK; American University FX This work was supported by the Intramural Research Program of the National Institutes of Health, NIDDK, and the American University. NR 51 TC 12 Z9 12 U1 3 U2 12 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 NOV 29 PY 2013 VL 288 IS 48 BP 34777 EP 34790 DI 10.1074/jbc.M113.503714 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 291FH UT WOS:000329812800046 PM 24133207 ER PT J AU Belugin, S Diogenes, AR Patil, MJ Ginsburg, E Henry, MA Akopian, AN AF Belugin, Sergei Diogenes, Anibal R. Patil, Mayur J. Ginsburg, Erika Henry, Michael A. Akopian, Armen N. TI Mechanisms of Transient Signaling via Short and Long Prolactin Receptor Isoforms in Female and Male Sensory Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Neuroendocrinology; Pain; PI3-kinase (PI3K); Prolactin; Protein Kinase C (PKC) ID PROTEIN-KINASE-C; DELTA-OPIOID-RECEPTOR; MESSENGER-RNA; PHOSPHATIDYLINOSITOL 3-KINASE; INFLAMMATORY HYPERALGESIA; TRIGEMINAL NOCICEPTORS; FUNCTIONAL COMPETENCE; INHIBITORY-ACTION; TRP CHANNELS; SHORT-FORM AB Background: Prolactin regulates the activity of nociceptors in pain conditions. Results: Prolactin regulation of sensory neurons is acute and mediated via PI3K and PKCE following activation of prolactin receptor short isoform. Prolactin receptor short isoform actions are inhibited by the long isoform. Conclusion: Prolactin receptor short isoform mediates transient sensitization of nociceptors. Significance: The proposed mechanism could underlie prolactin involvement in hyperalgesia/pain. Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches to show that PRL transiently enhanced capsaicin-evoked responses involve protein kinase C E (PKCE) or phosphatidylinositol 3-kinase (PI3K) pathways in female rat trigeminal (TG) neurons. We next reconstituted PRL-induced signaling in a heterologous expression system and TG neurons from PRL receptor (PRLR)-null mutant mice by expressing rat PRLR-long isoform (PRLR-L), PRLR-short isoform (PRLR-S), or a mix of both. Results show that PRLR-S, but not PRLR-L, is capable of mediating PRL-induced transient enhancement of capsaicin responses in both male and female TG neurons. However, co-expression of PRLR-L with PRLR-S (1:1 ratio) leads to the inhibition of the transient PRL actions. Co-expression of PRLR-L deletion mutants with PRLR-S indicated that the cytoplasmic site adjacent to the trans-membrane domain of PRLR-L was responsible for inhibitory effects of PRLR-L. Furthermore, in situ hybridization and immunohistochemistry data indicate that in normal conditions, PRLR-L is expressed mainly in glia with little expression in rat sensory neurons (3-5%) and human nerves. The predominant PRLR form in TG neurons/nerves from rats and humans is PRLR-S. Altogether, PRL-induced transient signaling in sensory neurons is governed by PI3K or PKCE, mediated via the PRLR-S isoform, and transient effects mediated by PRLR-S are inhibited by presence of PRLR-L in these cells. C1 [Belugin, Sergei; Diogenes, Anibal R.; Henry, Michael A.; Akopian, Armen N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Endodont, San Antonio, TX 78229 USA. [Patil, Mayur J.; Akopian, Armen N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Ginsburg, Erika] NCI, NIH, Bethesda, MD 20892 USA. RP Akopian, AN (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Endodont, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM akopian@uthscsa.edu OI Belugin, Sergei/0000-0001-9006-7732 FU National Institutes of Health [DE017696]; Intramural Research Program of the NCI/National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grant DE017696 (to A.N.A.) and by the Intramural Research Program of the NCI/National Institutes of Health (to E.G.). NR 63 TC 5 Z9 5 U1 0 U2 1 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 NOV 29 PY 2013 VL 288 IS 48 BP 34943 EP 34955 DI 10.1074/jbc.M113.486571 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 291FH UT WOS:000329812800060 PM 24142695 ER PT J AU Falivelli, G Lisabeth, EM de la Torre, ER Perez-Tenorio, G Tosato, G Salvucci, O Pasquale, EB AF Falivelli, Giulia Lisabeth, Erika Mathes de la Torre, Elena