FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Dash, C Scarth, BJ Badorrek, C Gotte, M Le Grice, SFJ AF Dash, Chandravanu Scarth, Brian J. Badorrek, Christopher Goette, Matthias Le Grice, Stuart F. J. TI Examining the ribonuclease H primer grip of HIV-1 reverse transcriptase by charge neutralization of RNA/DNA hybrids SO NUCLEIC ACIDS RESEARCH LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T7 DNA-POLYMERASE; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; KINETIC-ANALYSIS; DRUG-RESISTANCE; ACTIVE-SITE; SUBSTRATE; FINGERS; MODEL AB The crystal structure of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) bound to an RNA/DNA hybrid reveals an extensive network of contacts with the phosphate backbone of the DNA strand similar to 4-9 bp downstream from the ribonuclease H (RNase H) catalytic center. Collectively designated as 'the RNase H primer grip', this motif contains a phosphate binding pocket analogous to the human and Bacillus halodurans RNases H. The notion that the RNase H primer grip mediates the trajectory of RNA/DNA hybrids accessing the RNase H active site suggests that locally neutralizing the phosphate backbone may be exploited to manipulate nucleic acid flexibility. To examine this, we introduced single and tandem methylphosphonate substitutions through the region of the DNA primer contacted by the RNase H primer grip and into the RNase H catalytic center. The ability of mutant hybrids to support RNase H and DNA polymerase activity was thereafter examined. In addition, site-specific chemical footprinting was used to evaluate movement of the DNA polymerase and RNase H domains. We show here that minor alteration to the RNase H primer can have a dramatic effect on enzyme positioning, and discuss these findings in light of recent crystallography of human RNase H containing an RNA/DNA hybrid. C1 [Dash, Chandravanu; Badorrek, Christopher; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Scarth, Brian J.; Goette, Matthias] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. RP Le Grice, SFJ (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM slegrice@ncifcrf.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; Canadian Institutes of Health Research FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research ( to C. D. and S.F.J.LeG.); Canadian Institutes of Health Research ( to M. G.). Funding for open access charge: Intramural Research Program of the NIH, NCI and Center for Cancer Research. NR 39 TC 10 Z9 10 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2008 VL 36 IS 20 BP 6363 EP 6371 DI 10.1093/nar/gkn678 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 373NA UT WOS:000260977500011 PM 18836193 ER PT J AU Gardner, DB AF Gardner, Deborah B. TI From Wall Street to Main Street: How Will the Economic Meltdown Impact Health Care Reform? SO NURSING ECONOMICS LA English DT Editorial Material AB What will happen to health care in the wake of the financial market crisis? Many health policy and economic experts are asking whether it is possible for any of the promises for health care reform to be realized. We could find ourselves in a catastrophic collision between national security priorities and domestic policy goals. Nurses must be vocal regarding the need to reform health care or it may be sidestepped if budgeting continues to prioritize the war abroad and not the crisis at home. C1 NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Gardner, DB (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 12 TC 1 Z9 1 U1 0 U2 2 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD NOV-DEC PY 2008 VL 26 IS 6 BP 399 EP + PG 3 WC Nursing SC Nursing GA 388RU UT WOS:000262037700010 PM 19330976 ER PT J AU Beydoun, MA Beydoun, HA Wang, YF AF Beydoun, May A. Beydoun, Hind A. Wang, Youfa TI In reply to letter to editor from TL Huang and WW Yu SO OBESITY REVIEWS LA English DT Letter ID DEMENTIA; RISK C1 [Beydoun, May A.] NIA, Lab Personal & Cognit, NIH, IRP, Baltimore, MD 21224 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Wang, Youfa] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Human Nutr, Baltimore, MD USA. RP Beydoun, MA (reprint author), NIA, Lab Personal & Cognit, NIH, IRP, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov; BaydouHA@evms.edu; ywang@jhsph.edu NR 8 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1467-7881 J9 OBES REV JI Obes. Rev. PD NOV PY 2008 VL 9 IS 6 BP 633 EP 634 DI 10.1111/j.1467-789X.2008.00527.x PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 361AZ UT WOS:000260101200014 ER PT J AU Kimura, K Toyooka, S Tsukuda, K Yamamoto, H Suehisa, H Soh, J Otani, H Kubo, T Aoe, K Fujimoto, N Kishimoto, T Sano, Y Pass, HI Date, H AF Kimura, Kentaro Toyooka, Shinichi Tsukuda, Kazunori Yamamoto, Hiromasa Suehisa, Hiroshi Soh, Junichi Otani, Hiroki Kubo, Takafumi Aoe, Keisuke Fujimoto, Nobukazu Kishimoto, Takumi Sano, Yoshifumi Pass, Harvery I. Date, Hiroshi TI The aberrant promoter methylation of BMP3b and BMP6 in malignant pleural mesotheliomas SO ONCOLOGY REPORTS LA English DT Article DE DNA methylation; bone morphogenetic proteins; mesothelioma ID MORPHOGENETIC PROTEIN-6 GENE; LUNG-CANCER; EPIGENETIC REGULATION; EXPRESSION AB Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-ss superfamily. Recent studies have showed that aberrant methylation of BMP genes is present in several types of human cancer. We examined the expression and methylation status of BMP3b and BMP6 in malignant pleural mesotheliomas (MPMs). The expression status of BMP3b, and BMP6 mRNAs were examined in seven MPM cell lines by RT-PCR assay. The expression of BMP3b was completely suppressed in 2 and partially suppressed in 2 of 7 cell lines and expression of BMP6 was partially suppressed in 2 cell lines. Methylation status of BMP3b in cell lines was determined by methylation-specific assay to find aberrant methylation in 6 cell lines which include 4 cell lines with suppressed BMP3b expression. Partial methylation of BMP6 was found in 2 cell lines whose expression was partially suppressed. Treatment with 5-Aza-dC restored BMP3b expression in methylated cell lines. Next, we examined the methylation status in 57 surgically resected MPM cases and found aberrant methylation of BMP3b in 9 (53%) out of 17 cases from Japan and 3 (8%) of 40 cases from USA and that of BMP6 in 4 (24%) cases from Japan and 12 (30%) cases from USA, showing significant difference in frequency of BMP3b methylation between MPMs of the two countries (P=0.0004). Our study indicated that BMP3b and BMP6 genes were suppressed by DNA methylation and methylation of BMP3b is significantly frequent in Japanese C1 [Kimura, Kentaro; Toyooka, Shinichi; Tsukuda, Kazunori; Yamamoto, Hiromasa; Suehisa, Hiroshi; Soh, Junichi; Otani, Hiroki; Kubo, Takafumi; Sano, Yoshifumi] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Canc & Thorac Surg, Okayama 7008558, Japan. [Aoe, Keisuke] NHO Sanyo Natl Hosp, Dept Resp Med, Yamaguchi, Japan. [Fujimoto, Nobukazu; Kishimoto, Takumi] Okayama Rousai Hosp, Dept Internal Med, Okayama, Japan. [Pass, Harvery I.] NYU, Sch Med, Div Thorac Surg & Thorac Oncol, Dept Cardiothorac Surg, New York, NY USA. [Pass, Harvery I.] NCI Canc Ctr, New York, NY USA. [Date, Hiroshi] Kyoto Univ, Dept Thorac Surg, Grad Sch Med, Kyoto, Japan. RP Toyooka, S (reprint author), Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Canc & Thorac Surg, 2-5-1 Shikata Cho, Okayama 7008558, Japan. EM toyooka@md.okayama-u.acjp NR 16 TC 21 Z9 22 U1 0 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD NOV PY 2008 VL 20 IS 5 BP 1265 EP 1268 DI 10.3892/or_00000139 PG 4 WC Oncology SC Oncology GA 368UM UT WOS:000260648200039 PM 18949431 ER PT J AU Tuo, J Ross, RJ Reed, GF Yan, Q Wang, JJ Bojanowski, CM Chew, EY Feng, X Olsen, TW Ferris, FL Mitchell, P Chan, CC AF Tuo, Jingsheng Ross, Robert J. Reed, George F. Yan, Qing Wang, Jie Jin Bojanowski, Christine M. Chew, Emily Y. Feng, Xiao Olsen, Timothy W. Ferris, Frederick L., III Mitchell, Paul Chan, Chi-Chao TI The HtrA1 Promoter Polymorphism, Smoking, and Age-related Macular Degeneration in Multiple Case-control Samples SO OPHTHALMOLOGY LA English DT Article ID COMPLEMENT-FACTOR-H; BLUE-MOUNTAINS EYE; JAPANESE POPULATION; GENOMEWIDE-SCAN; RISK-FACTORS; GENETIC ASSOCIATION; EXTENDED FAMILIES; CHROMOSOME 10Q26; SERINE-PROTEASE; COMMON VARIANTS AB Objective: To assess the association and combined effect on the risk of age-related macular degeneration (AMD) by the HtrA1 and complement factor H (CFH) polymorphisms, smoking, and serum cholesterol. Design: Clinic-based and population-based case control study. Participants: A total of 805 AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study, Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank. Methods: DNA samples were genotyped for polymorphisms of rs11200638 in HtrA1 promoter and rs380390 in CFH. HtrA1 protein in ocular tissue was measured. Interactions of the HtrA1 risk allele with the CFH risk variant, smoking status, and cholesterol were assessed. Main Outcome Measures: AMD was evaluated by retinal specialists, and AMD subtypes (geographic atrophy and neovascularization) were determined. Results: Strong associations of the HtrA1 risk allele (A) with AMD were present in all sample sets. A similar magnitude of association was observed for central geographic atrophy and neovascular AMD. The combination of the HtrA1 and CFH risk alleles increased AMD susceptibility, as did the combination of the HtrA1 risk allele with smoking. No combined effect of HtrA1 risk allele and cholesterol level was found. Enhanced expression of HtrA1 protein was detected in retina with AMD. Conclusions: Findings from multiple samples support an AMD genetic variant harbored within HtrA1. The risk of advanced AMD increased when the presence of risk alleles from HtrA 1 was combined with either CFH risk alleles or history of smoking. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2008; 115:1891-1898 (C) 2008 by the American Academy of Ophthalmology. C1 [Tuo, Jingsheng; Ross, Robert J.; Bojanowski, Christine M.; Chan, Chi-Chao] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Reed, George F.; Yan, Qing; Chew, Emily Y.; Ferris, Frederick L., III] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Sci, Dept Ophthalmol, Westmead, NSW 2145, Australia. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Feng, Xiao; Olsen, Timothy W.] Univ Minnesota, Dept Ophthalmol, Minneapolis, MN 55455 USA. RP Chan, CC (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov RI Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Tuo, Jingsheng/0000-0002-1372-7810 FU Intramural NIH HHS [Z01 EY000418-04, Z99 EY999999, ZIA EY000489-01]; NIA NIH HHS [AG025392, R01 AG025392] NR 65 TC 27 Z9 29 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2008 VL 115 IS 11 BP 1891 EP 1898 DI 10.1016/j.ophtha.2008.05.021 PG 8 WC Ophthalmology SC Ophthalmology GA 365ZO UT WOS:000260448900006 PM 18718667 ER PT J AU Wong, WT Liang, KJ Hammel, K Coleman, HR Chew, EY AF Wong, Wai T. Liang, Katharine J. Hammel, Keri Coleman, Hanna R. Chew, Emily Y. TI Intravitreal Ranibizumab Therapy for Retinal Capillary Hemangioblastoma Related to von Hippel-Lindau Disease SO OPHTHALMOLOGY LA English DT Article ID RECEPTOR INHIBITOR SU5416; PHOTODYNAMIC THERAPY; TUMOR-SUPPRESSOR; MACULAR EDEMA; GROWTH; HEMANGIOMA; BEVACIZUMAB AB Purpose: To evaluate the effect of intravitreal ranibizumab on retinal capillary hemangioblastomas (RCHs) associated with von Hippel-Lindau (VHL) disease that are not amenable or responsive to standard therapy. Design: Prospective, noncomparative, interventional case series. Participants: Five patients with VHL-associated RCH with exudative changes and visual loss. Methods: Monthly intravitreal injections of ranibizumab (0.5 mg) were given over a course of 6 months for a total of 7 injections, with additional injections considered until week 52. The final study visit was designated as 8 weeks after the final study injection. Main Outcome Measures: The primary outcome was the change in best-corrected visual acuity (BCVA) of 15 letters at the final visit compared with baseline. Secondary outcomes included change in lesion size, exudation as assessed clinically and by fluorescein angiography, change in retinal thickness as evaluated by optical coherence tomography, and adverse event assessments. Results: Patients received an average of 10.0 +/- 3.1 injections over an average period of 47 14 weeks, including follow-up. Mean change in BCVA was a decrease of 9 20 letters, with 1 patient gaining 15 letters, and 2 patients losing :115 letters. Changes in both lesion size and exudation were variable. Conclusions: Intravitreal ranibizumab, delivered as monotherapy every 4 weeks, had minimal beneficial effects on most VHL-related RCHs. Possible treatment efficacy was demonstrated in the patient with the smallest lesion with less exudation. Future prospective studies are needed to determine the potential role of an antiangiogenic agent, possibly in combination with other therapies for the treatment of such advanced ocular tumors associated with VHL. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2008;115:1957-1964 (C) 2008 by the American Academy of Ophthalmology. C1 [Liang, Katharine J.; Coleman, Hanna R.; Chew, Emily Y.] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Wong, Wai T.] NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Hammel, Keri] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Res, NIH, 10 Ctr Dr MSC 1204,10 CRC,Room 3-2531, Bethesda, MD 20892 USA. RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Institutes of Health, Division of Epidemiology and Clinical Research; National Eye Institute FX Supported by the Intramural Research Program of the National Institutes of Health, Division of Epidemiology and Clinical Research. National Eye Institute. NR 24 TC 26 Z9 29 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2008 VL 115 IS 11 BP 1957 EP 1964 DI 10.1016/j.ophtha.2008.04.033 PG 8 WC Ophthalmology SC Ophthalmology GA 365ZO UT WOS:000260448900017 PM 18789534 ER PT J AU Colyer, MH Chun, DW Bower, KS Dick, JSB Weichel, ED AF Colyer, Marcus H. Chun, Dal W. Bower, Kraig S. Dick, John S. B. Weichel, Eric D. TI Perforating Globe Injuries during Operation Iraqi Freedom SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the American-Society-of-Retina-Specialists CY DEC, 2007 CL Indian Wells, CA SP Amer Soc Retina Specialists ID EYE INJURY AB Objective: To report the injury patterns associated with perforating (through-and-through) injuries of the globe and the visual impact of these injuries on patients with combat ocular trauma (COT) seen at Walter Reed Army Medical Center (WRAMC) from March 2003 through October 2006. Design: Retrospective, noncomparative, interventional case series. Participants: Sixty-five eyes of 61 United States military soldiers deployed during Operation Iraqi Freedom sustaining perforating globe injuries and treated subsequently at WRAMC. Intervention: Principal procedures included enucleation and 20-gauge 3-port pars plana vitrectomy with or without intraocular foreign body removal. Main Outcome Measures: Final visual acuity and rates of proliferative vitreoretinopathy, enucleation, and endophthalmitis. Results: Average patient age was 29 years, with an average of 200 days of postinjury follow-up (median, 97 days; range, 4-1023 days). Nineteen patients confirmed the use of eye protection at the time of injury, whereas 25 patients did not use eye protection. The median presenting visual acuity at WRAMC was no light perception (range, no light perception to hand movements). Twenty-five patients underwent primary enucleation, 1 was eviscerated, and 12 patients underwent secondary enucleation within 2 weeks of surgery. Of 19 patients undergoing pars plana vitrectomy, median visual acuity at presentation was light perception and the median final visual acuity was counting fingers, whereas 4 eyes (21 %) achieved final visual acuity of better than 20/200, and in 11 (61 %) of 17, proliferative vitreoretinopathy developed over a follow-up of at least 6 months. There were no cases of endophthalmitis or sympathetic ophthalmia. Neither mechanism of injury nor timing of surgery correlated with favorable outcomes. However, entry and exit wounds localized to the anterior half of the globe were associated with favorable anatomic outcome (P < 0.005, Fisher exact test, 2-tailed) and visual outcome (P = 0.041, Fisher exact test, 2-tailed). Conclusions: Perforating globe injuries associated with COT generally result in poor visual and anatomic outcomes despite surgical intervention. Prophylactic measures, such as eye protection, are helpful in reducing the likelihood of perforating injuries; however, novel surgical and pharmacologic therapies will be required to improve the functional and anatomic outcomes of these devastating injuries. C1 [Colyer, Marcus H.; Chun, Dal W.; Bower, Kraig S.; Weichel, Eric D.] Walter Reed Army Med Ctr, Ophthalmol Serv, Washington, DC 20307 USA. [Dick, John S. B.] Kaiser Permanente Hlth Syst, San Diego, CA USA. [Weichel, Eric D.] NEI, NIH, Bethesda, MD 20892 USA. RP Colyer, MH (reprint author), Walter Reed Army Med Ctr, Ophthalmol Clin 1F, Washington, DC 20307 USA. EM marcus.colyer@amedd.army.mil NR 5 TC 41 Z9 46 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2008 VL 115 IS 11 BP 2087 EP 2093 DI 10.1016/j.ophtha.2008.05.013 PG 7 WC Ophthalmology SC Ophthalmology GA 365ZO UT WOS:000260448900036 PM 18672293 ER PT J AU Windham, GC Zhang, LX Longnecker, MP Klebanoff, M AF Windham, Gayle C. Zhang, Lixia Longnecker, Matthew P. Klebanoff, Mark TI Maternal smoking, demographic and lifestyle factors in relation to daughter's age at menarche SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE puberty; menarche; maternal prenatal smoking; child growth; socio-economic status; maternal menarche; Collaborative Perinatal Project ID NUTRITION EXAMINATION SURVEY; CIGARETTE-SMOKING; CHILDHOOD GROWTH; FOLLOW-UP; ENDOCRINE DISRUPTERS; PUBERTAL DEVELOPMENT; PREMENOPAUSAL WOMEN; NATIONAL-HEALTH; GIRLS; PREGNANCY AB A previous study suggested a younger age at menarche (AAM) among daughters of heavy prenatal smokers, especially among non-Whites. The present study was designed to evaluate that association in another population and to examine other factors that may be related to AAM. We analysed data from the Collaborative Perinatal Project, a nationwide longitudinal study of pregnant women and their children conducted in 1959-66. At three sites, with a predominance of Black participants (80%), AAM was ascertained in the offspring when they were young adults. We included data on 1556 daughters who had a mean AAM of 12.7 years (standard deviation 1.8). Amount smoked by the mothers was obtained from a baseline interview and subsequent prenatal visits. Regression models were run including maternal smoking and other covariates, for only the prenatal period, as well as in models with some childhood characteristics. In the prenatal factor model, younger mean AAM in daughters was found with maternal characteristics of earlier AAM, being married, and of lower parity. Examining childhood variables, earlier AAM was found among girls with few or no siblings or with higher socio-economic status. Unlike our previous findings, mean AAM was later in daughters of heavy smokers (20+ cigarettes/day), with a delay of 0.31 years [95% confidence interval (CI) 0.008, 0.61], or about 3.7 months in the prenatal model, and 0.34 years [95% CI -0.02, 0.66] in the model with childhood variables included. The pattern was consistent by race. A number of prenatal and childhood factors related to AAM were identified that should be considered when examining exogenous exposures in relation to pubertal onset. C1 [Windham, Gayle C.] Calif Dept Publ Hlth, Richmond, CA 94804 USA. [Zhang, Lixia] Impact Assessment Inc, San Diego, CA USA. [Longnecker, Matthew P.