Rubio Perez-Tenorio, Gizeh Tosato, Giovanna Salvucci, Ombretta Pasquale, Elena B. TI Attenuation of Eph Receptor Kinase Activation in Cancer Cells by Coexpressed Ephrin Ligands SO PLOS ONE LA English DT Article ID TYROSINE KINASE; LUNG-CANCER; THERAPEUTIC TARGET; A LIGANDS; CIS; SUPPRESSES; EXPRESSION; MUTATIONS; PATHWAY; GROWTH AB The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting "in trans" with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral "cis" associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans. C1 [Falivelli, Giulia; Lisabeth, Erika Mathes; de la Torre, Elena Rubio; Perez-Tenorio, Gizeh; Pasquale, Elena B.] Sanford Burnham Med Res Inst, San Diego, CA 92101 USA. [Tosato, Giovanna; Salvucci, Ombretta] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pasquale, Elena B.] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Falivelli, Giulia] Univ Bologna, Dept Pharmacol, Bologna, Italy. RP Pasquale, EB (reprint author), Sanford Burnham Med Res Inst, San Diego, CA 92101 USA. EM elenap@sanfordburnham.org FU National Institutes of Health [P01CA138390, P01HD025938, T32CA121949]; Tobacco-Related Disease Research Program [18XT-0099, 20FT-0076]; Spanish Foundation for Science and Technology; Swedish Research Council [Dnr 2009-7360] FX This work was supported by National Institutes of Health grants P01CA138390 and P01HD025938, grant 18XT-0099 from the Tobacco-Related Disease Research Program (E.B.P.), a postdoctoral fellowship from the Spanish Foundation for Science and Technology (FECYT, E. R. T.), National Institutes of Health postdoctoral training grant T32CA121949 and postdoctoral fellowship 20FT-0076 from the Tobacco-Related Disease Research Program (E.M.L.), and postdoctoral fellowship Dnr 2009-7360 from the Swedish Research Council (G. P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 19 Z9 19 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 29 PY 2013 VL 8 IS 11 AR e81445 DI 10.1371/journal.pone.0081445 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261MX UT WOS:000327670300032 PM 24348920 ER PT J AU Trost, B Kindrachuk, J Maattanen, P Napper, S Kusalik, A AF Trost, Brett Kindrachuk, Jason Maeaettaenen, Pekka Napper, Scott Kusalik, Anthony TI PIIKA 2: An Expanded, Web-Based Platform for Analysis of Kinome Microarray Data SO PLOS ONE LA English DT Article ID PROTEIN-KINASE; PEPTIDE CHIPS; R-PACKAGE; EXPRESSION; TUMORS; SUBSTRATE; TESTS; SITE AB Kinome microarrays are comprised of peptides that act as phosphorylation targets for protein kinases. This platform is growing in popularity due to its ability to measure phosphorylation-mediated cellular signaling in a high-throughput manner. While software for analyzing data from DNA microarrays has also been used for kinome arrays, differences between the two technologies and associated biologies previously led us to develop Platform for Intelligent, Integrated Kinome Analysis (PIIKA), a software tool customized for the analysis of data from kinome arrays. Here, we report the development of PIIKA 2, a significantly improved version with new features and improvements in the areas of clustering, statistical analysis, and data visualization. Among other additions to the original PIIKA, PIIKA 2 now allows the user to: evaluate statistically how well groups of samples cluster together; identify sets of peptides that have consistent phosphorylation patterns among groups of samples; perform hierarchical clustering analysis with bootstrapping; view false negative probabilities and positive and negative predictive values for t-tests between pairs of samples; easily assess experimental reproducibility; and visualize the data using volcano plots, scatterplots, and interactive three-dimensional principal component analyses. Also new in PIIKA 2 is a web-based interface, which allows users unfamiliar with command-line tools to easily provide input and download the results. Collectively, the additions and improvements described here enhance both the breadth and depth of analyses available, simplify the user interface, and make the software an even more valuable tool for the analysis of kinome microarray data. Both the web-based and stand-alone versions of PIIKA 2 can be accessed via http://saphire.usask.ca. C1 [Trost, Brett; Kusalik, Anthony] Univ Saskatchewan, Dept Comp Sci, Saskatoon, SK S7N 0W0, Canada. [Trost, Brett; Kindrachuk, Jason] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD USA. [Maeaettaenen, Pekka; Napper, Scott] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. [Napper, Scott] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 0W0, Canada. RP Trost, B (reprint author), Univ Saskatchewan, Dept Comp Sci, Saskatoon, SK S7N 0W0, Canada. EM brett.trost@usask.ca RI Trost, Brett/K-4127-2016; OI Trost, Brett/0000-0003-4863-7273; Kindrachuk, Jason/0000-0002-3305-7084 FU Natural Sciences and Engineering Research Council of Canada (NSERC); Genome Canada; Intramural Research Program of the National Institutes of Health /National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Natural Sciences and Engineering Research Council of Canada (NSERC) (http://www.nserc-crsng.gc.ca), Genome Canada (http://www.genomecanada.ca), and the Intramural Research Program of the National Institutes of Health /National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 12 Z9 12 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 29 PY 2013 VL 8 IS 11 AR e80837 DI 10.1371/journal.pone.0080837 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261MX UT WOS:000327670300017 PM 24312246 ER PT J AU Carrington, M Bashirova, AA McLaren, PJ AF Carrington, Mary Bashirova, Arman A. McLaren, Paul J. TI On stand by: host genetics of HIV control SO AIDS LA English DT Editorial Material DE genome-wide association study; host genetics; human leukocyte antigen ID MAJOR HISTOCOMPATIBILITY COMPLEX; HLA-C EXPRESSION; GENOME-WIDE ASSOCIATION; NUMBER VARIANT ASSAYS; CLASS-I; MESSENGER-RNA; AIDS; INFECTION; RECOMBINATION; POLYMORPHISM AB The impact of host genetic variation on determining the differential outcomes after HIV infection has been studied by two approaches: targeting of candidate genes and genome-wide association studies (GWASs). The overlap in genetic variants that has been identified by these two means has essentially been restricted to variants near to the human leukocyte antigen (HLA) class I genes, although variation in the CCR5 locus, which was first shown to have an effect on HIV outcomes using the candidate gene approach, does reach significance genome-wide when very large samples sizes (i.e. thousands) are used in GWAS. Overall, many of the variants identified by the candidate gene approach are likely to be spurious, as no additional variants apart from a novel variant near the HLA-C gene have been consistently identified by GWAS. Variants with low frequency and/or low impact on HIV outcomes are likely to exist in the genome and there could be many of them, but these are not identifiable, given current GWAS sample sizes. Several loci centrally involved in the immune response, including the immunoglobulin genes, T-cell receptor loci, or leukocyte receptor complex, are either poorly covered on the GWAS chips or difficult to interpret due to their repetitive nature and/or the presence of insertion/deletion polymorphisms in the region. These loci warrant further interrogation, but genetic characterization of these regions across a range of individuals will first be required. Finally, synergistic interactions between loci may affect outcome after infection, as suggested by associations of specific, functionally relevant HLA and killer cell immunoglobulin-like receptor variants with HIV disease outcomes, and these require further consideration as well. C1 [Carrington, Mary; Bashirova, Arman A.] SAIC Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Carrington, Mary; Bashirova, Arman A.] Ragon Inst MGH & Harvard, Boston, MA USA. [McLaren, Paul J.] Ecole Polytech Fed Lausanne, Sch Life Sci, CH-1015 Lausanne, Switzerland. [McLaren, Paul J.] Univ Hosp Ctr, Inst Microbiol, Lausanne, Switzerland. [McLaren, Paul J.] Univ Lausanne, Lausanne, Switzerland. [McLaren, Paul J.