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Klebanoff, Mark] NICHHD, NICHD, Bethesda, MD 20892 USA. RP Windham, GC (reprint author), Calif Dept Publ Hlth, 850 Marina Bay Pkwy,Bldg P, Richmond, CA 94804 USA. EM gayle.windham@cdph.ca.gov OI Longnecker, Matthew/0000-0001-6073-5322 FU California Tobacco-related Disease Research Program [11RT-0173]; California Department of Health Services; Intramural Research Program of the NIH; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences FX Funding for these analyses was provided by the California Tobacco-related Disease Research Program, grant #11RT-0173. The research was also supported in part by the California Department of Health Services, and the Intramural Research Program of the NIH, National Institute of Child Health and Human Development, and National Institute of Environmental Health Sciences. We thank Dr Hardy and her staff, Dr Mary Hediger, and Xuguang Guo for providing and assembling data for these analyses. NR 60 TC 28 Z9 28 U1 0 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2008 VL 22 IS 6 BP 551 EP 561 DI 10.1111/j.1365-3016.2008.00948.x PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 357AH UT WOS:000259818200008 PM 19000293 ER PT J AU Hoffman, CS Messer, LC Mendola, P Savitz, DA Herring, AH Hartmann, KE AF Hoffman, Caroline S. Messer, Lynne C. Mendola, Pauline Savitz, David A. Herring, Amy H. Hartmann, Katherine E. TI Comparison of gestational age at birth based on last menstrual period and ultrasound during the first trimester SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE gestational age; measurement; accuracy; LMP; ultrasound estimates; maternal age; ethnic group; preterm; post-term; bias ID CROWN-RUMP LENGTH; IN-VITRO FERTILIZATION; ROUTINE ULTRASOUND; PRETERM BIRTH; PREGNANCY; DELIVERY; EPIDEMIOLOGY; SELECTION; RECORDS; DATE AB Reported last menstrual period (LMP) is commonly used to estimate gestational age (GA) but may be unreliable. Ultrasound in the first trimester is generally considered a highly accurate method of pregnancy dating. The authors compared first trimester report of LMP and first trimester ultrasound for estimating GA at birth and examined whether disagreement between estimates varied by maternal and infant characteristics. Analyses included 1867 singleton livebirths to women enrolled in a prospective pregnancy cohort. The authors computed the difference between LMP and ultrasound GA estimates (GA difference) and examined the proportion of births within categories of GA difference stratified by maternal and infant characteristics. The proportion of births classified as preterm, term and post-term by pregnancy dating methods was also examined. LMP-based estimates were 0.8 days (standard deviation = 8.0, median = 0) longer on average than ultrasound estimates. LMP classified more births as post-term than ultrasound (4.0% vs. 0.7%). GA difference was greater among young women, non-Hispanic Black and Hispanic women, women of non-optimal body weight and mothers of low-birthweight infants. Results indicate first trimester report of LMP reasonably approximates gestational age obtained from first trimester ultrasound, but the degree of discrepancy between estimates varies by important maternal characteristics. C1 [Hoffman, Caroline S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Messer, Lynne C.; Mendola, Pauline] US EPA, Natl Hlth & Environm Effects Res Lab, Human Studies Div, Res Triangle Pk, NC 27711 USA. [Savitz, David A.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [Hartmann, Katherine E.] Vanderbilt Univ, Sch Med, Dept Obstet & Gynecol, Nashville, TN 37212 USA. [Hartmann, Katherine E.] Vanderbilt Univ, Med Ctr, Inst Med & Publ Hlth, Nashville, TN 37212 USA. RP Hoffman, CS (reprint author), NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. EM dilworthch@niehs.nih.gov OI Mendola, Pauline/0000-0001-5330-2844 FU Awwa Research Foundation (AwwaRF); U. S. Environmental Protection Agency (USEPA) [CR825625-01, CR827268-01, CR828216-01]; National Institute of Environmental Health Sciences [P30ES10126]; NHEERL-DESE Cooperative Training [EPA CT8229471, CR83323601] FX This study was funded jointly by the Awwa Research Foundation (AwwaRF) and the U. S. Environmental Protection Agency (USEPA) under Cooperative Agreement Nos. CR825625-01, CR827268-01 and CR828216-01, a grant from the National Institute of Environmental Health Sciences (P30ES10126), and the NHEERL-DESE Cooperative Training grant in Environmental Sciences Research (EPA CT8229471 and CR83323601). NR 34 TC 53 Z9 53 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2008 VL 22 IS 6 BP 587 EP 596 DI 10.1111/j.1365-3016.2008.00965.x PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 357AH UT WOS:000259818200012 PM 19000297 ER PT J AU Whitcomb, BW Schisterman, EF AF Whitcomb, Brian W. Schisterman, Enrique F. TI Assays with lower detection limits: implications for epidemiological investigations SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE laboratory measurements; limit of detection; statistical analysis ID BAYESIAN-ANALYSIS; MEASUREMENT-ERROR; EXPOSURE; ORGANOCHLORINES; MISCARRIAGE; WOMEN; SERUM; RISK AB Epidemiological investigations of health effects related to chronic low-level exposures or other circumstances often face the difficult task of dealing with levels of biomarkers that are hard to detect and/or quantify. In these cases instrumentation may not adequately measure biomarker levels. Reasons include a failure of instruments to detect levels below a certain value or, alternatively, interference by error or 'noise'. Current laboratory practice determines a 'limit of detection (LOD)', or some other detection threshold, as a function of the distribution of instrument 'noise'. Although measurements are produced above and below this threshold in many circumstances, rather than numerical data, all points observed below this threshold may be reported as 'not detected'. The focus of this process of determination of the LOD is instrument noise and avoiding false positives. Moreover, uncertainty is assumed to apply only to the lowest values, which are treated differently from above-threshold values, thereby potentially creating a false dichotomy. In this paper we discuss the application of thresholds to measurement of biomarkers and illustrate how conventional approaches, though appropriate for certain settings, may fail epidemiological investigations. Rather than automated procedures that subject observed data to a standard threshold, the authors advocate investigators to seek information on the measurement process and request all observed data from laboratories (including the data below the threshold) to determine appropriate treatment of those data. C1 [Schisterman, Enrique F.] NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Schisterman, EF (reprint author), NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU NIH; Epidemiology Branch; DESPR; NICHD FX This research was supported by the Intramural Research Program of the NIH, Epidemiology Branch, DESPR, NICHD. NR 20 TC 20 Z9 20 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2008 VL 22 IS 6 BP 597 EP 602 DI 10.1111/j.1365-3016.2008.00969.x PG 6 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 357AH UT WOS:000259818200013 PM 19000298 ER PT J AU Saul, A AF Saul, A. TI Efficacy model for mosquito stage transmission blocking vaccines for malaria SO PARASITOLOGY LA English DT Article DE malaria; vaccine; transmission; mathematical model ID PLASMODIUM-FALCIPARUM INFECTION; VECTORIAL CAPACITY; POPULATIONS; CANDIDATES; MORTALITY; COMPLEX; TRIAL; RATES; TITER; SIZE AB Vaccines that target antigens found on the mosquito stages of Plasmodimn falciparum and Plasmodium vivax parasites are under development as transmission blocking vaccines. Antisera from vaccinated animals and humans are able to block oocyst development in artificially fed mosquitoes but it is not clear from these data what level of antibody response would be required for a useful vaccine in a field setting. This paper describes a mathematical model that takes into account the relationship between antibody levels and blocking of oocyst levels in artificial feeds, the distribution of antibody responses seen in human populations and the distribution of oocyst densities in infected mosquitoes in the field to calculate the levels of antibody in the host population that would be required to achieve a level of herd immunity in a vaccinated human population that would give an operationally useful level of transmission blocking. The model predicts that current formulations of Pfs25 are likely to achieve useful reductions in transmission when tested in human field trials. C1 [Saul, A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Saul, A.] NIH, Fogarty Int Ctr, Rockville, MD 20852 USA. RP Saul, A (reprint author), Novartis Vaccines Inst Global Hlth Srl NVGH, Via Fiorentina 1, I-53100 Siena, Italy. EM Allan.Saul@novartis.com RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 FU National Institutes of Health FX I am grateful to Tom Smith, Patricia Graves, Bernard Okech and Chris Drakeley for supplying oocyt density data and to my colleagues in the Malaria Vaccine Development Branch, MAID and the Fogarty International Center of the NIH for suggestions on the content of this paper. The study was supported by the Intramural Research Program of the National Institute for Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 13 Z9 13 U1 1 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD NOV PY 2008 VL 135 IS 13 BP 1497 EP 1506 DI 10.1017/S0031182008000280 PG 10 WC Parasitology SC Parasitology GA 381PQ UT WOS:000261548800003 PM 18257944 ER PT J AU Restif, O Wolfe, DN Goebel, EM Bjornstad, ON Harvill, ET AF Restif, O. Wolfe, D. N. Goebel, E. M. Bjornstad, O. N. Harvill, E. T. TI Of mice and men: asymmetric interactions between Bordetella pathogen species SO PARASITOLOGY LA English DT Article DE whooping cough; mathematical model; strain dynamics; vaccine ID ANTIGENICALLY DIVERSE PATHOGENS; IMMUNOLOGICAL DETERMINANTS; PARAPERTUSSIS INFECTIONS; VACCINATION STRATEGIES; RESPIRATORY-INFECTION; POPULATION-STRUCTURE; PERTUSSIS-VACCINE; CROSS-IMMUNITY; MOUSE MODEL; EPIDEMIOLOGY AB In a recent experiment, we found that mice previously infected with Bordetella pertussis were not protected against a later infection with Bordetella parapertussis, while primary infection with B. parapertussis conferred cross-protection. This challenges the common assumption made in most mathematical models for pathogenic strain dynamics that cross-immunity between strains is symmetric. Here we investigate the potential consequences of this pattern on the circulation of the two pathogens in human populations. To match the empirical dominance of B. pertussis, we made the additional assumption that B. Parapertussis pays a cost in terms of reduced fitness. We begin by exploring the range of parameter values that allow the coexistence of the two pathogens, with or without vaccination. We then track the dynamics of the system following the introduction of anti-pertussis vaccination. Our results suggest that (1) in order for B. pertussis to be more prevalent than B. parapertussis, the former must have a strong competitive advantage, possibly in the form of higher infectivity, and (2) because of asymmetric cross-immunity, the introduction of anti-pertussis vaccination should have little effect on the absolute prevalence of B. parapertussis. We discuss the evidence supporting these predictions, and the potential relevance of this model for other pathogens. C1 [Wolfe, D. N.; Harvill, E. T.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Goebel, E. M.] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. [Bjornstad, O. N.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Bjornstad, O. N.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Bjornstad, O. N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Restif, O.] Univ Cambridge, Dept Vet Med, Cambridge Infect Dis Consortium, Cambridge CB3 OES, England. RP Restif, O (reprint author), Univ Cambridge, Dept Vet Med, Cambridge Infect Dis Consortium, Madingley Rd, Cambridge CB3 0ES, England. EM or226@cam.ac.uk RI Bjornstad, Ottar/I-4518-2012; OI Restif, Olivier/0000-0001-9158-853X FU NIAID NIH HHS [R01 AI053075, R01 AI053075-04, R01 AI053075-05, R01 AI107016]; NIGMS NIH HHS [R01 GM083113, R01 GM083113-01, R01 GM083113-02, R01 GM083113-02S1] NR 61 TC 7 Z9 7 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD NOV PY 2008 VL 135 IS 13 BP 1517 EP 1529 DI 10.1017/S0031182008000279 PG 13 WC Parasitology SC Parasitology GA 381PQ UT WOS:000261548800005 PM 18261255 ER PT J AU Liu, H Manganiello, V Waleh, N Clyman, RI AF Liu, Hanguan Manganiello, Vincent Waleh, Nahid Clyman, Ronald I. TI Expression, Activity, and Function of Phosphodiesterases in the Mature and Immature Ductus Arteriosus SO PEDIATRIC RESEARCH LA English DT Article ID VASCULAR SMOOTH-MUSCLE; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; IN-VIVO DILATATION; NITRIC-OXIDE; CELLS; FETAL; INHIBITION; RAT; PROLIFERATION; CONSTRICTION AB A patent ductus arteriosus is due in large part to increased sensitivity of the premature ductus to PGE2. After PGE2 stimulation, cAMP concentrations are higher in the immature than in the mature ductus. cAMP concentrations depend on the rates of adenyl cyclase production and phosphodiesterase (PDE)-mediated degradation. We used ductus from immature (n = 25) and mature (it = 2 1) fetal sheep to investigate whether a developmental increase in PDE activity could explain the diminished cAMP accumulation that follows PGE2 stimulation in the mature ductus. With advancing gestation, mRNA expression of the smooth muscle PDE isoforms (PDE 1A, 1B, 1C, 3A, 3B, 4D, and 5A) increased in the ductus as did their hydrolytic activities. Selective inhibitors of PDE1, PDE3, and PDE4 relaxed the mature and immature ductus in the presence of inhibitors of prostaglandin and nitric oxide production. The mature ductus required higher concentrations of each of the PDE inhibitors to inhibit its tension to the same extent as in the immature ductus. There were no developmental changes in PDE expression in the fetal aorta. In conclusion, we observed a developmental increase in cAMP and cGMP PDE activity that contributes to the decreased sensitivity of the late-gestation ductus arteriosus to vasodilators like PGE2. (Pediatr Res 64: 477-481, 2008) C1 [Clyman, Ronald I.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Waleh, Nahid] SRI Int, Menlo Pk, CA 94025 USA. [Liu, Hanguan; Manganiello, Vincent] NHLBI, Cellular Metab Lab, Bethesda, MD 20892 USA. RP Clyman, RI (reprint author), Univ Calif San Francisco, Dept Pediat, 513 Parnassus Ave,Room 1408 HSW,UCSF Box 0544, San Francisco, CA 94143 USA. EM clymanr@peds.ucsf.edu FU U.S. Public Health Service (NIH) [HL46691, HL56061] FX Supported by grants from U.S. Public Health Service (NIH grants HL46691, HL56061) and by a gift from the Jamie and Bobby Cates Foundation. NR 32 TC 10 Z9 11 U1 0 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD NOV PY 2008 VL 64 IS 5 BP 477 EP 481 DI 10.1203/PDR.0b013e3181827c2c PG 5 WC Pediatrics SC Pediatrics GA 365JC UT WOS:000260400800004 PM 18552705 ER PT J AU Cheng, TL Haynie, D Brenner, R Wright, JL Chung, SE Simons-Morton, B AF Cheng, Tina L. Haynie, Denise Brenner, Ruth Wright, Joseph L. Chung, Shang-en Simons-Morton, Bruce TI Effectiveness of a Mentor-Implemented, Violence Prevention Intervention for Assault-Injured Youths Presenting to the Emergency Department: Results of a Randomized Trial SO PEDIATRICS LA English DT Article DE adolescent health; emergency department; fighting; injury prevention and control; youth violence ID PSYCHOSOCIAL NEEDS; PROGRAM; MODEL; ADOLESCENTS; RISK; CONSEQUENCES; MANAGEMENT; SMOKING; IMPACT; CARE AB OBJECTIVE. The goal was to assess the impact of a mentor-implemented, violence prevention intervention in reducing aggression, fighting, and reinjury among assault-injured youths. METHODS. In a randomized, controlled trial performed in the emergency departments of 2 large urban hospitals, 10- to 15-year-old youths who presented with peer assault injuries were recruited and randomly assigned to intervention and comparison groups. In the intervention group, youths received a mentor, who implemented a 6-session problem-solving curriculum, and parents received 3 home visits with a health educator, to discuss family needs and to facilitate service use and parental monitoring. The comparison group received a list of community resources, with 2 follow-up telephone calls to facilitate service use. Youths and parents were interviewed at baseline and at 6 months, for assessment of attitudes about violence, risk factors, fighting, and repeat injury. RESULTS. A total of 227 families were recruited, with 23% refusing participation and 4% providing partial interview completion. A total of 166 families were enrolled, with 87 assigned to the intervention group and 79 to the comparison group; 118 (71%) completed both youth and parent follow-up interviews, and 113 had usable data. The intervention and comparison groups were not significantly different at baseline with respect to demographic features or risk factors, except for increased knife-carrying and fewer deviant peers in the intervention group. After adjustment for baseline differences, there was a trend toward significant program effects, including reduced misdemeanor activity and youth-reported aggression scores and increased youth self-efficacy. Program impact was associated with the number of intervention sessions received. CONCLUSIONS. A community-based, mentor-implemented program with assault-injured youths who presented to the emergency department trended in the direction of decreased violence, with reduced misdemeanors and increased self-efficacy. Pediatrics 2008; 122: 938-946 C1 [Cheng, Tina L.; Chung, Shang-en] Johns Hopkins Univ, Div Gen Pediat & Adolescent Med, Dept Pediat, Baltimore, MD 21287 USA. [Brenner, Ruth] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study Program Off, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD USA. [Wright, Joseph L.] Childrens Natl Med Ctr, Child Hlth Advocacy Inst, Washington, DC 20010 USA. RP Cheng, TL (reprint author), Johns Hopkins Univ, Div Gen Pediat & Adolescent Med, Dept Pediat, 200 N Wolfe St,Suite 2055, Baltimore, MD 21287 USA. EM tcheng2@jhmi.edu OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 FU Maternal and Child Health Bureau (Title V Social Security Act), Health Resources and Services Administration [R40MC00174, 4H34MC00025]; DC-Baltimore Research Center on Child Health Disparities [P20 MD00165]; National Center on Minority Health and Health Disparities FX This project was supported by the Maternal and Child Health Bureau (Title V Social Security Act), Health Resources and Services Administration (grants R40MC00174 and 4H34MC00025), and DC-Baltimore Research Center on Child Health Disparities grant P20 MD00165, from the National Center on Minority Health and Health Disparities. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. NR 49 TC 26 Z9 26 U1 3 U2 14 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD NOV PY 2008 VL 122 IS 5 BP 938 EP 946 DI 10.1542/peds.2007-2096 PG 9 WC Pediatrics SC Pediatrics GA 367HG UT WOS:000260542500004 PM 18977971 ER PT J AU Gibson, CS MacLennan, AH Dekker, GA Goldwater, PN Sullivan, TR Munroe, DJ Tsang, S Stewart, C Nelson, KB AF Gibson, Catherine S. MacLennan, Alastair H. Dekker, Gustaaf A. Goldwater, Paul N. Sullivan, Thomas R. Munroe, David J. Tsang, Shirley Stewart, Claudia Nelson, Karin B. TI Candidate Genes and Cerebral Palsy: A Population-Based Study SO PEDIATRICS LA English DT Article DE cerebral palsy; genetics; prematurity; nitric-oxide synthase; IL-8 ID OXIDE SYNTHASE EXPRESSION; WHITE-MATTER INJURY; LYMPHOTOXIN-ALPHA GENE; DEVELOPING RAT-BRAIN; INTRAUTERINE INFECTION; PERINATAL STROKE; CHILDREN; POLYMORPHISMS; PROTEIN; BLOOD AB OBJECTIVE. The objective of this study was to examine whether selected genetic polymorphisms in the infant are associated with later-diagnosed cerebral palsy. METHODS. A population-based case-control study was conducted of 28 single-nucleotide polymorphisms measured in newborn screening blood spots. A total of 413 children with later-diagnosed cerebral palsy were born to white women in South Australia in 1986-1999, and there were 856 control children. Distributions of genotypic frequencies were examined in total cerebral palsy, in gestational age groups, and by types of cerebral palsy and gender. Genotyping was performed by using a TaqMan assay. RESULTS. For inducible nitric-oxide synthase, possession of the T allele was more common in all children with cerebral palsy and for heterozygotes who were born at term. For lymphotoxin alpha, homozygous variant status was associated with risk for cerebral palsy and with spastic hemiplegic or quadriplegic cerebral palsy. Among term infants, heterozygosity for the endothelial protein C receptor single-nucleotide polymorphism was more frequent in children with cerebral palsy. In preterm infants, the variant A allele of interleukin 8 and heterozygosity for the beta-2 adrenergic receptor were associated with cerebral palsy risk. Interleukin 8 heterozygote status was associated with spastic diplegia. Variants of several genes were associated with cerebral palsy in girls but not in boys. CONCLUSIONS. Two of the 28 single-nucleotide polymorphisms examined were associated with all types of spastic cerebral palsy in both gestational age groups and others with cerebral palsy in gestational age or cerebral palsy subgroups. Some of these associations support previous findings. There may be a genetic contribution to cerebral palsy risk, and additional investigation is warranted of genes and gene-environment interactions in cerebral palsy. Pediatrics 2008; 122: 1079-1085 C1 [Gibson, Catherine S.; MacLennan, Alastair H.; Dekker, Gustaaf A.; Goldwater, Paul N.] Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia. [Sullivan, Thomas R.] Univ Adelaide, Sch Populat Hlth & Clin Practice, Adelaide, SA, Australia. [Goldwater, Paul N.] Womens & Childrens Hosp, Dept Microbiol & Infect Dis, Adelaide, SA, Australia. [Munroe, David J.; Tsang, Shirley; Stewart, Claudia] NCI, Lab Mol Technol, SAIC Frederick Inc, Frederick, MD 21701 USA. [Nelson, Karin B.] NINDS, Bethesda, MD 20892 USA. [Nelson, Karin B.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. RP Nelson, KB (reprint author), NIH, Bldg 31,Room 8A03, Bethesda, MD 20892 USA. EM knelson@helix.