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. RP Carrington, M (reprint author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, POB B,Bldg 560, Frederick, MD 21702 USA. EM carringm@mail.nih.gov FU Intramural NIH HHS; PHS HHS [HHSN261200800001E] NR 53 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD NOV 28 PY 2013 VL 27 IS 18 BP 2831 EP 2839 DI 10.1097/01.aids.0000432536.85335.c8 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 295PQ UT WOS:000330128400002 PM 25119688 ER PT J AU Coghill, AE Newcomb, PA Madeleine, MM Richardson, BA Mutyaba, I Okuku, F Phipps, W Wabinga, H Orem, J Casper, C AF Coghill, Anna E. Newcomb, Polly A. Madeleine, Margaret M. Richardson, Barbra A. Mutyaba, Innocent Okuku, Fred Phipps, Warren Wabinga, Henry Orem, Jackson Casper, Corey TI Contribution of HIV infection to mortality among cancer patients in Uganda SO AIDS LA English DT Article DE cancer in Africa; cancer survival; HIV; immunosuppression; Uganda ID HUMAN-IMMUNODEFICIENCY-VIRUS; ORGAN TRANSPLANT RECIPIENTS; NON-HODGKIN-LYMPHOMA; T-CELL RESPONSES; ACTIVE-ANTIRETROVIRAL-THERAPY; AIDS-DEFINING MALIGNANCIES; UNITED-STATES; KAPOSIS-SARCOMA; KIDNEY-TRANSPLANTATION; TUMOR IMMUNOGENICITY AB Objective:HIV infection is associated with cancer risk. This relationship has resulted in a growing cancer burden, especially in resource-limited countries where HIV is highly prevalent. Little is known, however, about how HIV affects cancer survival in these settings. We therefore investigated the role of HIV in cancer survival in Uganda.Design:Retrospective cohort (N=802).Methods:Eligible cancer patients were residents of Kyadondo County, at least 18 years of age at cancer diagnosis, and diagnosed between 2003 and 2010 with one of the following: breast cancer, cervical cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, or esophageal cancer. Patients were classified as HIV-infected at cancer diagnosis based on a documented positive HIV antibody test, medical history indicating HIV infection, or an HIV clinic referral letter. The primary outcome, vital status at 1 year following cancer diagnosis, was abstracted from the medical record or determined through linkage to the national hospice database. The risk of death during the year after cancer diagnosis was compared between cancer patients with and without evidence of HIV infection using Cox proportional hazards regression.Results:HIV-infected cancer patients in Uganda experienced a more than two-fold increased risk of death during the year following cancer diagnosis compared to HIV-uninfected cancer patients [hazard ratio 2.28; 95% confidence interval (CI) 1.61-3.23]. This association between HIV and 1-year cancer survival was observed for both cancers with (hazard ratio 1.56; 95% CI 1.04-2.34) and without (hazard ratio 2.68; 95% CI 1.20-5.99) an infectious cause.Conclusion:This study demonstrates the role of HIV in cancer survival for both cancers with and without an infectious cause in a resource-limited, HIV-endemic setting. C1 [Coghill, Anna E.; Newcomb, Polly A.; Madeleine, Margaret M.; Richardson, Barbra A.; Phipps, Warren; Orem, Jackson; Casper, Corey] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Coghill, Anna E.; Newcomb, Polly A.; Madeleine, Margaret M.; Richardson, Barbra A.; Phipps, Warren; Casper, Corey] Univ Washington, Seattle, WA 98195 USA. [Coghill, Anna E.] NCI, Bethesda, MD USA. [Mutyaba, Innocent; Okuku, Fred; Phipps, Warren; Orem, Jackson; Casper, Corey] UCI Hutchinson Canc Ctr Alliance, Kampala, Uganda. [Wabinga, Henry] Kampala Canc Registry, Kampala, Uganda. RP Coghill, AE (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20892 USA. EM anna.coghill@nih.gov FU National Cancer Institute at the National Institutes of Health [T32 CA09168, R03 CA153371] FX This work was supported by the National Cancer Institute at the National Institutes of Health (T32 CA09168, R03 CA153371). NR 77 TC 12 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD NOV 28 PY 2013 VL 27 IS 18 BP 2933 EP 2942 DI 10.1097/01.aids.0000433236.55937.cb PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 295PQ UT WOS:000330128400012 PM 23921614 ER PT J AU Song, JY Jaffe, ES AF Song, Joo Y. Jaffe, Elaine S. TI HHV-8-positive