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 37 TC 28 Z9 28 U1 1 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD NOV PY 2008 VL 122 IS 5 BP 1079 EP 1085 DI 10.1542/peds.2007-3758 PG 7 WC Pediatrics SC Pediatrics GA 367HG UT WOS:000260542500023 PM 18977990 ER PT J AU Gillespie, JW Rosell, R Taron, M Queralt, C Wei, J AF Gillespie, John W. Rosell, Rafael Taron, Miquel Queralt, Cristina Wei, Jia TI Comparison of tissue procurement approaches for genomic profiling SO PERSONALIZED MEDICINE LA English DT Article ID MICRODISSECTION C1 [Gillespie, John W.] NCI Frederick, SAIC Frederick Inc, Biospecimen Res Network Lab, Frederick, MD 21702 USA. [Rosell, Rafael; Taron, Miquel; Queralt, Cristina; Wei, Jia] Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol, Barcelona 08916, Spain. [Rosell, Rafael; Taron, Miquel] USP Inst Univ Dexeus, Barcelona, Spain. [Wei, Jia] Nanjing Drum Tower Hosp, Nanjing, Peoples R China. RP Gillespie, JW (reprint author), NCI Frederick, SAIC Frederick Inc, Biospecimen Res Network Lab, Frederick, MD 21702 USA. EM jgill@mail.nih.gov; rrosell@ico.scs.es NR 4 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD NOV PY 2008 VL 5 IS 6 BP 567 EP 568 DI 10.2217/17410541.5.6.567 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 377BF UT WOS:000261226000008 ER PT J AU Savage, SA AF Savage, S. A. TI Cancer genetic association studies in the genome-wide age SO PERSONALIZED MEDICINE LA English DT Review DE cancer; cancer risk; genome-wide association study; genomics; population genetics; SNP ID PROSTATE-CANCER; BREAST-CANCER; COLORECTAL-CANCER; SUSCEPTIBILITY LOCUS; GASTRIC-CANCER; LUNG-CANCER; INTERLEUKIN-8 PROMOTER; CONFER SUSCEPTIBILITY; FAMILIAL SYNDROME; COMMON VARIANTS AB Genome-wide association studies of hundreds of thousands of SNPs have led to a deluge of studies of genetic variation in cancer and other common diseases. Large case-control and cohort studies have identified novel SNPs as markers of cancer risk. Genome-wide association study SNP data have also advanced understanding of population-specific genetic variation. While studies of risk profiles, combinations of SNPs that may increase cancer risk, are not yet clinically applicable, future, large-scale studies will make individualized cancer screening and prevention possible. C1 NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, Rockville, MD 20892 USA. RP Savage, SA (reprint author), NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, 6120 Executive Blvd,EPS 7018, Rockville, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU National Institutes of Health; National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. The author has 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 79 TC 3 Z9 3 U1 1 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD NOV PY 2008 VL 5 IS 6 BP 589 EP 597 DI 10.2217/17410541.5.6.589 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 377BF UT WOS:000261226000013 PM 19727433 ER PT J AU Malkesman, O Lavi-Avnon, Y Maayan, R Weizman, A AF Malkesman, O. Lavi-Avnon, Y. Maayan, R. Weizman, A. TI A cross-fostering study in a genetic animal model of depression: Maternal behavior and depression-like symptoms SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE childhood depression; animal models; cross-fostering; HPA axis; swim test; maternal behavior ID PITUITARY-ADRENAL AXIS; SENSITIVE LINE RATS; SWIM TEST; CHILDHOOD DEPRESSION; STRESS REACTIVITY; RATTUS-NORVEGICUS; BLOOD PRESSURES; PRENATAL STRESS; SEX-DIFFERENCES; IMMOBILITY AB Connections between maternal behavior and childhood depression were examined by using a "genetic animal model"; Flinder Sensitive Line - (FSL) rats, and cross-fostering the offspring with the control strain, Sprague Dawley (SD) rats. The control procedure was "in-fostering", where the foster dam and her pups were from the same strain. Contribution of pups' characteristics/genotype to maternal behavior was examined. After weaning, we measured male offspring's body weight, immobility in the swim test, and basal corticosterone (CORT) and adrenocorticotropin (ACTH) levels at the prepubertal age of 35 days. While maternal behavior (of "depressive-like" dams and their controls) was not altered significantly by the pups' strain, the adoption procedure per se appeared to have more adverse effects on "depressive-like" symptoms of the SD prepubertal rats than on the FSL pups. Nevertheless, the combination between abnormal maternal behavior and genetic predisposition affected the hormonal stress responses of the offspring in a more severe manner than genetic predisposition or abnormal maternal behavior per se. (c) 2008 Elsevier Inc. All rights reserved. C1 [Malkesman, O.] Bar Ilan Univ, Interdisciplinary Program Brain Sci, IL-52100 Ramat Gan, Israel. [Lavi-Avnon, Y.] Bar Ilan Univ, Dept Psychol, IL-52100 Ramat Gan, Israel. [Maayan, R.; Weizman, A.] Tel Aviv Univ, Felsenstein Med Res Ctr, Biol Psychiat Lab, Tel Aviv, Israel. [Maayan, R.; Weizman, A.] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Malkesman, O.; Lavi-Avnon, Y.] Bar Ilan Univ Ramat Gan, Gonda Goldschmied Multidisciplinary Brain Res Ctr, Ramat Gan, Israel. RP Malkesman, O (reprint author), NIMH, NIH, Mol Pathophysiol Lab, Bldg 35,Room 1C-912,35 Convent Dr,MSC-3711, Bethesda, MD 20892 USA. EM malkesmano@mail.nih.gov FU Bar-Ilan University FX The authors thank Prof. Aron Weller and Dr. Gal Yadid from the Gonda (Goldschmied) Brain Research Center, Bar-Ilan University, Israel, for their generous help in this study. The authors also thank Shai Nisenbaum and Orly Gross for help in performing the maternal behavior experiments. The research reported in this paper was completed as part of the first author's Ph.D. dissertation (OM in the Interdisciplinary Program in the Brain Sciences, Bar-Ilan University, Ramat-Gan, Israel). OM and YLA were supported by a President's fellowship, Bar-Ilan University. NR 49 TC 10 Z9 10 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD NOV PY 2008 VL 91 IS 1 BP 1 EP 8 DI 10.1016/j.pbb.2008.06.004 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 355NN UT WOS:000259715700001 PM 18593592 ER PT J AU Roma, PG Rinker, JA Serafine, KM Chen, SA Barr, CS Cheng, KJ Rice, KC Riley, AL AF Roma, Peter G. Rinker, Jennifer A. Serafine, Katherine M. Chen, Scott A. Barr, Christina S. Cheng, Kejun Rice, Kenner C. Riley, Anthony L. TI Genetic and early environmental contributions to alcohol's aversive and physiological effects SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE alcohol; gene-environment interaction; conditioned taste aversion; blood alcohol; hypothermia; kappa opioid system ID CONDITIONED TASTE-AVERSIONS; NUCLEUS-ACCUMBENS; LEWIS RATS; SEX-DIFFERENCES; BODY-WEIGHT; DRUG-ABUSE; KAPPA; ETHANOL; FISCHER; COCAINE AB Genetic and early environmental factors interact to influence ethanol's motivational effects. To explore these issues, a reciprocal cross-fostering paradigm was applied to Fischer and Lewis rats. The adult female offspring received vehicle or the kappa opioid antagonist nor-BNI (1 mg/kg) followed by assessments of conditioned taste aversion (CTA), blood alcohol concentrations (BACs) and hypothermia induced by 1.25 g/kg intraperitoneal ethanol. CTA acquisition in the in-fostered Fischer and Lewis animals did not differ; however, the Fischer maternal environment produced stronger acquisition in the cross-fostered Lewis rats versus their in-fostered counterparts. CTAs in the Fischer rats were not affected by cross-fostering. in extinction, the in-fostered Lewis animals displayed stronger aversions than the Fischer groups on two trials (of 12) whereas the cross-fostered Lewis differed from the Fischer groups on nine trials. Despite these CTA effects, Lewis rats exhibited higher BACs and stronger hypothermic responses than Fischer with no cross-fostering effects in either strain. No phenotypes were affected by nor-BNI. These data extend previous findings dissociating the aversive and peripheral physiological effects of ethanol in female Fischer and Lewis rats, and highlight the importance of genetic and early environmental factors in shaping subsequent responses to alcohol's motivational effects in adulthood. (c) 2008 Elsevier Inc. All rights reserved. C1 [Roma, Peter G.; Rinker, Jennifer A.; Serafine, Katherine M.; Riley, Anthony L.] American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Chen, Scott A.; Barr, Christina S.] NIAAA, Lab Clin & Translat Studies, Sect Primate Studies, Poolesville, MD USA. [Cheng, Kejun; Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Drug Design & Synth Sect, Bethesda, MD USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, Bethesda, MD USA. RP Roma, PG (reprint author), Inst Behav Resources, 2104 Maryland Ave, Baltimore, MD 21218 USA. EM PeteRoma@gmail.com OI Rinker, Jennifer/0000-0003-3738-3693 FU Mellon Foundation; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health/Public Health Service/US Department of Health and Human Services FX We are indebted to Dr. Markus Heilig of the National Institute on Alcohol Abuse and Alcoholism for generously providing access to the gas chromatography system and to Erick Singley for his expert technical assistance therein. This research was supported by a grant from the Mellon Foundation to A.L.R. and by intramural funds from the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, both of the National Institutes of Health/Public Health Service/US Department of Health and Human Services. NR 60 TC 9 Z9 10 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD NOV PY 2008 VL 91 IS 1 BP 134 EP 139 DI 10.1016/j.pbb.2008.06.022 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 355NN UT WOS:000259715700020 PM 18639579 ER PT J AU Bilski, PJ AF Bilski, Piotr J. TI Response to Comments by Ciani to our Rapid Communication on "The Photosensitizing Potential of Compact Fluorescent vs Incandescent Light Bulb" by CF Chignell, RH Sik and PJ Bilski. Photochem. Photobiol. (2008) SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Letter C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Bilski, PJ (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM bilski@niehs.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD NOV-DEC PY 2008 VL 84 IS 6 BP 1599 EP 1600 DI 10.1111/j.1751-1097.2008.00465.x PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 374ZC UT WOS:000261081200042 ER PT J AU Yue, CM Ponzio, TA Fields, RL Gainer, H AF Yue, Chunmei Ponzio, Todd A. Fields, Raymond L. Gainer, Harold TI Oxytocin and vasopressin gene expression and RNA splicing patterns in the rat supraoptic nucleus SO PHYSIOLOGICAL GENOMICS LA English DT Article DE real-time polymerase chain reaction; intron retention; hypothalamus ID REAL-TIME PCR; POLYMERASE-CHAIN-REACTION; INTRON-SPECIFIC PROBES; MESSENGER-RNA; RT-PCR; INSITU HYBRIDIZATION; ARGININE VASOPRESSIN; PRIMARY TRANSCRIPT; 1ST INTRON; IN-VIVO AB Yue C, Ponzio TA, Fields RL, Gainer H. Oxytocin and vasopressin gene expression and RNA splicing patterns in the rat supraoptic nucleus. Physiol Genomics 35: 231-242, 2008. First published September 2, 2008; doi: 10.1152/physiolgenomics.90218.2008.-In this study, we test the hypothesis that there are differential splicing patterns between the expressed oxytocin (OT) and vasopressin (VP) genes in the rat supraoptic nucleus (SON). We quantify the low abundance, intron-containing heteronuclear RNAs (hnRNAs) and the higher abundance mRNAs in the SON using two-step, quantitative SYBR Green real-time reverse transcription (RT)-PCR and external standard curves constructed using synthetic 90 nt sense-strand oligonucleotides. The levels of OT and VP mRNA in the SON were found to be similar, similar to 10(8) copies/SON pair, whereas the copy numbers of VP hnRNAs containing intron 1 or 2 and the OT hnRNA containing intron 1 are much lower, i.e., similar to 10(2)-10(3) copies/rat SON pair. However, the estimated copy number of the intron 2-containing OT hnRNA is much larger, similar to 10(6) copies/SON pair. The relative distributions of all the OT and VP RNA species were invariant and independent of the physiological status of the rats (e. g., osmotically stimulated or lactating rats). Using intron-specific riboprobes against hnRNAs, we demonstrate by fluorescence in situ hybridization strong signals of OT hnRNA containing intron 2 predominantly in the cytoplasm, in contrast to the localization of the VP hnRNA found only in the nuclei. Taken together, these data support the view that the splicing patterns between OT and VP gene transcripts are different and show that there is a selective cytoplasmic retention of OT intron C1 [Yue, Chunmei; Ponzio, Todd A.; Fields, Raymond L.; Gainer, Harold] NINDS, Mol Neurosci Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Mol Neurosci Sect, Neurochem Lab, NIH, Bldg 49,Rm 5A78, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov FU NIH; National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural research program of the NIH, National Institute of Neurological Disorders and Stroke. NR 64 TC 10 Z9 10 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD NOV PY 2008 VL 35 IS 3 BP 231 EP 242 DI 10.1152/physiolgenomics.90218.2008 PG 12 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 433QD UT WOS:000265220000005 PM 18765859 ER PT J AU Beller, M Sztalryd, C Southall, N Bell, M Jackle, H Auld, DS Oliver, B AF Beller, Mathias Sztalryd, Carole Southall, Noel Bell, Ming Jaeckle, Herbert Auld, Douglas S. Oliver, Brian TI COPI Complex Is a Regulator of Lipid Homeostasis SO PLOS BIOLOGY LA English DT Article ID HORMONE-SENSITIVE LIPASE; ADIPOSE TRIGLYCERIDE LIPASE; CHANARIN-DORFMAN-SYNDROME; THROUGHPUT SCREENING EXPERIMENTS; DIFFERENTIATION-RELATED PROTEIN; ENDOPLASMIC-RETICULUM; RNA INTERFERENCE; FATTY-ACID; ACYL-COA; STATISTICAL-METHODS AB Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT (perilipin, adipocyte differentiation related protein, tail interacting protein of 47 kDa) protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets. C1 [Beller, Mathias; Sztalryd, Carole; Oliver, Brian] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Beller, Mathias; Jaeckle, Herbert] Max Planck Inst Biophys Chem, Abt Mol Entwicklungsbiol, D-37077 Gottingen, Germany. [Sztalryd, Carole; Bell, Ming] Univ Maryland, Sch Med, Dept Med, Vet Affairs Med Ctr,GRECC Geriatr, Baltimore, MD 21201 USA. [Southall, Noel; Auld, Douglas S.] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Beller, M (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM mbeller@gwdg.de; csztalry@grecc.umaryland.edu; oliver@helix.nih.gov RI Southall, Noel/H-8991-2012; OI Southall, Noel/0000-0003-4500-880X; Beller, Mathias/0000-0003-0987-0080 FU National Institute of General Medical Sciences (NIGMS) [R01 GM067761]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH) [RO1 DK 075017-01A2]; American Diabetes Association [1-05-CD-17]; Geriatric Research, Education and Clinical Center; Baltimore Veterans Affairs Health Care and Center; Clinical Nutrition Research Unit of Maryland; Max Planck Society FX The work was funded in part by National Institute of General Medical Sciences (NIGMS) grant R01 GM067761 (DRSC), by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Institutes of Health (NIH) Intramural research program (M. Beller and B. Oliver), National Human Genome Research Institute (NHGRI) NIH intramural program, and NIH roadmap for molecular libraries (N. Southall and D. S. Auld), by a career development award 1-05-CD-17 from the American Diabetes Association (to C. Sztalryd), by a grant from NIH RO1 DK 075017-01A2 (to C. Sztalryd), by the Geriatric Research, Education and Clinical Center (C. Sztalryd), Baltimore Veterans Affairs Health Care and Center (C. Sztalryd), by the Clinical Nutrition Research Unit of Maryland (C. Sztalryd), and by the Max Planck Society (M. Beller and H. Jackle). NR 86 TC 165 Z9 170 U1 2 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2008 VL 6 IS 11 BP 2530 EP 2549 AR e292 DI 10.1371/journal.pbio.0060292 PG 20 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 376MO UT WOS:000261187900020 PM 19067489 ER PT J AU Antunes, A Troyer, JL Roelke, ME Pecon-Slattery, J Packer, C Winterbach, C Winterbach, H Hemson, G Frank, L Stander, P Siefert, L Driciru, M Funston, PJ Alexander, KA Prager, KC Mills, G Wildt, D Bush, M O'Brien, SJ Johnson, WE AF Antunes, Agostinho Troyer, Jennifer L. Roelke, Melody E. Pecon-Slattery, Jill Packer, Craig Winterbach, Christiaan Winterbach, Hanlie Hemson, Graham Frank, Laurence Stander, Philip Siefert, Ludwig Driciru, Margaret Funston, Paul J. Alexander, Kathy A. Prager, Katherine C. Mills, Gus Wildt, David Bush, Mitch O'Brien, Stephen J. Johnson, Warren E. TI The Evolutionary Dynamics of the Lion Panthera leo Revealed by Host and Viral Population Genomics SO PLOS GENETICS LA English DT Article ID FELINE IMMUNODEFICIENCY VIRUS; CLADE PHYLOGEOGRAPHIC ANALYSIS; ALLELE FREQUENCY DATA; CLADISTIC-ANALYSIS; PHENOTYPIC ASSOCIATIONS; AFRICAN LIONS; GENE FLOW; GEOGRAPHICAL-DISTRIBUTION; STATISTICAL TESTS; COMPUTER-PROGRAM AB The lion Panthera leo is one of the world's most charismatic carnivores and is one of Africa's key predators. Here, we used a large dataset from 357 lions comprehending 1.13 megabases of sequence data and genotypes from 22 microsatellite loci to characterize its recent evolutionary history. Patterns of molecular genetic variation in multiple maternal (mtDNA), paternal (Y-chromosome), and biparental nuclear (nDNA) genetic markers were compared with patterns of sequence and subtype variation of the lion feline immunodeficiency virus (FIV(Ple)), a lentivirus analogous to human immunodeficiency virus (HIV). In spite of the ability of lions to disperse long distances, patterns of lion genetic diversity suggest substantial population subdivision (mtDNA Phi(ST) = 0.92; nDNA F(ST) = 0.18), and reduced gene flow, which, along with large differences in seroprevalence of six distinct FIV(Ple) subtypes among lion populations, refute the hypothesis that African lions consist of a single panmictic population. Our results suggest that extant lion populations derive from several Pleistocene refugia in East and Southern Africa (similar to 324,000-169,000 years ago), which expanded during the Late Pleistocene (similar to 100,000 years ago) into Central and North Africa and into Asia. During the Pleistocene/Holocene transition (similar to 14,000-7,000 years), another expansion occurred from southern refugia northwards towards East Africa, causing population interbreeding. In particular, lion and FIV(Ple) variation affirms that the large, well-studied lion population occupying the greater Serengeti Ecosystem is derived from three distinct populations that admixed recently. C1 [Antunes, Agostinho; Troyer, Jennifer L.; Roelke, Melody E.] NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21701 USA. [Antunes, Agostinho] Univ Porto, CIMAR, Ctr Interdisciplinar Invest Marinha & Ambiental, P-4100 Oporto, Portugal. [Packer, Craig] Univ Minnesota, Dept Ecol Evolut & Behav, St Paul, MN 55108 USA. [Hemson, Graham] Wildlife Conservat Res Unit, Tubney, Oxon, England. [Winterbach, Christiaan; Winterbach, Hanlie] Tau Consultants, Maun, Botswana. [Frank, Laurence] Univ Calif Berkeley, Museum Vertebrate Zool, Laikipia Predator Project, Berkeley, CA 94720 USA. [Stander, Philip] Minist Environm & Tourism, Windhoek, Namibia. [Siefert, Ludwig] Makerere Univ, Dept Wildlife & Anim Resources Management, Kampala, Uganda. [Driciru, Margaret] Uganda Wildlife Author, Kampala, Uganda. [Funston, Paul J.] Tshwane Univ Technol, Nat Conservat Dept, Pretoria, South Africa. [Alexander, Kathy A.] Dept Wildlife & Natl Pk, Wildlife Vet Unit, Kasane, Botswana. [Prager, Katherine C.