but EBV-negative primary effusion lymphoma SO BLOOD LA English DT Editorial Material C1 [Song, Joo Y.] Univ Calif Davis, Davis, CA 95616 USA. [Jaffe, Elaine S.] Natl Canc Inst, Bethesda, MD USA. RP Song, JY (reprint author), Univ Calif Davis, Davis, CA 95616 USA. RI Song, Joo/E-5356-2016; OI Song, Joo/0000-0003-3497-2513; Jaffe, Elaine/0000-0003-4632-0301 NR 0 TC 2 Z9 2 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 NOV 28 PY 2013 VL 122 IS 23 BP 3712 EP 3712 DI 10.1182/blood-2013-07-515882 PG 1 WC Hematology SC Hematology GA 290EA UT WOS:000329735000008 PM 24427809 ER PT J AU Assie, G Libe, R Espiard, S Rizk-Rabin, M Guimier, A Luscap, W Barreau, O Lefevre, L Sibony, M Guignat, L Rodriguez, S Perlemoine, K Rene-Corail, F Letourneur, F Trabulsi, B Poussier, A Chabbert-Buffet, N Borson-Chazot, F Groussin, L Bertagna, X Stratakis, CA Ragazzon, B Bertherat, J AF Assie, Guillaume Libe, Rossella Espiard, Stephanie Rizk-Rabin, Marthe Guimier, Anne Luscap, Windy Barreau, Olivia Lefevre, Lucile Sibony, Mathilde Guignat, Laurence Rodriguez, Stephanie Perlemoine, Karine Rene-Corail, Fernande Letourneur, Franck Trabulsi, Bilal Poussier, Alix Chabbert-Buffet, Nathalie Borson-Chazot, Francoise Groussin, Lionel Bertagna, Xavier Stratakis, Constantine A. Ragazzon, Bruno Bertherat, Jerome TI ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing's Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GASTRIC-INHIBITORY POLYPEPTIDE; ADRENOCORTICAL TUMORS; GENE-EXPRESSION; FREQUENT; PROTEIN; RECEPTORS; HYPERCORTISOLISM; PATHWAY; DISEASE; CANCERS AB BackgroundCorticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition. MethodsWe genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models. ResultsThe most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival. ConclusionsSome cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.) C1 [Assie, Guillaume; Libe, Rossella; Espiard, Stephanie; Rizk-Rabin, Marthe; Guimier, Anne; Luscap, Windy; Barreau, Olivia; Lefevre, Lucile; Rodriguez, Stephanie; Perlemoine, Karine; Rene-Corail, Fernande; Letourneur, Franck; Groussin, Lionel; Bertagna, Xavier; Ragazzon, Bruno; Bertherat, Jerome] Inst Cochin, INSERM Unite 1016, CNRS, UMR 8104, Paris, France. [Assie, Guillaume; Espiard, Stephanie; Guimier, Anne; Barreau, Olivia; Lefevre, Lucile; Sibony, Mathilde; Perlemoine, Karine; Rene-Corail, Fernande; Groussin, Lionel; Bertagna, Xavier; Bertherat, Jerome] Univ Paris 05, Fac Med Paris Descartes, Sorbonne Paris Cite, Paris, France. [Assie, Guillaume; Libe, Rossella; Barreau, Olivia; Guignat, Laurence; Groussin, Lionel; Bertagna, Xavier; Bertherat, Jerome] Referral Ctr Rare Adrenal Dis, Dept Endocrinol, Paris, France. [Sibony, Mathilde] Hop Cochin, AP HP, Dept Pathol, F-75674 Paris, France. [Chabbert-Buffet, Nathalie] Hop Tenon, Dept Obstet & Gynecol, Unit Endocrinol, F-75970 Paris, France. [Trabulsi, Bilal] Ctr Hosp, Ctr Bretagne, Unit Endocrinol, Noyal Pontivy, France. [Poussier, Alix] Hotel Dieu Creusot, Unit Endocrinol, Le Creusot, France. [Borson-Chazot, Francoise] Grp Hosp Est, Dept Endocrinol Lyon Est, Bron, France. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Inter Inst, Training Program, NIH, Bethesda, MD USA. RP Bertherat, J (reprint author), Hop Cochin, Serv Malad Endocriniennes & Metab, Ctr Reference Malad Rares Surrenale, 27 Rue Faubourg St Jacques, F-75014 Paris, France. EM jerome.bertherat@cch.aphp.fr RI Ragazzon, Bruno/E-6541-2017; OI Ragazzon, Bruno/0000-0001-9476-4973; Borson-Chazot, Francoise/0000-0003-2515-7840 FU Agence Nationale de la Recherche [ANR-10-Blan-1136]; Corticomedullosurrenale Tumeur Endocrine Network (Programme Hospitalier de Recherche Clinique grant) [AOM95201]; Assistance Publique-Hopitaux de Paris (Clinical Research Center) [Genhyper P061006]; Institut National du Cancer [Recherche Translationelle 2009-RT-02]; Seventh Framework Program of the European Commission [F2-2010-259735]; INSERM (Contrat d'Interface); Conny-Maeva Charitable Foundation; intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported in part by grants from Agence Nationale de la Recherche (ANR-10-Blan-1136), Corticomedullosurrenale