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Mills, Gus] Univ Pretoria, Mammal Res Inst, Skukuza, South Africa. [Mills, Gus] SANParks, Endangered Wildlife Trust, Skukuza, South Africa. [Wildt, David; Bush, Mitch] Smithsonians Natl Zool Pk, Conservat & Res Ctr, Front Royal, VA USA. RP Antunes, A (reprint author), NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21701 USA. EM aantunes@ncifcrf.gov; johnsonw@ncifcrf.gov RI Alexander, Kathleen/A-9765-2010; Troyer, Jennifer/B-8415-2012; Scientific output, CIIMAR/E-5122-2012; Johnson, Warren/D-4149-2016; OI Alexander, Kathleen/0000-0001-7338-5341; Scientific output, CIIMAR/0000-0001-6270-2153; Johnson, Warren/0000-0002-5954-186X; Antunes, Agostinho/0000-0002-1328-1732 FU National Cancer Institute; National Institutes of Health [N01-CO-12400]; Center for Cancer Research; National Science Foundation [0343960]; Portuguese Foundation for Science and Technology [PTDC/BIA-BDE/69144/2006, SFRH/BPD/5700/2001] FX This research has been funded in part by federal funds from the National Cancer Institute, National Institutes of Health (N01-CO-12400), by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by the National Science Foundation (No. 0343960) and by the Portuguese Foundation for Science and Technology (PTDC/BIA-BDE/69144/2006). AA received a grant from the Portuguese Foundation for Science and Technology (SFRH/BPD/5700/2001). NR 80 TC 38 Z9 40 U1 0 U2 31 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2008 VL 4 IS 11 AR e1000251 DI 10.1371/journal.pgen.1000251 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 380QT UT WOS:000261481000006 PM 18989457 ER PT J AU Kempf, L Nicodemus, KK Kolachana, B Vakkalanka, R Verchinski, BA Egan, MF Straub, RE Mattay, VA Callicott, JH Weinberger, DR Meyer-Lindenberg, A AF Kempf, Lucas Nicodemus, Kristin K. Kolachana, Bhaskar Vakkalanka, Radhakrishna Verchinski, Beth A. Egan, Michael F. Straub, Richard E. Mattay, Venkata A. Callicott, Joseph H. Weinberger, Daniel R. Meyer-Lindenberg, Andreas TI Functional Polymorphisms in PRODH Are Associated with Risk and Protection for Schizophrenia and Fronto-Striatal Structure and Function SO PLOS GENETICS LA English DT Article ID VOXEL-BASED MORPHOMETRY; CARDIO-FACIAL SYNDROME; 22Q11 DELETION SYNDROME; GENETIC-VARIATION; LINKAGE DISEQUILIBRIUM; CHINESE POPULATION; BIPOLAR DISORDER; BRAIN-FUNCTION; BASAL GANGLIA; HYPERPROLINEMIA AB PRODH, encoding proline oxidase (POX), has been associated with schizophrenia through linkage, association, and the 22q11 deletion syndrome (Velo-Cardio-Facial syndrome). Here, we show in a family-based sample that functional polymorphisms in PRODH are associated with schizophrenia, with protective and risk alleles having opposite effects on POX activity. Using a multimodal imaging genetics approach, we demonstrate that haplotypes constructed from these risk and protective functional polymorphisms have dissociable correlations with structure, function, and connectivity of striatum and prefrontal cortex, impacting critical circuitry implicated in the pathophysiology of schizophrenia. Specifically, the schizophrenia risk haplotype was associated with decreased striatal volume and increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity. Our findings suggest a role for functional genetic variation in POX on neostriatal-frontal circuits mediating risk and protection for schizophrenia. C1 [Kempf, Lucas; Meyer-Lindenberg, Andreas] NIMH, Unit Syst Neurosci Psychiat, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Kempf, Lucas; Nicodemus, Kristin K.; Kolachana, Bhaskar; Vakkalanka, Radhakrishna; Verchinski, Beth A.; Egan, Michael F.; Straub, Richard E.; Mattay, Venkata A.; Callicott, Joseph H.; Weinberger, Daniel R.; Meyer-Lindenberg, Andreas] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Verchinski, Beth A.; Mattay, Venkata A.; Meyer-Lindenberg, Andreas] NIMH, Neuroimaging Core Facil, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. RP Kempf, L (reprint author), NIMH, Unit Syst Neurosci Psychiat, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM weinberd@mail.nih.gov; a.meyer-lindenberg@zi-mannheim.de RI Callicott, Joseph/C-9102-2009; Meyer-Lindenberg, Andreas/H-1076-2011 OI Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU National Institute of Mental Health Intramural Program FX Funded by the National Institute of Mental Health Intramural Program. NR 73 TC 56 Z9 59 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2008 VL 4 IS 11 AR e1000252 DI 10.1371/journal.pgen.1000252 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 380QT UT WOS:000261481000007 PM 18989458 ER PT J AU Li, HC Pascal, V Martin, MP Carrington, M Anderson, SK AF Li, Hongchuan Pascal, Veronique Martin, Maureen P. Carrington, Mary Anderson, Stephen K. TI Genetic Control of Variegated KIR Gene Expression: Polymorphisms of the Bi-Directional KIR3DL1 Promoter Are Associated with Distinct Frequencies of Gene Expression SO PLOS GENETICS LA English DT Article ID NATURAL-KILLER-CELLS; INHIBITORY RECEPTOR GENES; NK-CELLS; HLA-B; PERIPHERAL-BLOOD; DNA METHYLATION; CUTTING EDGE; IDENTIFICATION; REPERTOIRE; ALLELE AB Natural killer (NK) cells play an important role in the detection and elimination of tumors and virus-infected cells by the innate immune system. Human NK cells use cell surface receptors (KIR) for class I MHC to sense alterations of class I on potential target cells. Individual NK cells only express a subset of the available KIR genes, generating specialized NK cells that can specifically detect alteration of a particular class I molecule or group of molecules. The probabilistic behavior of human KIR bi-directional promoters is proposed to control the frequency of expression of these variegated genes. Analysis of a panel of donors has revealed the presence of several functionally relevant promoter polymorphisms clustered mainly in the inhibitory KIR family members, especially the KIR3DL1 alleles. We demonstrate for the first time that promoter polymorphisms affecting the strength of competing sense and antisense promoters largely explain the differential frequency of expression of KIR3DL1 allotypes on NK cells. KIR3DL1/S1 subtypes have distinct biological activity and coding region variants of the KIR3DL1/S1 gene strongly influence pathogenesis of HIV/AIDS and other human diseases. We propose that the polymorphisms shown in this study to regulate the frequency of KIR3DL1/S1 subtype expression on NK cells contribute substantially to the phenotypic variation across allotypes with respect to disease resistance. C1 [Li, Hongchuan; Martin, Maureen P.; Carrington, Mary; Anderson, Stephen K.] NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21701 USA. [Li, Hongchuan; Pascal, Veronique; Martin, Maureen P.; Carrington, Mary; Anderson, Stephen K.] NCI, Canc & Inflammat Program, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21701 USA. RP Li, HC (reprint author), NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21701 USA. EM andersonst@mail.nih.gov RI Anderson, Stephen/B-1727-2012 OI Anderson, Stephen/0000-0002-7856-4266 FU National Cancer Institute; National Institutes of Health [N01 CO 12400]; 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 N01 CO 12400. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 46 TC 61 Z9 62 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2008 VL 4 IS 11 AR e1000254 DI 10.1371/journal.pgen.1000254 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 380QT UT WOS:000261481000009 PM 19008943 ER PT J AU Yang, Y Sterling, J Storici, F Resnick, MA Gordenin, DA AF Yang, Yong Sterling, Joan Storici, Francesca Resnick, Michael A. Gordenin, Dmitry A. TI Hypermutability of Damaged Single-Strand DNA Formed at Double-Strand Breaks and Uncapped Telomeres in Yeast Saccharomyces cerevisiae SO PLOS GENETICS LA English DT Article ID SITE-DIRECTED MUTAGENESIS; POLYMERASE-ZETA; PYRIMIDINE DIMER; REPAIR; MUTATION; ROLES; OLIGONUCLEOTIDES; REARRANGEMENTS; CHECKPOINT; TOLERANCE AB The major DNA repair pathways operate on damage in double-strand DNA because they use the intact strand as a template after damage removal. Therefore, lesions in transient single-strand stretches of chromosomal DNA are expected to be especially threatening to genome stability. To test this hypothesis, we designed systems in budding yeast that could generate many kilobases of persistent single-strand DNA next to double-strand breaks or uncapped telomeres. The systems allowed controlled restoration to the double-strand state after applying DNA damage. We found that lesions induced by UV-light and methyl methanesulfonate can be tolerated in long single-strand regions and are hypermutagenic. The hypermutability required PCNA monoubiquitination and was largely attributable to translesion synthesis by the error-prone DNA polymerase zeta. In support of multiple lesions in single-strand DNA being a source of hypermutability, analysis of the UV-induced mutants revealed strong strand-specific bias and unexpectedly high frequency of alleles with widely separated multiple mutations scattered over several kilobases. Hypermutability and multiple mutations associated with lesions in transient stretches of long single-strand DNA may be a source of carcinogenesis and provide selective advantage in adaptive evolution. C1 [Yang, Yong; Sterling, Joan; Storici, Francesca; Resnick, Michael A.; Gordenin, Dmitry A.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yang, Y (reprint author), NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov; gordenin@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU NIH; National Institute of Environmental Health Sciences [1 Z01 ES065073] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Project 1 Z01 ES065073). NR 43 TC 72 Z9 72 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2008 VL 4 IS 11 AR e1000264 DI 10.1371/journal.pgen.1000264 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 380QT UT WOS:000261481000019 PM 19023402 ER PT J AU Carucci, DJ Gottlieb, M AF Carucci, Daniel J. Gottlieb, Michael TI The Future of TDR: The Need to Adapt to a Changing Global Health Environment SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Editorial Material C1 [Carucci, Daniel J.] United Nations Fdn, Washington, DC USA. [Gottlieb, Michael] Fdn Natl Inst Hlth, Bethesda, MD USA. RP Carucci, DJ (reprint author), United Nations Fdn, Washington, DC USA. EM dcarucci@unfoundation.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2008 VL 2 IS 11 AR e310 DI 10.1371/journal.pntd.0000310 PG 2 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 385IM UT WOS:000261807900004 PM 19030156 ER PT J AU Belov, GA Feng, Q Nikovics, K Jackson, CL Ehrenfeld, E AF Belov, George A. Feng, Qian Nikovics, Krisztina Jackson, Catherine L. Ehrenfeld, Ellie TI A Critical Role of a Cellular Membrane Traffic Protein in Poliovirus RNA Replication SO PLOS PATHOGENS LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTOR; A-RESISTANT MUTANT; BREFELDIN-A; ENDOPLASMIC-RETICULUM; FACTOR GBF1; VERO CELLS; IN-VITRO; VIRUS; GOLGI; COMPLEX AB Replication of many RNA viruses is accompanied by extensive remodeling of intracellular membranes. In poliovirus-infected cells, ER and Golgi stacks disappear, while new clusters of vesicle-like structures form sites for viral RNA synthesis. Virus replication is inhibited by brefeldin A (BFA), implicating some components(s) of the cellular secretory pathway in virus growth. Formation of characteristic vesicles induced by expression of viral proteins was not inhibited by BFA, but they were functionally deficient. GBF1, a guanine nucleotide exchange factor for the small cellular GTPases, Arf, is responsible for the sensitivity of virus infection to BFA, and is required for virus replication. Knockdown of GBF1 expression inhibited virus replication, which was rescued by catalytically active protein with an intact N-terminal sequence. We identified a mutation in GBF1 that allows growth of poliovirus in the presence of BFA. Interaction between GBF1 and viral protein 3A determined the outcome of infection in the presence of BFA. C1 [Belov, George A.; Feng, Qian; Ehrenfeld, Ellie] NIAID, NIH, Bethesda, MD 20892 USA. [Nikovics, Krisztina; Jackson, Catherine L.] CNRS, Lab Enzymol & Biochim Struct, Gif Sur Yvette, France. RP Belov, GA (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM eehrenfeld@niaid.nih.gov RI Belov, George/B-4625-2008; Jackson, Catherine/A-3421-2013 OI Belov, George/0000-0002-0892-1731; Jackson, Catherine/0000-0002-0843-145X FU NIAID; NIH FX This work was supported in part by the intramural research programs of the NIAID, NIH. NR 62 TC 66 Z9 67 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2008 VL 4 IS 11 AR e1000216 DI 10.1371/journal.ppat.1000216 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 380QV UT WOS:000261481200020 PM 19023417 ER PT J AU Geisbert, TW Daddario-DiCaprio, KM Lewis, MG Geisbert, JB Grolla, A Leung, A Paragas, J Matthias, L Smith, MA Jones, SM Hensley, LE Feldmann, H Jahrling, PB AF Geisbert, Thomas W. Daddario-DiCaprio, Kathleen M. Lewis, Mark G. Geisbert, Joan B. Grolla, Allen Leung, Anders Paragas, Jason Matthias, Lennox Smith, Mark A. Jones, Steven M. Hensley, Lisa E. Feldmann, Heinz Jahrling, Peter B. TI Vesicular Stomatitis Virus-Based Ebola Vaccine Is Well-Tolerated and Protects Immunocompromised Nonhuman Primates SO PLOS PATHOGENS LA English DT Article ID ATTENUATED RECOMBINANT VACCINE; HEMORRHAGIC-FEVER; POSTEXPOSURE PROTECTION; REPLICATION-COMPETENT; CYNOMOLGUS MACAQUES; ADENOVIRUS VECTORS; IMMUNE-RESPONSES; MARBURG VIRUSES; MATRIX PROTEIN; INFECTION AB Ebola virus (EBOV) is a significant human pathogen that presents a public health concern as an emerging/re-emerging virus and as a potential biological weapon. Substantial progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against EBOV. Among these prospects, a vaccine based on recombinant vesicular stomatitis virus (VSV) is particularly robust, as it can also confer protection when administered as a postexposure treatment. A concern that has been raised regarding the replication-competent VSV vectors that express EBOV glycoproteins is how these vectors would be tolerated by individuals with altered or compromised immune systems such as patients infected with HIV. This is especially important as all EBOV outbreaks to date have occurred in areas of Central and Western Africa with high HIV incidence rates in the population. In order to address this concern, we evaluated the safety of the recombinant VSV vector expressing the Zaire ebolavirus glycoprotein (VSV Delta G/ZEBOVGP) in six rhesus macaques infected with simian-human immunodeficiency virus (SHIV). All six animals showed no evidence of illness associated with the VSV Delta G/ZEBOVGP vaccine, suggesting that this vaccine may be safe in immunocompromised populations. While one goal of the study was to evaluate the safety of the candidate vaccine platform, it was also of interest to determine if altered immune status would affect vaccine efficacy. The vaccine protected 4 of 6 SHIV-infected macaques from death following ZEBOV challenge. Evaluation of CD4+ T cells in all animals showed that the animals that succumbed to lethal ZEBOV challenge had the lowest CD4+ counts, suggesting that CD4+ T cells may play a role in mediating protection against ZEBOV. C1 [Geisbert, Thomas W.; Daddario-DiCaprio, Kathleen M.; Geisbert, Joan B.] Natl Emerging Infect Dis Labs Inst, Boston, MA USA. [Geisbert, Thomas W.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Geisbert, Thomas W.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Geisbert, Thomas W.; Daddario-DiCaprio, Kathleen M.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. [Geisbert, Thomas W.; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick, NIH, Bethesda, MD 20892 USA. [Geisbert, Thomas W.; Daddario-DiCaprio, Kathleen M.; Geisbert, Joan B.; Hensley, Lisa E.] BIOQUAL, Div Virol, Rockville, MD USA. [Leung, Anders; Jones, Steven M.; Feldmann, Heinz] Publ Hlth Agcy Canada, Natl Microbiol Lab, Special Pathogens Program, Winnipeg, MB, Canada. [Paragas, Jason; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. [Smith, Mark A.] USA, Med Res Inst Infect Dis, Div Pathol, Ft Detrick, MD 21702 USA. [Jones, Steven M.] Univ Manitoba, Dept Immunol, Winnipeg, MB, Canada. RP Geisbert, TW (reprint author), Natl Emerging Infect Dis Labs Inst, Boston, MA USA. EM geisbert@bu.edu FU Defense Threat Reduction Agency [04-4-7J-012]; Canadian Institutes of Health Research [MOP-39321]; Chemical, Biological, Radiological, and Nuclear (CBRN) Research and Technology Initiative (CRTI) FX Work on filoviruses at USAMRIID was funded by the Defense Threat Reduction Agency (project 04-4-7J-012). Work on filoviruses at the NML was supported by PHAC, a grant awarded to HF from the Canadian Institutes of Health Research (MOP-39321), and a grant awarded to SMJ from Chemical, Biological, Radiological, and Nuclear (CBRN) Research and Technology Initiative (CRTI). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by Boston University, the U. S. Army, the National Institutes of Health, or the Public Health Agency of Canada. NR 54 TC 73 Z9 77 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2008 VL 4 IS 11 AR e1000225 DI 10.1371/journal.ppat.1000225 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 380QV UT WOS:000261481200027 PM 19043556 ER PT J AU Zhu, P Winkler, H Chertova, E Taylor, KA Roux, KH AF Zhu, Ping Winkler, Hanspeter Chertova, Elena Taylor, Kenneth A. Roux, Kenneth H. TI Cryoelectron Tomography of HIV-1 Envelope Spikes: Further Evidence for Tripod-Like Legs SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROXIMAL EXTERNAL REGION; NEUTRALIZING ANTIBODY; OLIGOMERIC STRUCTURE; ELECTRON TOMOGRAPHY; VIRION SURFACE; GP120 CORE; SUBTYPE-C; GP41; MEMBRANE AB A detailed understanding of the morphology of the HIV-1 envelope (Env) spike is key to understanding viral pathogenesis and for informed vaccine design. We have previously presented a cryoelectron microscopic tomogram (cryoET) of the Env spikes on SIV virions. Several structural features were noted in the gp120 head and gp41 stalk regions. Perhaps most notable was the presence of three splayed legs projecting obliquely from the base of the spike head toward the viral membrane. Subsequently, a second 3D image of SIV spikes, also obtained by cryoET, was published by another group which featured a compact vertical stalk. We now report the cryoET analysis of HIV-1 virion-associated Env spikes using enhanced analytical cryoET procedures. More than 2,000 Env spike volumes were initially selected, aligned, and sorted into structural classes using algorithms that compensate for the "missing wedge'' and do not impose any symmetry. The results show varying morphologies between structural classes: some classes showed trimers in the head domains; nearly all showed two or three legs, though unambiguous three-fold symmetry was not observed either in the heads or the legs. Subsequently, clearer evidence of trimeric head domains and three splayed legs emerged when head and leg volumes were independently aligned and classified. These data show that HIV-1, like SIV, also displays the tripod-like leg configuration, and, unexpectedly, shows considerable gp41 leg flexibility/heteromorphology. The tripod-like model for gp41 is consistent with, and helps explain, many of the unique biophysical and immunological features of this region. C1 [Zhu, Ping; Winkler, Hanspeter; Taylor, Kenneth A.; Roux, Kenneth H.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Zhu, Ping; Winkler, Hanspeter; Taylor, Kenneth A.; Roux, Kenneth H.] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. [Zhu, Ping] Chinese Acad Sci, Ctr Struct & Mol Biol, Beijing, Peoples R China. [Zhu, Ping] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100080, Peoples R China. [Chertova, Elena] NCI, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21701 USA. RP Zhu, P (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. EM roux@bio.fsu.edu FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [AI055461, R01 AI055461]; NIGMS NIH HHS [GM082948, GM30598, R01 GM030598, R01 GM082948] NR 47 TC 45 Z9 46 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD NOV PY 2008 VL 4 IS 11 AR e1000203 DI 10.1371/journal.ppat.1000203 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 380QV UT WOS:000261481200008 PM 19008954 ER PT J AU Dunton, GF Berrigan, D Ballard-Barbash, R Graubard, BI Atienza, AA AF Dunton, Genevieve Fridlund Berrigan, David Ballard-Barbash, Rachel Graubard, Barry I. Atienza, Audie A. TI Social and physical environments of sports and exercise reported among adults in the American Time Use Survey SO PREVENTIVE MEDICINE LA English DT Article DE Exercise; Time; Environment; Social environment; Age groups; Education; Seasons ID HEALTH PROMOTION; OLDER-ADULTS; HOME; PREFERENCES; PREVENTION; EQUIPMENT; PROXIMITY; WALKING AB Objective. Demographic and temporal patterns in the social and physical environments of sports and exercise in the American Time Use Survey (years 2003-2006) are described. Method. The sample consisted of adult respondents (ages 21+) reporting at least one bout of sports or exercise (N=8844). During the interview, participants reported where (e.g., outdoors, home, work) and with whom (e.g., alone, family, coworkers) each bout occurred. Sample-weighted multinomial logistic regression analyses estimated the adjusted proportion of bouts occurring in each environment by gender, age, education, race/ethnicity, season, weekend/weekday, and time of day. Results. Among members of the oldest age group (ages 60+), more exercise bouts occurred alone and outdoors compared to younger age groups. Among college graduates, more exercise bouts occurred at a gym/health club compared to groups with lower levels of education. Exercise bouts occurring alone were most likely to happen in the winter, on weekdays, and in the morning. Exercise bouts occurring outdoors were most likely to happen in the summer, on weekend days, and in the morning. Conclusion. Future research and intervention efforts exploring where, when and with whom exercise bouts occur may prove beneficial to addressing public health concerns about physical inactivity. Published by Elsevier Inc. C1 [Dunton, Genevieve Fridlund; Atienza, Audie A.] NCI, Hlth Promot Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Berrigan, David; Ballard-Barbash, Rachel] NCI, Off Associate Director, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Biostat Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Biostat, Bethesda, MD 20892 USA. RP Dunton, GF (reprint author), NCI, Hlth Promot Res Branch, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4051C,MSC 7365, Bethesda, MD 20892 USA. EM duntong@mail.nih.gov FU Cancer Prevention Fellowship Program; Office of the Director, National Cancer Institute; National Institutes of Health FX We would like to thank the ATUS staff at the U.S. Bureau of Labor and Statistics for their technical assistance with this project. The first author was supported by the Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute, National Institutes of Health during the preparation of this paper. The views and opinions expressed in this paper are those of the authors and not necessarily those of the Department of Health and Human Services, the National Institutes of Health, or the National Cancer Institute. NR 32 TC 18 Z9 18 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD NOV PY 2008 VL 47 IS 5 BP 519 EP 524 DI 10.1016/j.ypmed.2008.07.001 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 385MV UT WOS:000261819200014 PM 18675293 ER PT J AU Kifer, I Nussinov, R Wolfson, HJ AF Kifer, Ilona Nussinov, Ruth Wolfson, Haim J. TI Constructing templates for protein structure prediction by simulation of protein folding pathways SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE protein structure prediction; template based; fragment assembly ID SECONDARY STRUCTURE; GLOBULAR-PROTEINS; ENERGY LANDSCAPE; FRAGMENTS; SEQUENCES; DOMAINS; UNITS AB How a one-dimensional protein sequence folds into a specific 3D structure remains a difficult challenge in structural biology. Many computational methods have been developed in an attempt to predict the tertiary structure of the protein; most of these employ approaches that are based on the accumulated knowledge of solved protein structures. Here we introduce a novel and fully automated approach for predicting the 3D structure of a protein that is based on the well accepted notion that protein folding is a hierarchical process. Our algorithm follows the hierarchical model by employing two stages: the first aims to find a match between the sequences of short independently-folding structural entities and parts of the target sequence and assigns the respective structures. The second assembles these local structural parts into a complete 3D structure, allowing for long-range interactions between them. We present the results of applying our method to a subset of the targets from CASP6 and CASP7. Our results indicate that for targets with a significant sequence similarity to known structures we are often able to provide predictions that are better than those achieved by two leading servers, and that the most significant improvements in comparison with these methods occur in regions of a gapped structural alignment between the native structure and the closest available structural template. We conclude that in addition to performing well for targets with known homologous structures, our method shows great promise for addressing the more general category of comparative modeling targets, which is our next goal. C1 [Kifer, Ilona; Wolfson, Haim J.] Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] SAIC Frederick Inc, Basic Res Program, Ctr Canc Res, Nanobiol Program,NCI, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Kifer, I (reprint author), Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. EM ilonak@post.tau.ac.il; wolfson@post.tau.ac.il RI Wolfson, Haim/A-1837-2011 FU Israel Science Foundation [281/05]; NIAID; NIH [1UC1AI067231]; National Cancer Institute; National Institutes of Health [NO1-CO-12400]; Hermann Minkowski-Minerva Center for Geometry; Binational US-Israel Science Foundation (BSF); Center for Cancer Research FX Grant sponsor: Israel Science Foundation; Grant number: 281/05; Grant sponsor: NIAID, NIH; Grant number: 1UC1AI067231; Grant sponsor: National Cancer Institute, National Institutes of Health; Grant number: NO1-CO-12400; Grant sponsors: Hermann Minkowski-Minerva Center for Geometry; Binational US-Israel Science Foundation (BSF); Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research. NR 32 TC 6 Z9 6 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD NOV 1 PY 2008 VL 73 IS 2 BP 380 EP 394 DI 10.1002/prot.22073 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 351MX UT WOS:000259429500010 PM 18433063 ER PT J AU Mason, BJ AF Mason, Barbara J. TI Challenges in Comorbidity SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. [Mason, Barbara J.] Scripps Res Inst, Comm Neurobiol, Lab Clin Psychopharmacol, La Jolla, CA USA. [Mason, Barbara J.] Univ Miami, Sch Med, Coral Gables, FL 33124 USA. NIDA, Translat Ctr Clin Neurobiol, Bethesda, MD 20892 USA. [Mason, Barbara J.] NIAAA, Sci Advisory Council, Rockville, MD 20852 USA. [Mason, Barbara J.] US FDA, Rockville, MD 20857 USA. RP Mason, BJ (reprint author), NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD NOV PY 2008 VL 38 IS 11 BP 703 EP 705 PG 7 WC Psychiatry SC Psychiatry GA 374LX UT WOS:000261046000002 ER PT J AU Seidenberg, GR AF Seidenberg, Gordon R. TI Could Noah's Life Have Been Saved? Confronting Dual Diagnosis and a Fragmented Mental Health System SO PSYCHIATRIC SERVICES LA English DT Editorial Material C1 [Seidenberg, Gordon R.] NIMH, Div AIDS & Hlth & Behav Res, Bethesda, MD 20892 USA. EM gseidenberg@hotmail.com NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD NOV PY 2008 VL 59 IS 11 BP 1254 EP 1255 DI 10.1176/appi.ps.59.11.1254 PG 2 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 366RT UT WOS:000260501800006 PM 18971400 ER PT J AU Morasso, G Costantini, M Di Leo, S Roma, S Miccinesi, G Merlo, DF Beccaro, M AF Morasso, Gabriella Costantini, Massimo Di Leo, Silvia Roma, Serena Miccinesi, Guido Merlo, Domenico Franco Beccaro, Monica TI End-of-life care in Italy: personal experience of family caregivers. A content analysis of open questions from the Italian Survey of the Dying of Cancer (ISDOC) SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; oncology; family caregiver; personal experience; post-bereavement survey ID PALLIATIVE HOME-CARE; TERMINALLY-ILL; MEMBERS; AMBIVALENCE; DEPRESSION; POSTAL; IMPACT; DEATH AB Objective: This study aims at describing the emotional and practical experience of a representative sample of Italian non-professional caregivers when caring for a terminally ill family member and is part of the 'Italian Survey of the Dying of Cancer', which involved 2000 adult cancer deaths representative of the whole country. Methods: Information on patients' experience was gathered from non-profession a caregivers by an interview. A specific question was asked about the caregivers' emotional and practical experiences while assisting a terminally ill relative. A content analysis of the open question on caregivers' perceptions was performed on transcribed answers. Three researchers independently generated categories. Subsequently,, areas where they differed were reconsidered and an interpretation was agreed upon. Results: Valid interviews were obtained from 1231 non-professional caregivers. Answers were classified according to the perception of the experience as positive (33.1%), negative (65.1%) or neutral (1.8%). Conclusion: Assisting a family member with cancer in his/her last three months of life is a very strong physical and mental stress for the caregiver. In some cases, this experience is nevertheless perceived as an evolution chance. Health-care providers should need to develop programs to ensure that family caregivers' needs for information and support are given great importance. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Morasso, Gabriella; Di Leo, Silvia; Roma, Serena] Natl Canc Inst, Unit Psychooncol, I-16132 Genoa, Italy. [Costantini, Massimo; Beccaro, Monica] Natl Canc Inst, Reg Palliat Care Network, I-16132 Genoa, Italy. [Miccinesi, Guido] Ctr Study & Prevent Canc, Florence, Italy. RP Morasso, G (reprint author), Natl Canc Inst, Unit Psychooncol, Largo R Benzi 10, I-16132 Genoa, Italy. EM gabriella.morasso@istge.it RI costantini, massimo/G-1443-2012; OI costantini, massimo/0000-0002-5293-7079 FU Italian Minister of Health FX This work was supported by a grant of the Italian Minister of Health (Progetti di Ricerca Finalizzata 2001-2003). We thank Jacqueline Luzardo (Unit of Clinical Epidemiology, IST Genoa) for data entry. NR 33 TC 15 Z9 15 U1 2 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD NOV PY 2008 VL 17 IS 11 BP 1073 EP 1080 DI 10.1002/pon.1332 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 375PC UT WOS:000261124800002 PM 18317991 ER PT J AU Gorelick, DA Kim, YK Bencherif, B Boyd, SJ Nelson, R Copersino, ML Dannals, RF Frost, JJ AF Gorelick, David A. Kim, Yu Kyeong Bencherif, Badreddine Boyd, Susan J. Nelson, Richard Copersino, Marc L. Dannals, Robert F. Frost, J. James TI Brain mu-opioid receptor binding: relationship to relapse to cocaine use after monitored abstinence SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine; mu-opioid receptor; positron emission tomography; relapse; carfentanil; frontal cortex; temporal cortex ID MESSENGER-RNA LEVELS; DRUG-USE; DEPENDENT INDIVIDUALS; OUTCOME PREDICTORS; NUCLEUS-ACCUMBENS; FRONTAL-CORTEX; VALIDITY; ADDICTION; DOPAMINE; SEVERITY AB Rationale Cocaine users have increased regional brain muopioid receptor (mOR) binding which correlates with cocaine craving. The relationship of mOR binding to relapse is unknown. Objective To evaluate regional brain mOR binding as a predictor of relapse to cocaine use is the objective of the study. Materials and methods Fifteen nontreatment-seeking, adult cocaine users were housed on a closed research ward for 12 weeks of monitored abstinence and then followed for up to 1 year after discharge. Regional brain mOR binding was measured after 1 and 12 weeks using positron emission tomography (PET) with [(11)C] carfentanil (a selective mOR agonist). Time to first cocaine use (lapse) and to first two consecutive days of cocaine use (relapse) after discharge was based on self-report and urine toxicology. Results A shorter interval before relapse was associated with increased mOR binding in frontal and temporal cortical regions at 1 and 12 weeks of abstinence (Ps < 0.001) and with a lesser decrease in binding between 1 and 12 weeks (Ps < 0.0008). There were significant positive correlations between mOR binding at 12 weeks and percent days of cocaine use during first month after relapse (Ps < 0.002). In multiple linear regression analysis, mOR binding contributed significantly to the prediction of time to relapse (R(2) = 0.79, P< 0.001), even after accounting for clinical variables. Conclusions Increased brain mOR binding in frontal and temporal cortical regions is a significant independent predictor of time to relapse to cocaine use, suggesting an important role for the brain endogenous opioid system in cocaine addiction. C1 [Gorelick, David A.] NIDA, IRP, Baltimore, MD 21224 USA. [Gorelick, David A.; Boyd, Susan J.; Nelson, Richard; Copersino, Marc L.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Kim, Yu Kyeong; Bencherif, Badreddine; Dannals, Robert F.; Frost, J. James] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD USA. RP Gorelick, DA (reprint author), NIDA, IRP, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM dgorelic@mail.nih.gov FU National Institutes of Health; National Institute on Drug Abuse; NIH [RO1 DA-09479] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse and NIH grant RO1 DA-09479 to JJF. NR 62 TC 28 Z9 28 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2008 VL 200 IS 4 BP 475 EP 486 DI 10.1007/s00213-008-1225-5 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 353PD UT WOS:000259579100003 PM 18762918 ER PT J AU Ballard, ED Pao, M Horowitz, L Lee, LM Henderson, DK Rosenstein, DL AF Ballard, Elizabeth D. Pao, Maryland Horowitz, Lisa Lee, Laura M. Henderson, David K. Rosenstein, Donald L. TI Aftermath of Suicide in the Hospital: Institutional Response SO PSYCHOSOMATICS LA English DT Article ID INPATIENT STANDARDS; RISK-MANAGEMENT; PATIENT; PSYCHIATRISTS; TRAUMA; CARE AB Background: A suicide can be a devastating event in the hospital, and few guidelines exist to aid an institution's response. Method: The authors describe a framework of immediate, short-term and long-term responses in the event of an in-hospital suicide. Conclusion: Implications for administration, communication, assessment, physical environment, and standards of care throughout the hospital are discussed that are relevant to both general-medical and psychiatric settings. Suggestions for the successful management of the aftermath of a suicide, such as the formation of a multidisciplinary leadership team, are included. (Psychosomatics 2008; 49: 461-469) C1 [Rosenstein, Donald L.] NIMH, Clin Res Ctr, Bethesda, MD 20892 USA. RP Rosenstein, DL (reprint author), NIMH, Clin Res Ctr, Bldg 10,Room 6-5340, Bethesda, MD 20892 USA. EM rosenstd@mail.nih.gov FU National Institute of Mental Health Intramural Research Program; National Institutes of Health Clinical Center FX This research was supported by the National Institute of Mental Health Intramural Research Program and the National Institutes of Health Clinical Center. NR 34 TC 8 Z9 10 U1 1 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD NOV-DEC PY 2008 VL 49 IS 6 BP 461 EP 469 PG 9 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 390IN UT WOS:000262157600001 PM 19122122 ER PT J AU Chef, T Simon, SL Land, CE Miller, DL AF Chef, Thierry Simon, S. L. Land, C. E. Miller, D. L. TI Radiation Dose to the Brain and Subsequent Risk of Developing Brain Tumors in Pediatric Patients Undergoing Interventional Neuroradiology Procedures SO RADIATION RESEARCH LA English DT Article ID FLUOROSCOPICALLY GUIDED PROCEDURES; CARDIAC-CATHETERIZATION; RADIOLOGY PROCEDURES; RAD-IR; SKIN INJURIES; PART I; EXPOSURE; CHILDREN; HEAD; VALUES AB Radiation dose to the brain and subsequent lifetime risk of diagnosis of radiation-related brain tumors were estimated for pediatric patients undergoing intracranial embolization. Average dose to the whole brain was calculated using dosimetric data from the Radiation Doses in Interventional Radiology Study for 49 pediatric patients who underwent neuroradiological procedures, and lifetime risk of developing radiation-related brain tumors was estimated using published algorithms based on A-bomb survivor data. The distribution of absorbed dose within the brain can vary significantly depending on field size and movement during procedures. Depending on the exposure conditions and age of the patient, organ-averaged brain dose was estimated to vary from 6 to 1600 mGy. The lifetime risk of brain tumor diagnosis was estimated to be increased over the normal background rates (57 cases per 10,000) by 3 to 40% depending on the dose received, age at exposure, and gender. While significant uncertainties are associated with these estimates, we have quantified the range of possible dose and propagated the uncertainty to derive a credible range of estimated lifetime risk for each subject. Collimation and limiting fluoroscopy time and dose rate are the most effective means to minimize dose and risk of future induction of radiation-related tumors. (c) 2008 by Radiation Research Society C1 [Chef, Thierry] Int Agcy Res Canc, F-69372 Lyon 08, France. [Chef, Thierry; Simon, S. L.; Land, C. E.] NCI, Div Cancer Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Miller, D. L.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD USA. RP Chef, T (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM thierrychefi@iarc.fr FU National Cancer Institute; NCI intramural program funds; Cardiovascular and Interventional Radiology Research and Education Foundation (CIRREF) FX The study presented here was conducted as part of a postdoctoral fellowship in the Radiation Epidemiology Branch of the National Cancer Institute and was supported by NCI intramural program funds. The original RADAR study was partially supported by a grant from the Cardiovascular and Interventional Radiology Research and Education Foundation (CIRREF). NR 51 TC 0 Z9 0 U1 0 U2 0 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD NOV PY 2008 VL 170 IS 5 BP 553 EP 565 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 367ZO UT WOS:000260591300001 ER PT J AU Vrijheid, M Cardis, E Ashmore, P Auvinen, A Gilbert, E Habib, RR Malker, H Muirhead, CR Richardson, DB Rogel, A Schubauer-Berigan, M Tardy, H Telle-Lamberton, M AF Vrijheid, Martine Cardis, Elisabeth Ashmore, Patrick Auvinen, Anssi Gilbert, Ethel Habib, Rima R. Malker, Hans Muirhead, Colin R. Richardson, David B. Rogel, Agnes Schubauer-Berigan, Mary Tardy, Helene Telle-Lamberton, Maylis CA 15-Country Study Grp TI Ionizing Radiation and Risk of Chronic Lymphocytic Leukemia in the 15-Country Study of Nuclear Industry Workers SO RADIATION RESEARCH LA English DT Article ID CANCER-RISK; EPIDEMIOLOGY; COUNTRIES; LYMPHOMA AB In contrast to other types of leukemia, chronic lymphocytic leukemia (CLL) has long been regarded as non-radiogenic, i.e. not caused by ionizing radiation. However, the justification for this view has been challenged. We therefore report on the relationship between CLL mortality and external ionizing radiation dose within the 15-country nuclear workers cohort study. The analyses included, in seven countries with CLL deaths, a total of 295,963 workers with more than 4.5 million person-years of follow-up and an average cumulative bone marrow dose of 15 mSv; there were 65 CLL deaths in this cohort. The relative risk (RR) at an occupational dose of 100 mSv compared to 0 mSv was 0.84 (95% CI 0.39, 1.48) under the assumption of a 10-year exposure lag. Analyses of longer lag periods showed little variation in the RR, but they included very small numbers of cases with relatively high doses. In conclusion, the largest nuclear workers cohort study to date finds little evidence for an association between low doses of external ionizing radiation and CLL mortality. This study had little power due to low doses, short follow up periods, and uncertainties in CLL ascertainment from death certificates; an extended follow-up of the cohorts is merited and would ideally include incident cancer cases. (c) 2008 by Radiation Research Society C1 [Vrijheid, Martine; Cardis, Elisabeth] Ctr Res Environm Epidemiol CREAL, Municipal Inst Med Res IMIM, Barcelona, Spain. [Vrijheid, Martine; Cardis, Elisabeth; Tardy, Helene] Int Agcy Res Canc, F-69372 Lyon, France. [Ashmore, Patrick] Hlth Canada, Radiat Protect Bureau, Ottawa, ON K1A 0L2, Canada. [Auvinen, Anssi] Univ Tampere, FIN-33101 Tampere, Finland. [Auvinen, Anssi] STUK Radiat & Nucl Safety Author, Helsinki, Finland. [Gilbert, Ethel] NCI, Radiat Epidemiol Branch, Div Epidemiol & Genet, Bethesda, MD 20892 USA. [Habib, Rima R.] Amer Univ Beirut, Fac Hlth Sci, Lebanon, NH USA. [Malker, Hans] Sundsvall Hosp, Midsweden Res & Dev Ctr, Sundsvall, Sweden. [Muirhead, Colin R.] Hlth Protect Agcy, Radiat Protect Div, Didcot, Oxon, England. [Richardson, David B.