Tumeur Endocrine Network (Programme Hospitalier de Recherche Clinique grant AOM95201), Assistance Publique-Hopitaux de Paris (Clinical Research Center Grant Genhyper P061006), Institut National du Cancer (Recherche Translationelle 2009-RT-02), the Seventh Framework Program of the European Commission (F2-2010-259735), INSERM (Contrat d'Interface, to Dr. Assie), the Conny-Maeva Charitable Foundation, and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 29 TC 82 Z9 85 U1 1 U2 7 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 NOV 28 PY 2013 VL 369 IS 22 BP 2105 EP 2114 DI 10.1056/NEJMoa1304603 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 258OB UT WOS:000327467500008 PM 24283224 ER PT J AU Patnaik, S Marugan, JJ Liu, K Zheng, W Southall, N Dehdashti, SJ Thorsell, A Heilig, M Bell, L Zook, M Eskay, B Brimacombe, KR Austin, CP AF Patnaik, Samarjit Marugan, Juan J. Liu, Ke Zheng, Wei Southall, Noel Dehdashti, Seameen J. Thorsell, Annika Heilig, Markus Bell, Lauren Zook, Michelle Eskay, Bob Brimacombe, Kyle R. Austin, Christopher P. TI Structure-Activity Relationship of Imidazopyridinium Analogues as Antagonists of Neuropeptide S Receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BIOLOGICAL-ACTIVITY; FOOD-INTAKE; DISCOVERY; BRAIN; AROUSAL; SYSTEM; POTENT; RATS; MICE AB The discovery and characterization of a novel chemical series of phosphorothioyl-containing imidazopyridines as potent neuropeptide S receptor antagonists is presented. The synthesis of analogues and their structure-activity relationship with respect to the Gq, Gs, and ERK pathways is detailed. The pharmacokinetics and in vivo efficacy of a potent analogue in a food intake rodent model are also included, underscoring its potential therapeutic value for the treatment of sleep, anxiety, and addiction disorders. C1 [Patnaik, Samarjit; Marugan, Juan J.; Liu, Ke; Zheng, Wei; Southall, Noel; Dehdashti, Seameen J.; Brimacombe, Kyle R.; Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Thorsell, Annika; Heilig, Markus; Bell, Lauren; Zook, Michelle; Eskay, Bob] NIAAA, NIH, Bethesda, MD 20892 USA. RP Marugan, JJ (reprint author), Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM maruganj@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757; Heilig, Markus/0000-0003-2706-2482; Thorsell, Annika/0000-0003-3535-3845 FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism, NIH FX This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism, NIH. We thank Dr. Reinscheid for generously providing the NPSR clone originally used to generate the CHO-NPSR cell line; Sam Michael for assistance in robotic screening; and William Leister, Paul Shinn, Jeremy Smith, Danielle van Leer, and James Bougie for compound management. NR 37 TC 7 Z9 7 U1 0 U2 6 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 NOV 28 PY 2013 VL 56 IS 22 BP 9045 EP 9056 DI 10.1021/jm400904m PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 263ML UT WOS:000327812600008 PM 24171469 ER PT J AU Xu, R Zanotti-Fregonara, P Zoghbi, SS Gladding, RL Woock, AE Innis, RB Pike, VW AF Xu, Rong Zanotti-Fregonara, Paolo Zoghbi, Sami S. Gladding, Robert L. Woock, Alicia E. Innis, Robert B. Pike, Victor W. TI Synthesis and Evaluation in Monkey of [F-18]4-Fluoro-N-methyl-N-(4-(6-(methylannino)pyrimidin-4-yl)thiazol-2-y l)benzamide ([F-18]FIMX): A Promising Radioligand for PET Imaging of Brain Metabotropic Glutamate Receptor 1 (mGluR1) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DIARYLIODONIUM-SALTS; IN-VIVO; EXTRUSION REACTIONS; R2I-F IODINE(III); FREE-FRACTION; AB-INITIO; RADIOFLUORINATION; TOSYLATES; LIGAND AB We sought to develop a PET radioligand that would be useful for imaging human brain metabotropic subtype 1 receptors (mGluR1) in neuropsychiatric disorders and in drug development. 4-Fluoro-N-methyl-N-(4-(6(methylamino)pyrimidin-4-yOthiazol-2-ylbenzamide (FIMX, 11) was identified as having favorable properties for development as a PET radioligand. We developed a method for preparing [F-18]11 in useful radiochemical yield and in high specific activity from [18F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (15). In baseline experiments in rhesus monkey, [F-18 ]11 gave high brain radioactivity uptake, reflecting the expected distribution of mGluR1 with notably high uptake in cerebellum, which became 47% lower by 120 min after radioligand injection. Pharmacological challenges demonstrated that a very high proportion of the radioactivity in monkey brain was bound specifically and reversibly to mGluRl. [F-18]11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects. C1 [Xu, Rong; Zanotti-Fregonara, Paolo; Zoghbi, Sami S.; Gladding, Robert L.; Woock, Alicia E.; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU project officer Jamie Driscol (NIMH), at the University of North Carolina at Chapel Hill [NO1MH32004] FX This work is support by the Intramural Research Program of NIMH. We thank the NIH Clinical PET Center (Director Dr. P. Herscovitch) for radioisotope production and the PDSP for performing binding assays. The PDSP is directed by Bryan L. Roth, Ph.D., with project officer Jamie Driscol (NIMH), at the University of North Carolina at Chapel Hill (contract no. NO1MH32004). NR 55 TC 11 Z9 11 U1 0 U2 15 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 NOV 28 PY 2013 VL 56 IS 22 BP 9146 EP 9155 DI 10.1021/jm4012017 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 263ML UT WOS:000327812600016 PM 24147864 ER PT J AU Romagnoli, R Baraldi, PG Lopez-Cara, C Preti, D Tabrizi, MA Balzarini, J Bassetto, M Brancale, A Fu, XH Gao, Y Li, J Zhang, SZ Hamel, E Bortolozzi, R Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Lopez-Cara, Carlota Preti, Delia Tabrizi, Mojgan Aghazadeh Balzarini, Jan Bassetto, Marcella Brancale, Andrea Fu, Xian-Hua Gao, Yang Li, Jun Zhang, Su-Zhan Hamel, Ernest Bortolozzi, Roberta Basso, Giuseppe Viola, Giampietro TI Concise Synthesis and Biological Evaluation of 2-Aroyl-5-Amino Benzo[b]thiophene Derivatives As a Novel Class of Potent Antimitotic Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COMBRETASTATIN A-4 PHOSPHATE; CELL-DEATH; ANTICANCER AGENTS; MESSENGER-RNA; TUBULIN; APOPTOSIS; CANCER; COLCHICINE; BINDING; MICROTUBULES AB The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2(3',4',5'-trimethoxybenzoyl)-5-aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure-activity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c-e showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC50 values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound 3c (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Lopez-Cara, Carlota; Preti, Delia; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. [Balzarini, Jan] Catholic Univ Louvain, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Bassetto, Marcella; Brancale, Andrea] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales. [Fu, Xian-Hua; Gao, Yang; Li, Jun; Zhang, Su-Zhan] Zhejiang Univ, Inst Canc, Key Lab Canc Prevent & Intervent, China Natl Minist Educ,Sch Med,Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Lab Oncoematol, Dipartimento Salute Donna & Bambino, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. EM rmr@unife.it; pgb@unife.it; giampietro.violal@unipd.it RI Aghazadeh Tabrizi, Mojgan/I-9169-2014; Viola, Giampietro/I-4095-2012; Brancale, Andrea/N-9445-2014; Bortolozzi, Roberta/D-4950-2015; preti, delia/G-9916-2015; Romagnoli, Romeo/G-9887-2015; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Baraldi, Pier Giovanni/B-7933-2017; OI Viola, Giampietro/0000-0001-9329-165X; Brancale, Andrea/0000-0002-9728-3419; Bortolozzi, Roberta/0000-0002-3357-4815; preti, delia/0000-0002-1075-3781; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Bassetto, Marcella/0000-0002-2491-5868; BASSO, GIUSEPPE/0000-0002-2634-9302 FU GOA (Krediet) of the KU Leuven [10/14] FX Jan Balzarini is funded by GOA (Krediet no. 10/14) of the KU Leuven. We gratefully acknowledge Alberto Casolari and Lizette van Berckelaer for their excellent technical assistance. NR 54 TC 20 Z9 20 U1 1 U2 16 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 NOV 28 PY 2013 VL 56 IS 22 BP 9296 EP 9309 DI 10.1021/jm4013938 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 263ML UT WOS:000327812600027 PM 24164557 ER EF