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Rogel, Agnes; Telle-Lamberton, Maylis] Inst Radioprotect & Surete Nucl, Fontenay Aux Roses, France. [Schubauer-Berigan, Mary] NIOSH, Cincinnati, OH 45226 USA. RP Vrijheid, M (reprint author), Ctr Res Environm Epidemiol CREAL, Municipal Inst Med Res IMIM, Barcelona, Spain. EM mvrijheid@creal.cat RI Schubauer-Berigan, Mary/B-3149-2009; Gulis, Gabriel/E-4505-2013; Cardis, Elisabeth/C-3904-2017; Vrijheid, M/H-2702-2014; OI Schubauer-Berigan, Mary/0000-0002-5175-924X; Vrijheid, M/0000-0002-7090-1758; Auvinen, Anssi/0000-0003-1125-4818; Gulis, Gabriel/0000-0002-8174-4591 FU NIOSH [211-2004-M-08102]; European Union [F13P-CT930066, F14P-CT96-0062, FIGH-CTI999-20001]; U.S. Centers for Disease Control and Prevention [U50/CCU011778]; Canadian Nuclear Safety Commission; Japanese Institute for Radiation Epidemiology; Australian Nuclear Science and Technology Organisation; Health Canada and Statistics Canada; La Ligue Nationale contre le Cancer, France; La Compagnie Generale des Matiere Nucleaire, France; Electricite de France; UK Health and Safety Executive; U.S. Department of Energy FX The authors thank the National Institute for Occupational Safety and Health, NIOSH (R. D. Daniels and S. Silver), for instigating the CLL project. We also acknowledge Prof. G. Howe (deceased) for providing the data for the U.S. NPP cohort. Funding for this project was received from NIOSH (contract 211-2004-M-08102). Financial support for coordination of the International Study was provided by the European Union (contracts F13P-CT930066, F14P-CT96-0062, FIGH-CTI999-20001), U.S. Centers for Disease Control and Prevention (Co-operative agreement U50/CCU011778), the Canadian Nuclear Safety Commission, and the Japanese Institute for Radiation Epidemiology. Funding sources for the national studies included: Australian Nuclear Science and Technology Organisation; Health Canada and Statistics Canada; La Ligue Nationale contre le Cancer, France; La Compagnie Generale des Matiere Nucleaire, France; Electricite de France; the UK Health and Safety Executive; U.S. Department of Energy. NR 19 TC 22 Z9 27 U1 0 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD NOV PY 2008 VL 170 IS 5 BP 661 EP 665 DI 10.1667/RR1443.1 PG 5 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 367ZO UT WOS:000260591300012 PM 18959468 ER PT J AU Zerhouni, EA AF Zerhouni, Elias A. TI Major Trends in the Imaging Sciences: 2007 Eugene P. Pendergrass New Horizons Lecture SO RADIOLOGY LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; BREAST-CANCER; RISK; VARIANTS; SUSCEPTIBILITY; ALLELES; CONTRIBUTE; MULTIPLE C1 NIH, Off Director, OCPL, Bethesda, MD 20892 USA. RP Zerhouni, EA (reprint author), NIH, Off Director, OCPL, Bldg 1,Rm 332,1 Ctr Dr, Bethesda, MD 20892 USA. EM ez26y@nih.gov NR 30 TC 7 Z9 7 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2008 VL 249 IS 2 BP 403 EP 409 DI 10.1148/radiol.2492080481 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 362RS UT WOS:000260215400003 PM 18936303 ER PT J AU Lockhart, ME Fielding, JR Richter, HE Brubaker, L Salomon, CG Ye, W Hakim, CM Wai, CY Stolpen, AH Weber, AM AF Lockhart, Mark E. Fielding, Julia R. Richter, Holly E. Brubaker, Linda Salomon, Caryl G. Ye, Wen Hakim, Christiane M. Wai, Clifford Y. Stolpen, Alan H. Weber, Anne M. TI Reproducibility of Dynamic MR Imaging Pelvic Measurements: A Multi-institutional Study SO RADIOLOGY LA English DT Article ID FECAL INCONTINENCE; ANAL-SPHINCTER; ORGAN PROLAPSE; DEFECTS; WOMEN; FLOOR; INTEROBSERVER; DEFECOGRAPHY; RELIABILITY; AGREEMENT AB Purpose: To assess the reproducibility of bone and soft-tissue pelvimetry measurements obtained from dynamic magnetic resonance (MR) imaging studies in primiparous women across multiple centers. Materials and Methods: All subjects prospectively gave consent for participation in this institutional review board -approved, HIPAA-compliant study. At six clinical sites, standardized dynamic pelvic 1.5-T multiplanar T2-weighted MR imaging was performed in three groups of primiparous women at 6 -12 months after birth: Group 1, vaginal delivery with anal sphincter tear (n = 93); group 2, vaginal delivery without anal sphincter tear (n = 79); and group 3, cesarean delivery without labor (n = 26). After standardized central training, blinded readers at separate clinical sites and a blinded expert central reader measured nine bone and 10 soft-tissue pelvimetry parameters. Subsequently, three readers underwent additional standardized training, and reread 20 MR imaging studies. Measurement variability was assessed by using intraclass correlation for agreement between the clinical site and central readers. Acceptable agreement was defined as an intraclass correlation coefficient (ICC) of at least 0.7. Results: There was acceptable agreement (ICC range, 0.71-0.93) for eight of 19 MR imaging parameters at initial readings of 198 subjects. The remaining parameters had an ICC range of 0.13-0.66. Additional training reduced measurement variability: Twelve of 19 parameters had acceptable agreement (ICC range, 0.70-0.92). Correlations were greater for bone (ICC, >= 0.70 in five [initial readings] and eight of nine [rereadings] variables) than for soft-tissue measurements (ICC, >= 0.70 in three [initial readings] of 10 and four [rereadings] of 10 readings, respectively). Conclusion: Despite standardized central training, there is high variability of pelvic MR imaging measurements among readers, particularly for soft-tissue structures. Although slightly improved with additional training, measurement variability adversely affects the utility of many MR imaging measurements for multicenter pelvic floor disorder research. (C) RSNA, 2008 C1 [Lockhart, Mark E.] Univ Alabama, Dept Radiol, Birmingham, AL 35249 USA. [Richter, Holly E.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35249 USA. [Fielding, Julia R.] Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. [Brubaker, Linda] Loyola Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Dept Urol, Chicago, IL 60611 USA. [Salomon, Caryl G.] Loyola Univ, Dept Radiol, Chicago, IL 60611 USA. [Ye, Wen] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Hakim, Christiane M.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Wai, Clifford Y.] Univ Texas SW, Dept Obstet & Gynecol, Dallas, TX USA. [Stolpen, Alan H.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Salomon, Caryl G.] VA Hosp, Hines, IL USA. [Weber, Anne M.] NICHHD, Bethesda, MD 20892 USA. RP Lockhart, ME (reprint author), Univ Alabama, Dept Radiol, 625 19th St S,JTN Room 363, Birmingham, AL 35249 USA. EM mlockhart@uabmc.edu FU National Institute of Child Health and Human Development [2U10 HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD41248, 1U10 HD41263, 1U10 HD41268, 1U10 HD41269] FX Supported in part by National Institute of Child Health and Human Development grants 2U10 HD41249, 2U10 HD41250, 2U10 HD41261, 2U10 HD41267, 1U10 HD41248, 1U10 HD41263, 1U10 HD41268, and 1U10 HD41269. NR 19 TC 21 Z9 21 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2008 VL 249 IS 2 BP 534 EP 540 DI 10.1148/radiol.2492072009 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 362RS UT WOS:000260215400019 PM 18796659 ER PT J AU Liu, ZF Zhang, YL Hua, YF Covey, JM Benbrook, DM Chan, KK AF Liu, Zhongfa Zhang, Yilong Hua, Yousheng Frank Covey, Joseph M. Benbrook, Doris M. Chan, Kenneth K. TI Metabolism of a sulfur-containing heteroarotionoid antitumor agent, SHetA2, using liquid chromatography/tandem mass spectrometry SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID RETINOIC ACID RECEPTOR; BIOLOGICAL-ACTIVITY; ANTICANCER AGENTS; INDUCE APOPTOSIS; X-RECEPTOR; IN-VITRO; CANCER; CELLS; INHIBIT; RAR AB SHetA2 {[(4-nitrophenyl)amino][2,2,4,4-tetramethylthiochroman-6-yl)amino]methanethione], NSC 726189}, a sulfur-containing heteroarotinoid, selectively inhibits cancer cell growth and induces apoptosis without activation of nuclear retinoic acid receptors (RARs). The objective of this study was to investigate its in vitro metabolism in rat and human liver microsomes and in vivo metabolism in the mouse and rat using liquid chromatography-ultraviolet/multi-stage mass spectrometry (LC-UV/MSn) on an ion-trap mass spectrometer coupled with a photo-diode array (PDA) detector. In vitro, in the absence of glutathione (GSH), oxidation of the four aliphatic methyl groups of SHetA2 yielded one mono-, two di-, and one tri-hydroxylated SHetA2 metabolites, which were identified based on their UV and multi-stage mass spectra. In the presence of GSH, in addition to these primary oxidative metabolites, four GSH adducts of SHetA2 and a novel rare form thioether GSH adduct was detected and characterized. In vivo, the monohydroxylated SHetA2 metabolites were also detected in mouse and rat plasma and two GSH adducts were detected in rat liver following intravenous (i.v.) bolus administration of SHetA2 at 40 mg/kg. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Liu, Zhongfa; Zhang, Yilong; Hua, Yousheng Frank; Chan, Kenneth K.] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Covey, Joseph M.] NCI, Rockville, MD 20852 USA. [Benbrook, Doris M.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73190 USA. [Chan, Kenneth K.] Ohio State Univ, Coll Med & Publ Hlth, Columbus, OH 43210 USA. RP Chan, KK (reprint author), Ohio State Univ, Coll Pharm, 410 W 12th Ave, Columbus, OH 43210 USA. EM chan.56@osu.edu RI Liu, Zhongfa/G-8549-2013 FU RAID; NCI [NO1-CM-07019]; BioMedical Mass Spectrometry Laboratory; Ohio State University FX Contract/grant sponsor: RAID App. 196.; Contract/grant sponsor: NCI; contract/grant number: NO1-CM-07019.; Contract/grant sponsor: The BioMedical Mass Spectrometry Laboratory, The Ohio State University. NR 33 TC 10 Z9 10 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0951-4198 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PD NOV PY 2008 VL 22 IS 21 BP 3371 EP 3381 DI 10.1002/rcm.3744 PG 11 WC Chemistry, Analytical; Spectroscopy SC Chemistry; Spectroscopy GA 370OU UT WOS:000260772300004 PM 18837006 ER PT J AU Kato, S Sadarangani, A Lange, S Delpiano, AM Vargas, M Branes, J Carvajal, J Lipkowitz, S Owen, GI Cuello, MA AF Kato, Sumie Sadarangani, Anil Lange, Soledad Delpiano, Ana M. Vargas, Macarena Branes, Jorge Carvajal, Jorge Lipkowitz, Stanley Owen, Gareth I. Cuello, Mauricio A. TI 2-Methoxyestradiol Mediates Apoptosis Through Caspase-Dependent and Independent Mechanisms in Ovarian Cancer Cells But Not in Normal Counterparts SO REPRODUCTIVE SCIENCES LA English DT Article DE AIF; 2ME; TRAIL; death receptors; chemotherapy; ovarian cancer ID SURFACE EPITHELIAL-CELLS; PROSTATE-CANCER; CARCINOMA-CELLS; ESTROGEN METABOLITE; CYTOTOXIC DRUGS; LIGAND TRAIL; HUMAN-BREAST; G2/M ARREST; IN-VIVO; COMBINATION AB Objective: The estrogen metabolite 2-methoxyestradiol has shown antitumorigenic action in some epithelial tumors. In the present work its investigate its effects in ovarian cancer used alone or in combination with other apoptotic-inducing reagents stick as tumor necrosis factor-related apoptosis-inducing ligand. Methods: To assess the effect of 2-methoxyestradiol, dose response and little courses in ovarian cancer and normal cells there conducted. Apoptosis was confirmed through DNA laddering, by flow cytometry, and Western blotting of proteins involved in the apoptotic cascade. Results: 2-Methoxyestradiol induced apoptosis in ovarian cancer cells but not in normal counterparts. 2-Methoxyestradiol both the intrinsic and extrinsic apoptotic pathways. 2-Methoxyestradiol-mediated apoptosis involves reactive oxygen species generation and caspase-dependent and caspase-independent mechanisms. We also demonstrate that 2-methoxyestradiol selectively induces art additive/synergistic apoptotic response in ovarian cancer cells when used in combination with tumor necrosis factor-related apoptosis-inducing ligand. Conclusions: 2-Methoxyestradiol, alone or in combination with tumor necrosis factor-related apoptosis-inducing ligand, should be considered as a potential treament for ovarian cancer. C1 [Kato, Sumie; Delpiano, Ana M.; Branes, Jorge; Carvajal, Jorge; Cuello, Mauricio A.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Fac Med, Santiago, Chile. [Sadarangani, Anil; Lange, Soledad; Vargas, Macarena; Owen, Gareth I.] Pontificia Univ Catolica Chile, Dept Physiol, Fac Biol Sci, Santiago, Chile. [Lipkowitz, Stanley] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cuello, MA (reprint author), Lira 85,5th Floor, Santiago 8330074, Chile. EM macuello@med.puc.cl FU FONDECYT [1060495, 1050744] FX We thank Drs Horacio Croxatto and Pedro Orihuela for their advice on the action of 2ME, Dr David Mayerson for recruiting patients and collecting samples, and Dr Carmen Romero of the University of Chile for the use of the normal human ovarian cell line. This work was supported by FONDECYT 1060495 (GO) and 1050744 (MC). NR 54 TC 16 Z9 16 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD NOV PY 2008 VL 15 IS 9 BP 878 EP 894 DI 10.1177/1933719108324171 PG 17 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 375UL UT WOS:000261138800006 PM 19050321 ER PT J AU Stupina, VA Meskauskas, A McCormack, JC Yingling, YG Shapiro, BA Dinman, JD Simon, AE AF Stupina, Vera A. Meskauskas, Arturas McCormack, John C. Yingling, Yaroslava G. Shapiro, Bruce A. Dinman, Jonathan D. Simon, Anne E. TI The 3 ' proximal translational enhancer of Turnip crinkle virus binds to 60S ribosomal subunits SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE cap-independent translation; internal ribosome entry site; Turnip crinkle virus; translational enhancer ID CAP-INDEPENDENT TRANSLATION; TRANSFER-RNA BINDING; PLANT VIRAL RNAS; ESCHERICHIA-COLI RIBOSOMES; EUKARYOTIC MESSENGER-RNA; MINUS-STRAND SYNTHESIS; ENTRY SITE; 3'-UNTRANSLATED REGION; REPLICATION REPRESSOR; INITIATION-FACTORS AB During cap-dependent translation of eukaryotic mRNAs, initiation factors interact with the 5' cap to attract ribosomes. When animal viruses translate in a cap-independent fashion, ribosomes assemble upstream of initiation codons at internal ribosome entry sites (IRES). In contrast, many plant viral genomes do not contain 5' ends with substantial IRES activity but instead have 3' translational enhancers that function by an unknown mechanism. A 393-nucleotide (nt) region that includes the entire 3' UTR of the Turnip crinkle virus (TCV) synergistically enhances translation of a reporter gene when associated with the TCV 5' UTR. The major enhancer activity was mapped to an internal region of similar to 140 nt that partially overlaps with a 100-nt structural domain previously predicted to adopt a form with some resemblance to a tRNA, according to a recent study by J.C.McCormack and colleagues. The T-shaped structure binds to 80S ribosomes and 60S ribosomal subunits, and binding is more efficient in the absence of surrounding sequences and in the presence of a pseudoknot that mimics the tRNA-acceptor stem. Untranslated TCV satellite RNA satC, which contains the TCV 3' end and 6-nt differences in the region corresponding to the T-shaped element, does not detectably bind to 80S ribosomes and is not predicted to form a comparable structure. Binding of the TCV T-shaped element by 80S ribosomes was unaffected by salt-washing, reduced in the presence of AcPhe-tRNA, which binds to the P-site, and enhanced binding of Phe-tRNA to the ribosome A site. Mutations that reduced translation in vivo had similar effects on ribosome binding in vitro. This strong correlation suggests that ribosome entry in the 3' UTR is a key function of the 3' translational enhancer of TCV and that the T-shaped element contains some tRNA-like properties. C1 [Stupina, Vera A.; Meskauskas, Arturas; McCormack, John C.; Dinman, Jonathan D.; Simon, Anne E.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Yingling, Yaroslava G.; Shapiro, Bruce A.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. RP Simon, AE (reprint author), Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. EM simona@umd.edu RI Yingling, Yaroslava/B-2901-2008; OI Yingling, Yaroslava/0000-0002-8557-9992; Dinman, Jonathan/0000-0002-2402-9698 FU U.S. Public Health Service [GM 061515-05A2/G120CD, GM 61515-01]; National Science Foundation [MCB-0615154]; American Heart Association [0630163N]; NIH [T32-AI51967-01]; National Cancer Institute; Center for Cancer Research; [GM R0158859]; [GM 059958] FX This work was supported by grants from the U.S. Public Health Service (GM 061515-05A2/G120CD and GM 61515-01) and the National Science Foundation (MCB-0615154) to A. E. S, the U. S. Public Health Service (GM R0158859 and GM 059958) to J.D.D., and the American Heart Association to A.M. (AHA 0630163N). V.A.S. and J.C.M were supported by NIH Institutional Training Grant T32-AI51967-01. This research was supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. The computational support was provided in part by the National Cancer Institute's Advanced Biomedical Computing Center. NR 64 TC 50 Z9 50 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD NOV PY 2008 VL 14 IS 11 BP 2379 EP 2393 DI 10.1261/rna.1227808 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 366CV UT WOS:000260459100012 PM 18824512 ER PT J AU Green, MF Penn, DL Bentall, R Carpenter, WT Gaebel, W Gur, RC Kring, AM Park, S Silverstein, SM Heinssen, R AF Green, Michael F. Penn, David L. Bentall, Richard Carpenter, William T. Gaebel, Wolfgang Gur, Ruben C. Kring, Ann M. Park, Sohee Silverstein, Steven M. Heinssen, Robert TI Social Cognition in Schizophrenia: An NIMH Workshop on Definitions, Assessment, and Research Opportunities SO SCHIZOPHRENIA BULLETIN LA English DT Review DE social cognition; schizophrenia; NIMH ID FACIAL-AFFECT RECOGNITION; MEDIAL PREFRONTAL CORTEX; PERSECUTORY DELUSIONS; EMOTION RECOGNITION; SPECTRUM DISORDERS; TRAINING-PROGRAM; MIND DEFICIT; NEURAL BASIS; PERCEPTION; PARANOIA AB Social cognition has become a high priority area for the study of schizophrenia. However, despite developments in this area, progress remains limited by inconsistent terminology and differences in the way social cognition is measured. To address these obstacles, a consensus-building meeting on social cognition in schizophrenia was held at the National Institute of Mental Health in March 2006. Agreement was reached on several points, including definitions of terms, the significance of social cognition for schizophrenia research, and suggestions for future research directions. The importance of translational interdisciplinary research teams was emphasized. The current article presents a summary of these discussions. C1 [Green, Michael F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Penn, David L.] Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. [Bentall, Richard] Univ Wales, Sch Psychol, Bangor, Gwynedd, Wales. [Carpenter, William T.] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Carpenter, William T.] Vet Adm, VISN 5, Mental Illness Res Educ & Clin Ctr, Baltimore, MD USA. [Gaebel, Wolfgang] Univ Dusseldorf, Dept Psychiat, D-4000 Dusseldorf, Germany. [Gur, Ruben C.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Kring, Ann M.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Park, Sohee] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Park, Sohee] Vanderbilt Univ, Dept Psychiat, Nashville, TN 37240 USA. [Silverstein, Steven M.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Silverstein, Steven M.] Univ Med & Dent New Jersey, Univ Behav HealthCare, Piscataway, NJ 08854 USA. [Heinssen, Robert] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. RP Green, MF (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 300 Med Plaza,Room 2263, Los Angeles, CA 90095 USA. EM mgreen@ucla.edu OI Park, Sohee/0000-0003-3797-4776 FU NIMH FX This article presents a summary of the discussion from a workshop supported by the NIMH. The views expressed are those of the authors and do not necessarily reflect the official views of the NIMH, the National Institutes of Health, or any other branch of the US Department of Health and Human Services. NR 101 TC 261 Z9 274 U1 7 U2 30 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD NOV PY 2008 VL 34 IS 6 BP 1211 EP 1220 DI 10.1093/schbul/sbm145 PG 10 WC Psychiatry SC Psychiatry GA 361OI UT WOS:000260136600027 PM 18184635 ER PT J AU Waldman, M Marshall, V Whitby, D Kopp, JB AF Waldman, Meryl Marshall, Vickie Whitby, Denise Kopp, Jeffrey B. TI Viruses and Kidney Disease: Beyond HIV SO SEMINARS IN NEPHROLOGY LA English DT Review DE Hepatitis C; BK virus; adenovirus; cytomegalovirus; parvovirus ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C-VIRUS; PARVOVIRUS B19 INFECTION; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; POLYOMA BK VIRUS; NECROTIZING TUBULOINTERSTITIAL NEPHRITIS; ACTIVE ANTIRETROVIRAL THERAPY; RENAL-ALLOGRAFT RECIPIENTS AB Human immunodeficiency virus (HIV)-infected patients may acquire new viral co-infections; they also may experience the reactivation or worsening of existing viral infections, including active, smoldering, or latent infections. HIV-infected patients may be predisposed to these viral infections owing to immunodeficiency or risk factors common to HIV and other viruses. A number of these affect the kidney, either by direct infection or by deposition Of immune complexes. In this review we discuss the renal manifestations and treatment of hepatitis C virus, BK virus, adenovirus, cytomegalovirus, and parvovirus B19 in patients with HI-V disease. We also discuss an approach to the identification of new viral renal pathogens, using a viral gene chip to identify viral DNA or RNA. C1 [Waldman, Meryl; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD USA. RP Waldman, M (reprint author), NIH, 10 Ctr Dr,Clin Res Bldg 10, Bethesda, MD 20892 USA. EM waldmanm@niddk.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute [N01-CO-12400]; National Institutes of Health FX This review was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute (Under contract N01-CO-12400), National Institutes of Health. NR 111 TC 8 Z9 8 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 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD NOV PY 2008 VL 28 IS 6 BP 595 EP 607 DI 10.1016/j.semnephrol.2008.08.010 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 377NO UT WOS:000261258100011 PM 19013331 ER PT J AU Fagan, P AF Fagan, Pebbles TI Examining the evidence base of mass media campaigns for socially disadvantaged populations: What do we know, what do we need to learn, and what should we do now? A commentary on Niederdeppe's article SO SOCIAL SCIENCE & MEDICINE LA English DT Editorial Material DE Smoking cessation; Health disparities; Media campaigns; Community interventions; Socioeconomic status (SES); Ethnicity C1 NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. RP Fagan, P (reprint author), NCI, Tobacco Control Res Branch, 6130 Execut Blvd,EPN 4034,MS 7337, Bethesda, MD 20892 USA. EM faganp@mail.nih.gov NR 15 TC 7 Z9 7 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2008 VL 67 IS 9 BP 1356 EP 1358 DI 10.1016/j.socscimed.2008.06.036 PG 3 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 358QE UT WOS:000259931800003 PM 18684545 ER PT J AU Thakkar, RN Popat, VB Orbegoso, C AF Thakkar, Rajiv N. Popat, Vaishali B. Orbegoso, Carlos TI Right Atrial Intramural Hematoma Associated with Aortic Dissection SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE atrial hematoma; intramural hematoma; intramyocardial hematoma ID MYOCARDIAL-INFARCTION; SURGERY AB A 75-year-old male presented with shortness of breath and abdominal pain; he had undergone coronary artery bypass graft surgery three months ago and had a history of coronary artery disease, hypertension, and end-stage renal disease. Transthoracic echocardiogram showed a right atrial mass. A computed axial tomography scan showed an atrial mass and type A aortic dissection. The patient sustained cardiorespiratory arrest and died. An autopsy showed an 8 cm atrial intramural hematoma originating from a dissecting aneurysm. This is the first case of right atrial intramural hematoma associated with aortic dissection exhibiting high mortality. Early diagnosis using multiple imaging modalities including magnetic resonance imaging and timely surgical intervention may improve Survival. Intramural hematomas should be considered in patients presenting with right-sided cardiac lesions. C1 [Thakkar, Rajiv N.] Johns Hopkins Univ, Sch Med, CIMS Div, Baltimore, MD 21224 USA. NIH, Bethesda, MD 20892 USA. Union Mem Hosp, Baltimore, MD USA. RP Thakkar, RN (reprint author), Johns Hopkins Univ, Sch Med, CIMS Div, 5200 Eastern Ave,Mason F Lord Bldg,W Wing 6th Flo, Baltimore, MD 21224 USA. EM Rthakka2@Jhmi.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD NOV PY 2008 VL 101 IS 11 BP 1177 EP 1179 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 372MU UT WOS:000260906500038 PM 19088537 ER PT J AU Kalichman, L Li, L Kim, DH Guermazi, A Berkin, V O'Donnell, CJ Hoffmann, U Cole, R Hunter, DJ AF Kalichman, Leonid Li, Ling Kim, David H. Guermazi, Ali Berkin, Valery O'Donnell, Christopher J. Hoffmann, Udo Cole, Rob Hunter, David J. TI Facet Joint Osteoarthritis and Low Back Pain in the Community-Based Population SO SPINE LA English DT Article ID COMPUTED-TOMOGRAPHY; LUMBAR SPINE; DEGENERATIVE SPONDYLOLISTHESIS; ZYGAPOPHYSIAL JOINT; CLINICAL-FEATURES; DISC DEGENERATION; GENERAL-PRACTICE; CORONARY-ARTERY; PREVALENCE; COMORBIDITY AB Study Design. Cross-sectional study. Objective. To evaluate the association between lumbar spine facet joint osteoarthritis (FJ OA) identified by multidetector computed tomography (CT) and low back pain (LBP) in the community-based Framingham Heart Study. Summary of Background Data. The association between lumbar FJ OA and LBP remains unclear. Methods. This study was an ancillary project to the Framingham Heart Study. A sample of 3529 participants of the Framingham Heart Study aged 40 to 80 underwent multidetector CT imaging to assess aortic calcification. One hundred eighty-eight individuals were consecutively enrolled in this ancillary study to assess radiographic features associated with LBP. LBP in the preceding 12 months was evaluated using a self-report questionnaire. FJ OA was evaluated on CT scans using a 4-grade scale. The association between FJ OA and LBP was examined used multiple logistic regression models, while adjusting for gender, age, and BMI. Results. CT imaging revealed a high prevalence of FJ OA (59.6% of males and 66.7% of females). Prevalence of FJ OA increases with age. By decade, FJ OA was present in 24.0% of < 40-years-olds, 44.7% of 40- to 49-years-olds, 74.2% of 50- to 59-years-olds, 89.2% of 60- to 69-year-olds, and 69.2% of > 70-years-olds. By spinal level the prevalence of FJ OA was: 15.1% at L2-L3, 30.6% at L3-L4, 45.1% at L4-L5, and 38.2% at L5-S1. In this community-based population, individuals with FJ OA at any spinal level showed no association with LBP. Conclusion. There is a high prevalence of FJ OA in the community. Prevalence of FJ OA increases with age with the highest prevalence at the L4-L5 spinal level. At low spinal levels women have a higher prevalence of lumbar FJ OA than men. In the present study, we failed to find an association between FJ OA, identified by multidetector CT, at any spinal level and LBP in a community-based study population. Spine 2008;33:2560-2565 C1 [Li, Ling; Kim, David H.; Hunter, David J.] New England Baptist Hosp, Div Res, Boston, MA 02120 USA. [Guermazi, Ali] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Div Cardiol, MA Gen Hosp, Boston, MA 02115 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, MA Gen Hosp,Cardiac MR CT PET Program, Boston, MA 02115 USA. RP Hunter, DJ (reprint author), New England Baptist Hosp, Div Res, 125 Parker Hill Ave, Boston, MA 02120 USA. EM djhunter@caregroup.harvard.edu RI Kalichman, Leonid/C-6266-2008; Hunter, David/A-4622-2010 OI Kalichman, Leonid/0000-0003-2987-4396; Hunter, David/0000-0003-3197-752X FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Arthritis Foundation Postdoctoral FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study contract (No. N01-HC-25195) for the recruitment, enrollment, and examination of the Offspring and Third Generation Cohort and the imaging by computed tomography scan. L. K. is supported by an Arthritis Foundation Postdoctoral Grant. Address correspondence and reprint requests to David J. Hunter, Chief, Division of Research, NewEngland Baptist Hospital, 125 Parker Hill Ave, Boston MA. 02120; E-mail: djhunter@caregroup.harvard.edu NR 62 TC 66 Z9 77 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD NOV 1 PY 2008 VL 33 IS 23 BP 2560 EP 2565 DI 10.1097/BRS.0b013e318184ef95 PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 369DA UT WOS:000260673300012 PM 18923337 ER PT J AU Park, S Balakrishnan, N Zheng, G AF Park, Sangun Balakrishnan, N. Zheng, Gang TI Fisher information in hybrid censored data SO STATISTICS & PROBABILITY LETTERS LA English DT Article ID EXACT LIKELIHOOD INFERENCE; EXPONENTIAL-DISTRIBUTION; ORDER-STATISTICS; TIME SAVINGS AB A hybrid censoring is a mixture of Type I and II censoring. Type I and Type II hybrid censoring models are considered in this work. When n items are placed oil a life-test, the experiment terminates under the Type I (Type II) hybrid censoring when either the r-th failure (1 <= r <= n) or the pre-determined censoring time T comes first (later). We study the decomposition of Fisher information in both hybrid censored data, and show that the Fisher information satisfies all additive rule in the case of hybrid censored data. The results are then applied to exponential and Weibull distributions for illustrative purposes. (c) 2008 Elsevier B.V. All rights reserved. C1 [Park, Sangun] Yonsei Univ, Dept Appl Stat, Seoul 120749, South Korea. [Balakrishnan, N.] McMaster Univ, Dept Math & Stat, Hamilton, ON L8S 4K1, Canada. [Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Park, S (reprint author), Yonsei Univ, Dept Appl Stat, Shinchon Dong 134, Seoul 120749, South Korea. EM sangun@yonsei.ac.kr FU College of Business and Economics of Yonsei University; Natural Sciences and Engineering Research Council of Canada FX The authors are grateful to an anonymous referee for his careful comments. Park's research was supported in part by the Fund for supporting basic science research in the College of Business and Economics of Yonsei University. Professor N. Balakrishnan would like to thank the Natural Sciences and Engineering Research Council of Canada for funding this research and the visit of Professor Sangun Park to McMaster University during the summer of 2006. NR 22 TC 13 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7152 J9 STAT PROBABIL LETT JI Stat. Probab. Lett. PD NOV PY 2008 VL 78 IS 16 BP 2781 EP 2786 DI 10.1016/j.spl.2008.03.019 PG 6 WC Statistics & Probability SC Mathematics GA 370HB UT WOS:000260752200037 ER PT J AU Das, RR Seshadri, S Beiser, AS Kelly-Hayes, M Au, R Himali, JJ Kase, CS Benjamin, EJ Polak, JF O'Donnell, CJ Yoshita, M D'Agostino, RB DeCarli, C Wolf, PA AF Das, Rohit R. Seshadri, Sudha Beiser, Alexa S. Kelly-Hayes, Margaret Au, Rhoda Himali, Jayandra J. Kase, Carlos S. Benjamin, Emelia J. Polak, Joseph F. O'Donnell, Christopher J. Yoshita, Mitsuhiro D'Agostino, Ralph B. DeCarli, Charles Wolf, Philip A. TI Prevalence and Correlates of Silent Cerebral Infarcts in the Framingham Offspring Study SO STROKE LA English DT Article DE carotid intimal medial thickness; carotid stenosis; carotid ultrasound; cerebral infarct; epidemiology; homocysteinemia; imaging; magnetic resonance; prevention ID NONRHEUMATIC ATRIAL-FIBRILLATION; STROKE RISK PROFILE; BRAIN INFARCTION; CAROTID ATHEROSCLEROSIS; WHITE-MATTER; OLDER-ADULTS; CARDIOVASCULAR HEALTH; PLASMA HOMOCYSTEINE; ROTTERDAM SCAN; HEART-DISEASE AB Background and Purpose-Previous estimates of the prevalence of silent cerebral infarction (SCI) on MRI in community-based samples have varied between 5.8% and 17.7% depending on age, ethnicity, presence of comorbidities, and imaging techniques. We document the prevalence and risk factors associated with SCI at midlife in the community-based Framingham sample. Methods-Our study sample comprised 2040 Framingham Offspring (53% female; mean age, 62 +/- 9 years) who attended the sixth examination (1996-1998), underwent volumetric brain MRI (1999-2005,) and were free of clinical stroke at MRI. We examined the age- and sex-specific prevalences and the clinical correlates of SCI using multivariable logistic regression models. Results-At least 1 SCI was present in 10.7% of participants; 84% had a single lesion. SCI was largely located in the basal ganglia (52%), other subcortical (35%) areas, and cortical areas (11%). Prevalent SCI was associated with the Framingham Stroke Risk Profile score (OR, 1.27; 95% CI, 1.10-1.46); stage I hypertension was determined by JNC-7 criteria (OR, 1.56; CI, 1.15-2.11), an elevated plasma homocysteine in the highest quartile (OR, 2.23; CI, 1.42-3.51), atrial fibrillation (OR, 2.16; CI, 1.07-4.40), carotid stenosis >25% (OR, 1.62; 1.13-2.34), and increased carotid intimal-medial thickness above the lowest quintile (OR, 1.65; CI, 1.22-2.24). Conclusion-The prevalence and distribution of SCI in the Framingham Offspring are comparable to previous estimates. Risk factors previously associated with clinical stroke were also found to be associated with midlife SCI. Our results support current guidelines emphasizing early detection and treatment of stroke risk factors. (Stroke. 2008; 39: 2929-2935.) C1 [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa S.; Himali, Jayandra J.] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Wolf, Philip A.] Boston Univ, Dept Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Dept Med, Boston, MA 02118 USA. [D'Agostino, Ralph B.] Boston Univ, Dept Math, Boston, MA 02118 USA. Tufts Univ, Dept Radiol, Boston, MA 02111 USA. [Seshadri, Sudha; Beiser, Alexa S.; Kelly-Hayes, Margaret; Au, Rhoda; Kase, Carlos S.; Benjamin, Emelia J.; O'Donnell, Christopher J.; D'Agostino, Ralph B.; Wolf, Philip A.] Framingham Heart Study & Natl Heart Lung & Blood, Framingham, MA USA. [Yoshita, Mitsuhiro; DeCarli, Charles] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. RP Seshadri, S (reprint author), Boston Univ, Sch Med, Dept Neurol, 715 Albany St,B 605, Boston, MA 02118 USA. EM suseshad@bu.edu RI DeCarli, Charles/B-5541-2009; OI Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Benjamin, Emelia/0000-0003-4076-2336; Beiser, Alexa/0000-0001-8551-7778; /0000-0003-1391-9481 FU Framingham Heart Study's National Heart, Lung, and Blood Institute [N01-HC-25195]; National Institute on Aging [R01 AG16495, AG08122]; National Institute of Neurological Disorders and Stroke [R01 NS17950] FX This work was supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract (N01-HC-25195), and by grants from the National Institute on Aging (R01 AG16495; AG08122) and the National Institute of Neurological Disorders and Stroke (R01 NS17950). NR 46 TC 140 Z9 154 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD NOV PY 2008 VL 39 IS 11 BP 2929 EP 2935 DI 10.1161/STROKEAHA.108.516575 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 365SC UT WOS:000260427100004 PM 18583555 ER PT J AU Bevans, MF Mitchell, SA Marden, S AF Bevans, Margaret F. Mitchell, Sandra A. Marden, Susan TI The symptom experience in the first 100 days following allogeneic hematopoietic stem cell transplantation (HSCT) SO SUPPORTIVE CARE IN CANCER LA English DT Article DE complications; cancer; recovery; clinical assessment; symptom burden ID QUALITY-OF-LIFE; BONE-MARROW-TRANSPLANTATION; CANCER-RELATED FATIGUE; HIGH-DOSE CHEMOTHERAPY; VERSUS-HOST-DISEASE; FUNCTIONAL STATUS; LUNG-CANCER; DISTRESS; HEALTH; INTENSITY AB Goals of work Despite advances in allogeneic hematopoietic stem cell transplantation (HSCT), post-transplant complications are common, and patients' symptom experience has not been well documented. Purpose To characterize the symptom experience of adult patients pre-transplantation and days 0, 30, and 100 after allogeneic HSCT. Methods Data from 76 participants enrolled in a prospective health-related quality of life (HRQL) study were used. Symptom occurrence, distress, and clusters were determined based on the 11 symptoms of the Symptom Distress Scale (SDS). Results Participants were on average 40 years old (SD +/- 13.5). The majority (54%) received reduced intensity conditioning. Prevalent symptoms included fatigue (68%) and worry (68%) at baseline, appetite change (88%) at day 0, and fatigue at days 30 (90%) and 100 (81%). Participants reported the following symptoms as severely distressing: worry (16%) [baseline], insomnia (32%) [day 0], appetite change (22%) [day 30], and fatigue (11%) [day 100]. The total SDS score was highest at day 0 (M = 26.6 +/- 7.6) when the highest number of symptoms were reported [median=8 (1-11)]. Symptoms formed clusters comprised of fatigue, appearance change, and worry at baseline, and fatigue, insomnia, and bowel changes at days 0 and 30. Compared to those with low symptom distress, participants with moderate/severe symptom distress reported poorer HRQL. Conclusion Allogeneic HSCT patients present for transplantation with low symptom distress yet experience multiple symptoms and high symptom distress after HSCT conditioning. Understanding the symptom experience of allogeneic HSCT patients can guide management strategies and improve HRQL. C1 [Bevans, Margaret F.; Mitchell, Sandra A.; Marden, Susan] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Bevans, MF (reprint author), 5061 Durham Rd W, Columbia, MD 21044 USA. EM mbevans@cc.nih.gov FU Intramural NIH HHS [Z01 CL001147-01] NR 85 TC 45 Z9 46 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD NOV PY 2008 VL 16 IS 11 BP 1243 EP 1254 DI 10.1007/s00520-008-0420-6 PG 12 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 356HT UT WOS:000259770000004 PM 18322708 ER PT J AU Isenberg, JS Maxhimer, JB Powers, P Tsokos, M Frazier, WA Roberts, DD AF Isenberg, Jeff S. Maxhimer, Justin B. Powers, Perlita Tsokos, Maria Frazier, William A. Roberts, David D. TI Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling SO SURGERY LA English DT Article ID HEPATIC ISCHEMIA/REPERFUSION INJURY; NITRIC-OXIDE; CELL RESPONSES; L-ARGININE; MYOCARDIAL ISCHEMIA/REPERFUSION; NEUTROPHIL TRANSMIGRATION; VASCULAR ENDOTHELIUM; CD47; APOPTOSIS; TISSUE AB Background. Ischemia-reperfusion (I/R) injury remains a primary complication of transplant surgery, accounting for about 80% of liver transplant failures, and is a major source of morbidity in other pathologic conditions. Activation of endothelium and inflammatory cell recruitment are central to the initiation and promulgation of I/R injury, which can be limited by the bioactive gas nitric oxide (NO). The discovery that thrombsospondin-1 (TSP1), via CD47, limits No signaling in vascular cells and ischemic injuries in vivo suggested that I/R injury could be another important target of this signaling pathway. Methods. Wild-type TSP1-null, and CD47-null mice underwent liver I/R injury. Wild-type animals were pretreated with CD47 or control antibodies before liver I/R injury. Tissue perfusion via laser Doppler imaging, serum enzymes, histology, and immunohistology were assessed. Results. TSP1-null, and CD47-null mice subjected to subtotal liver I/R injury showed improved perfusion relative to wild-type mice. Null mice subjected to liver I/R had decreased liver enzyme release and less histologic evidence of injury. Elevated TSP1 expression in liver tissue after I/R injury suggested that preventing its interaction with CD47 could be protective. Thus, pretreatment of wild-type mice using a blocking CD47 antibody improved recovery of tissue perfusion and preserved liver integrity after I/R injury. Conclusions. Tissue survival and perfusion after liver I/R injury are limited by TSP1 and CD47. Targeting CD47 before I/R injury enhances tissue survival and perfusion in a model of liver I/R injury and suggests therapeutics for enhancing organ survival in transplantation surgery. (Surgery 2008; 144:752-61). C1 [Isenberg, Jeff S.; Maxhimer, Justin B.; Tsokos, Maria; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Isenberg, Jeff S.; Powers, Perlita] NIH, Hematol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Frazier, William A.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Isenberg, JS (reprint author), NIH, Hematol Serv, Ctr Clin, Bldg 10,Room 2A33,10 Ctr Dr MSC1500, Bethesda, MD 20892 USA. EM isenberj@mail.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NIH [HL54390, GM57573] FX Supported by the Intramural Research Program of the NIH NCI (M.T., D.D.R.) mid NIH grants HL54390 and GM57573 (W.A.F). NR 47 TC 34 Z9 34 U1 0 U2 1 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 NOV PY 2008 VL 144 IS 5 BP 752 EP 761 DI 10.1016/j.surg.2008.07.009 PG 10 WC Surgery SC Surgery GA 372NK UT WOS:000260908100006 PM 19081017 ER PT J AU Erickson, DL Spouge, J Resch, A Weigt, LA Kress, WJ AF Erickson, David L. Spouge, John Resch, Alissa Weigt, Lee A. Kress, W. John TI DNA barcoding in land plants: developing standards to quantify and maximize success SO TAXON LA English DT Article DE barcoding; evolution; identification; land plants; PCI; probability ID LIFE; SEQUENCES; PROSPECTS; IDENTIFY; TAXONOMY; PROGRESS AB The selection of a DNA barcode in plants has been impeded in part due to the relatively low rates of nucleotide substitution observed at the most accessible plastid markers. However, the absence of consensus also reflects a lack of standards for comparing potential barcode markers. While many publications have suggested a host of plant DNA barcodes, the studies cannot be readily compared with each other through any quantitative or statistical parameter, partly because they put forward no single compelling rationale relevant to the adoption of a DNA barcode in plants. Here, we argue that the efficacy of any particular plant DNA barcode selection should reflect the anticipated performance of the resulting barcode database in assignment of a query sequence to species. While legitimate scientific disagreement exists over the criteria relevant to "database performance". the notion gives a unifying rationale for prioritizing selection criteria. Accordingly, we suggest a measure of barcode efficacy based on the rationale of database performance, "the probability of correct identification" (PCI). Moreover, the definition of PCI is left flexible enough to handle most of the scientific disagreement over how to best evaluate DNA barcodes. Finally. we consider how different types of barcodes might require different methods of analysis and database design and indicate how the analysis might affect the selection of the most broadly effective barcode for land plants. C1 [Erickson, David L.; Kress, W. John] Smithsonian Inst, Natl Museum Nat Hist, Dept Bot, MRC 166, Washington, DC 20013 USA. [Spouge, John; Resch, Alissa] NIH, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. [Weigt, Lee A.] Smithsonian Inst, Labs Analyt Biol, Natl Museum Nat Hist, Suitland, MD 20746 USA. RP Erickson, DL (reprint author), Smithsonian Inst, Natl Museum Nat Hist, Dept Bot, MRC 166, POB 37012, Washington, DC 20013 USA. EM ericksond@si.edu FU Smithsonian Institution; National Library of Medicine at the National Institutes Health FX We wish to thank Dr. P, Hollingsworth, M. Chase, K. Wurdack and two reviewers for helpful discussion and comments on all earlier draft of this manuscript. Funding support was provided by the Smithsonian Institution and the Intramural Research Program of the National Library of Medicine at the National Institutes Health. NR 38 TC 38 Z9 43 U1 2 U2 14 PU INT ASSOC PLANT TAXONOMY PI VIENNA PA C/O UNIV VIENNA, INST BOTANY, RENNWEG 14, A-1030 VIENNA, AUSTRIA SN 0040-0262 J9 TAXON JI Taxon PD NOV PY 2008 VL 57 IS 4 BP 1304 EP 1316 PG 13 WC Plant Sciences; Evolutionary Biology SC Plant Sciences; Evolutionary Biology GA 377WO UT WOS:000261283000020 PM 19779570 ER PT J AU Guo, WG AF Guo, Wenge TI Comments on: Control of the false discovery rate under dependence using the bootstrap and subsampling SO TEST LA English DT Editorial Material C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Guo, WG (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM wenge.guo@gmail.com OI Guo, Wenge/0000-0003-3777-2058 NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1133-0686 J9 TEST JI Test PD NOV PY 2008 VL 17 IS 3 BP 446 EP 449 DI 10.1007/s11749-008-0128-4 PG 4 WC Statistics & Probability SC Mathematics GA 383SJ UT WOS:000261693400003 ER PT J AU Troendle, JF AF Troendle, James F. TI Comments on: Control of the false discovery rate under dependence using the bootstrap and subsampling SO TEST LA English DT Editorial Material C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. RP Troendle, JF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. EM jt3t@nih.gov NR 2 TC 3 Z9 3 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1133-0686 J9 TEST JI Test PD NOV PY 2008 VL 17 IS 3 BP 456 EP 457 DI 10.1007/s11749-008-0130-x PG 2 WC Statistics & Probability SC Mathematics GA 383SJ UT WOS:000261693400005 ER PT J AU Byers, BA Mauck, RL Chiang, IE Tuan, RS AF Byers, Benjamin A. Mauck, Robert L. Chiang, Ian E. Tuan, Rocky S. TI Transient Exposure to Transforming Growth Factor Beta 3 Under Serum-Free Conditions Enhances the Biomechanical and Biochemical Maturation of Tissue-Engineered Cartilage SO TISSUE ENGINEERING PART A LA English DT Article ID MESENCHYMAL STEM-CELLS; ARTICULAR-CARTILAGE; IN-VITRO; SEEDING DENSITY; AGAROSE CULTURE; CHONDROGENIC DIFFERENTIATION; EXTRACELLULAR-MATRIX; BONE-MARROW; CHONDROCYTES; SCAFFOLDS AB A goal of cartilage tissue engineering is the production of cell-laden constructs possessing sufficient mechanical and biochemical features to enable native tissue function. This study details a systematic characterization of a serum-free (SF) culture methodology employing transient growth factor supplementation to promote robust maturation of tissue-engineered cartilage. Bovine chondrocyte agarose hydrogel constructs were cultured under free-swelling conditions in serum-containing or SF medium supplemented continuously or transiently with varying doses of transforming growth factor beta 3 (TGF-beta 3). Constructs were harvested weekly or bi-weekly and assessed for mechanical and biochemical properties. Transient exposure (2 weeks) to low concentrations (2.5-5 ng/mL) of TGF-beta 3 in chemically defined medium facilitated robust and highly reproducible construct maturation. Constructs receiving transient TGF-beta 3 exposure achieved native tissue levels of compressive modulus (0.8 MPa) and proteoglycan content (6-7% of wet weight) after less than 2 months of in vitro culture. This maturation response was far superior to that observed after continuous growth factor supplementation or transient TGF-beta 3 treatment in the presence of serum. These findings represent a significant advance in developing an ex vivo culture methodology to promote production of clinically relevant and mechanically competent tissue-engineered cartilage constructs for implantation to repair damaged articular surfaces. C1 [Byers, Benjamin A.; Mauck, Robert L.; Chiang, Ian E.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, 50 S Dr,Bldg 50,Room 1503,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU Intramural Research Program of NIAMS; NIH [ZO1 AR41131] FX This work was supported by the Intramural Research Program of NIAMS, NIH (ZO1 AR41131). NR 41 TC 96 Z9 98 U1 0 U2 15 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD NOV PY 2008 VL 14 IS 11 BP 1821 EP 1834 DI 10.1089/ten.tea.2007.0222 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 369VG UT WOS:000260721400006 PM 18611145 ER PT J AU Hegedus, CM Skibola, CF Warner, M Skibola, DR Alexander, D Lim, S Dangleben, NL Zhang, L Clark, M Pfeiffer, RM Steinmaus, C Smith, AH Smith, MT Moore, LE AF Hegedus, Christine M. Skibola, Christine F. Warner, Marcella Skibola, Danica R. Alexander, David Lim, Sophia Dangleben, Nygerma L. Zhang, Luoping Clark, Michael Pfeiffer, Ruth M. Steinmaus, Craig Smith, Allan H. Smith, Martyn T. Moore, Lee E. TI Decreased urinary beta-defensin-1 expression as a biomarker of response to arsenic SO TOXICOLOGICAL SCIENCES LA English DT Article DE arsenic; human beta-defensin-1; proteomics; SELDI-TOF MS ID MONOMETHYLARSONOUS ACID MMA(III); EXFOLIATED BLADDER CELLS; DRINKING-WATER; BETA-DEFENSINS; CANCER RISK; AMINO-ACID; METHYLATION; EXPOSURE; TIME; INDIVIDUALS AB Ingestion of arsenic (As) through contaminated drinking water results in increased risks of skin, lung, kidney, and bladder cancers. Due to its association with kidney and bladder cancers, we hypothesized that analysis of the urinary proteome could provide insight into the mechanisms of As toxicity. Urine from participants in a cross-sectional As biomarker study conducted in Nevada, classified as having either high (>= 100 mu g total urinary As/l) or low exposure (< 100 mu g total urinary As/l) was analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Two polypeptides, 2.21 and 4.37 kDa, were significantly decreased in the high exposure group (p < 0.05) and were limited to men when stratified by sex. To replicate these findings, urine from participants in a second As study in Chile was analyzed and results confirmed the decrease of the 4.37 kDa polypeptide as well as a 4.76 kDa polypeptide among highly exposed men. These peaks were identified and confirmed as human beta-defensin-1 (HBD-1) peptides. In a separate in vitro experiment, gene expression analysis of As-treated cell lines demonstrated reduced HBD1 mRNA confirming that the observed decrease in HBD-1 resulted from As exposure. HBD-1 is an antimicrobial peptide constitutively expressed in multiple tissues including epithelial cells of the respiratory and urogenital systems. Recent studies support its role as a tumor suppressor gene for urological cancers suggesting that decreased HBD-1 levels may play a role in the development of cancers associated with As exposure. Further studies are warranted to investigate the role of HBD-1 in As-related toxicity. C1 [Skibola, Christine F.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Pfeiffer, Ruth M.; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Steinmaus, Craig] Calif Environm Protect Agcy, Off Environm Hlth Hazard Assessment, Oakland, CA 94612 USA. RP Skibola, CF (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Room 237A,B84 Hildebrand Hall MC7356, Berkeley, CA 94720 USA. EM chrisfs@berkeley.edu; moorele@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Smith, Allan/F-9249-2011 FU National Institute for Environmental Health Sciences [P42 ES04705]; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX National Institute for Environmental Health Sciences (P42 ES04705) to M. T. S.; and Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics to L. E. M. NR 40 TC 21 Z9 22 U1 3 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2008 VL 106 IS 1 BP 74 EP 82 DI 10.1093/toxsci/kfn104 PG 9 WC Toxicology SC Toxicology GA 359GU UT WOS:000259975200008 PM 18511430 ER PT J AU Stern, ST Zolnik, BS McLeland, CB Clogston, J Zheng, JW McNeil, SE AF Stern, Stephan T. Zolnik, Banu S. McLeland, Christopher B. Clogston, Jeffery Zheng, Jiwen McNeil, Scott E. TI Induction of autophagy in porcine kidney cells by quantum dots: A common cellular response to nanomaterials? SO TOXICOLOGICAL SCIENCES LA English DT Article DE quantum dots; autophagy; anomaterials ID VASCULAR ENDOTHELIAL-CELLS; LLC-PK1 CELLS; SURFACE-COATINGS; N-ACETYLCYSTEINE; IN-VITRO; CYTOTOXICITY; NANOPARTICLES; TOXICITY; FULLERENE; APOPTOSIS AB Quantum dots (QDs) are being investigated as novel in vivo imaging agents. The leaching of toxic metals from these QDs in biological systems is of great concern. This study compared the cytotoxic mechanisms of two QD species made of different core materials (cadmium selenide [CdSe] vs. indium gallium phosphide [InGaP]) but similar core sizes (5.1 vs. 3.7 nm) and surface compositions (both ZnS capped, lipid-coated and pegylated). The CdSe QD was found to be 10-fold more toxic to porcine renal proximal tubule cells (LLC-PK1) than the InGaP QD on a molar basis, as determined by MTT assay (48 h IC(50) 10nM for CdSe vs. 100nM for InGaP). Neither of the QD species induced appreciable oxidative stress, as determined by lipid peroxide and reduced glutathione content, suggesting that toxicity was not metal associated. In agreement, treatment of cells with CdSe QDs was not associated with changes in metallothionein-IA (MT-IA) gene expression or Cd-associated caspase 3 enzyme activation. By contrast, incubation of the LLC-PK1 cells with the InGaP QD resulted in a dramatic increase in MT-IA expression by 21- and 43-fold, at 8 and 24 h, respectively. The most remarkable finding was evidence of extensive autophagy in QD-treated cells, as determined by Lysotracker Red dye uptake, TEM, and LC3 immunobloting. Autophagy induction has also been described for other nanomaterials and may represent a common cellular response. These data suggest that QD cytotoxicity is dependent upon properties of the particle as a whole, and not exclusively the metal core materials. C1 [Stern, Stephan T.; Zolnik, Banu S.; McLeland, Christopher B.; Clogston, Jeffery; Zheng, Jiwen; McNeil, Scott E.] NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Stern, ST (reprint author), NCI, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. EM sternstephan@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute; National Institutes of Health [N01-CO-12400] 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 N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 54 TC 115 Z9 121 U1 4 U2 49 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2008 VL 106 IS 1 BP 140 EP 152 DI 10.1093/toxsci/kfn137 PG 13 WC Toxicology SC Toxicology GA 359GU UT WOS:000259975200014 PM 18632727 ER PT J AU DeGiorgis, JA Petukhova, TA Evans, TA Reese, TS AF DeGiorgis, Joseph A. Petukhova, Tatyana A. Evans, Teresa A. Reese, Thomas S. TI Kinesin-3 is an Organelle Motor in the Squid Giant Axon SO TRAFFIC LA English DT Article DE antibody inhibition; axonal transport; Kinesin-1; Kinesin-3; organelle motility; squid giant axon; vesicle trafficking ID SYNAPTIC VESICLE TRANSPORT; MICROTUBULES; AXOPLASM; PROTEIN; MOVEMENT; ANTEROGRADE; DROSOPHILA; FILAMENTS; UNC-104; ELEGANS AB Conventional kinesin (Kinesin-1), the founding member of the kinesin family, was discovered in the squid giant axon, where it is thought to move organelles on microtubules. In this study, we identify a second squid kinesin by searching an expressed sequence tag database derived from the ganglia that give rise to the axon. The full-length open reading frame encodes a 1753 amino acid sequence that classifies this protein as a Kinesin-3. Immunoblots demonstrate that this kinesin, unlike Kinesin-1, is highly enriched in chaotropically stripped axoplasmic organelles, and immunogold electron microscopy (EM) demonstrates that Kinesin-3 is tightly bound to the surfaces of these organelles. Video microscopy shows that movements of purified organelles on microtubules are blocked, but organelles remain attached, in the presence Kinesin-3 antibody. Immunogold EM of axoplasmic spreads with antibody to Kinesin-3 decorates discrete sites on many, but not all, free organelles and localizes Kinesin-3 to organelle/microtubule interfaces. In contrast, label for Kinesin-1 decorates microtubules but not organelles. The presence of Kinesin-3 on purified organelles, the ability of an antibody to block their movements along microtubules, the tight association of Kinesin-3 with motile organelles and its distribution at the interface between native organelles and microtubules suggest that Kinesin-3 is a dominant motor in the axon for unidirectional movement of organelles along microtubules. C1 [DeGiorgis, Joseph A.; Petukhova, Tatyana A.; Evans, Teresa A.; Reese, Thomas S.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [DeGiorgis, Joseph A.; Petukhova, Tatyana A.; Evans, Teresa A.; Reese, Thomas S.] Marine Biol Lab, Woods Hole, MA 02543 USA. RP DeGiorgis, JA (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 49,Room 3A60,49 Convent Dr, Bethesda, MD 20892 USA. EM jdegiorg@providence.edu NR 31 TC 6 Z9 6 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 EI 1600-0854 J9 TRAFFIC JI Traffic PD NOV PY 2008 VL 9 IS 11 BP 1867 EP 1877 DI 10.1111/j.1600-0854.2008.00809.x PG 11 WC Cell Biology SC Cell Biology GA 359BR UT WOS:000259961700006 PM 18928504 ER PT J AU Joshi, A Munshi, U Ablan, SD Nagashima, K Freed, EO AF Joshi, Anjali Munshi, Utpal Ablan, Sherimay D. Nagashima, Kunio Freed, Eric O. TI Functional Replacement of a Retroviral Late Domain by Ubiquitin Fusion SO TRAFFIC LA English DT Article DE Alix; assembly and release; EIAV; Gag; retroviruses; Tsg101; ubiquitin ID IMMUNODEFICIENCY-VIRUS TYPE-1; INFECTIOUS-ANEMIA VIRUS; PROTEIN-SORTING PATHWAY; MURINE LEUKEMIA-VIRUS; YPXL LATE DOMAINS; PARTICLE RELEASE; ASSEMBLY DOMAIN; GAG; TSG101; HIV-1 AB Retroviral Gag polyprotein precursors are both necessary and sufficient for the assembly and release of virus-like particles (VLPs) from infected cells. It is well established that small Gag-encoded motifs, known as late domains, promote particle release by interacting with components of the cellular endosomal sorting and ubiquitination machinery. The Gag proteins of a number of different retroviruses are ubiquitinated; however, the role of Gag ubiquitination in particle egress remains undefined. In this study, we investigated this question by using a panel of equine infectious anemia virus (EIAV) Gag derivatives bearing the wild-type EIAV late domain, heterologous retroviral late domains or no late domain. Ubiquitin was fused in cis to the C-termini of these Gag polyproteins, and the effects on VLP budding were measured. Remarkably, fusion of ubiquitin to EIAV Gag lacking a late domain (EIAV/Delta YPDL-Ub) largely rescued VLP release. We also determined the effects of ubiquitin fusion on the sensitivity of particle release to budding inhibitors and to depletion of key endosomal sorting factors. Ubiquitin fusion rendered EIAV/Delta YPDL-Ub sensitive to depletion of cellular endosomal sorting factors Tsg101 and Alix and to overexpression of dominant-negative fragments of Tsg101 and Alix. These findings demonstrate that ubiquitin can functionally compensate for the absence of a retroviral late domain and provide insights into the host-cell machinery engaged by ubiquitin during particle egress. C1 [Joshi, Anjali; Munshi, Utpal; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Nagashima, Kunio] NCI, Image Anal Lab, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM efreed@nih.gov FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute; National Institutes of Health (NIH) [N01-CO-12400]; Intramural AIDS Targeted Antiviral Program FX We thank A. Ono and members of the Freed laboratory for helpful discussions and critical review of the manuscript and F. Soheilian for expert assistance with EM. We thank W. Sundquist for siRNA-resistant Tsg101 expression constructs, P. Woodman for the Vps4 expression vector, Z. Sun for TSG-5 ' and TSG-3 ' expression vectors and R. Montelaro for anti-EIAV Gag antiserum. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), and by the Intramural AIDS Targeted Antiviral Program and was funded in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400. NR 60 TC 36 Z9 37 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD NOV PY 2008 VL 9 IS 11 BP 1972 EP 1983 DI 10.1111/j.1600-0854.2008.00817.x PG 12 WC Cell Biology SC Cell Biology GA 359BR UT WOS:000259961700015 PM 18817521 ER PT J AU McCormick, PJ Dumaresq-Doiron, K Pluviose, AS Pichette, V Tosato, G Lefrancois, S AF McCormick, Peter J. Dumaresq-Doiron, Karine Pluviose, Anne-Sophie Pichette, Vincent Tosato, Giovanna Lefrancois, Stephane TI Palmitoylation Controls Recycling in Lysosomal Sorting and Trafficking SO TRAFFIC LA English DT Article DE endosomes; Golgi apparatus; lysosomal trafficking; palmitoylation; sortilin ID MANNOSE 6-PHOSPHATE RECEPTOR; FACTOR-II RECEPTOR; MAMMALIAN RETROMER; REQUIRES RETROMER; CYTOPLASMIC TAIL; PROTEIN COMPLEX; GOLGI MEMBRANES; COAT PROTEINS; BINDING; AP-1 AB For the efficient trafficking of lysosomal proteins, the cationic-dependent and -independent mannose 6-phosphate receptors and sortilin must bind cargo in the Golgi apparatus, be packaged into clathrin-coated trafficking vesicles and traffic to the endosomes. Once in the endosomes, the receptors release their cargo into the endosomal lumen and recycle back to the Golgi for another round of trafficking, a process that requires retromer. In this study, we demonstrate that palmitoylation is required for the efficient retrograde trafficking of sortilin, and the cationic-independent mannose 6-phosphate as palmitoylation-deficient receptors remain trapped in the endosomes. Importantly, we also show that palmitoylation is required for receptor interaction with retromer as nonpalmitoylated receptor did not interact with retromer. In addition, we have identified DHHC-15 as the palmitoyltransferase responsible for this modification. In summary, we have shown the functional significance of palmitoylation in lysosomal receptor sorting and trafficking. C1 [Dumaresq-Doiron, Karine; Pluviose, Anne-Sophie; Pichette, Vincent; Lefrancois, Stephane] Univ Montreal, Hop Maison Neuve Rosemont, Ctr Rech, Montreal, PQ H1T 2M4, Canada. [McCormick, Peter J.; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lefrancois, S (reprint author), Univ Montreal, Hop Maison Neuve Rosemont, Ctr Rech, Montreal, PQ H1T 2M4, Canada. EM stephane.lefrancois@umontreal.ca RI McCormick, Peter/E-7387-2012 OI McCormick, Peter/0000-0002-2225-5181 FU la Fondation de l'Hopital Maisonneuve-Rosemont; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX This work was funded by start-up funds to S.L. from la Fondation de l'Hopital Maisonneuve-Rosemont and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research to P.J.M. and G.T. We would like to thank E.B. Affar, J.B. McCormick and S. Fisher-Hoch for critical reading of this manuscript. We would also like to thank Dr M. Fukata (National Institute for Longevity Sciences, Japan) for providing us with the DHHC constructs that were confirmed to have palmitoyltransferase activity. NR 36 TC 42 Z9 44 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD NOV PY 2008 VL 9 IS 11 BP 1984 EP 1997 DI 10.1111/j.1600-0854.2008.00814.x PG 14 WC Cell Biology SC Cell Biology GA 359BR UT WOS:000259961700016 PM 18817523 ER PT J AU Kunkel, TA Burgers, PM AF Kunkel, Thomas A. Burgers, Peter M. TI Dividing the workload at a eukaryotic replication fork SO TRENDS IN CELL BIOLOGY LA English DT Review ID DNA-POLYMERASE-DELTA; CELL NUCLEAR ANTIGEN; XENOPUS EGG EXTRACTS; SACCHAROMYCES-CEREVISIAE; ACTIVE-SITE; CATALYTIC DOMAINS; MOTIF-A; S-PHASE; EPSILON; FIDELITY AB Efficient and accurate replication of the eukaryotic nuclear genome requires DNA polymerases (Pols) alpha, delta and epsilon. In all current replication fork models, polymerase a initiates replication. However, several models have been proposed for the roles of Poll 8 and Pol epsilon in subsequent chain elongation and the division of labor between these two polymerases is still unclear. Here, we revisit this issue, considering recent studies with diagnostic mutator polymerases that support a model wherein Poll epsilon is primarily responsible for copying the leading-strand template and Pol 8 is primarily responsible for copying the lagging-strand template. We also review earlier studies in light of this model and then consider prospects for future investigations of possible variations on this simple division of labor. C1 [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Burgers, Peter M.] Washington Univ, Sch Med, Dept Biochem, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU National Institutes of Health [GM032431]; Intramural Research Program of the NIH; National Institute of Environmental Health Sciences FX The authors thank Stephanie A. Nick McElhinny for help in preparing Figure I and Stephanie A. Nick McElhinny and Zachary Pursell for thoughtful comments on the manuscript. The research conducted by the authors was supported, in part, by National Institutes of Health Grant GM032431 to P.M.B. and, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to T.A.K. NR 45 TC 159 Z9 159 U1 1 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD NOV PY 2008 VL 18 IS 11 BP 521 EP 527 DI 10.1016/i.tcb.2008.08.005 PG 7 WC Cell Biology SC Cell Biology GA 374WM UT WOS:000261074400002 PM 18824354 ER PT J AU Gross, KL Cidlowski, JA AF Gross, Katherine L. Cidlowski, John A. TI Tissue-specific glucocorticoid action: a family affair SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; ACUTE LYMPHOBLASTIC-LEUKEMIA; CORONARY-ARTERY-DISEASE; RECEPTOR-BETA-ISOFORM; FACTOR-KAPPA-B; ADIPOSE-TISSUE; IN-VITRO; ER22/23EK POLYMORPHISM; GENE POLYMORPHISMS; OBESE-PATIENTS AB Glucocorticoids exert a wide variety of physiological and pathological responses, most of which are mediated by the ubiquitously expressed glucocorticoid receptor (GR). The glucocorticoid response varies among individuals, as well as within tissues from the same individual, and this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of GR. This review focuses on the recent advances in our understanding of prereceptor ligand metabolism, GR subtypes and GR polymorphisms. Furthermore, we evaluate the impact of tissue- and individual-specific diversity in the glucocorticoid pathway on human health and disease. C1 [Gross, Katherine L.; Cidlowski, John A.] Natl Inst Environm Hlth Sci, Mol Endocrinol Grp, Lab Signal Transduct, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), Natl Inst Environm Hlth Sci, Mol Endocrinol Grp, Lab Signal Transduct, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIH; National Institute of Environmental Health Sciences FX We thank Robert H. Oakley and Christine M. Jewell for their helpful comments and discussion concerning this manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 78 TC 84 Z9 92 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD NOV PY 2008 VL 19 IS 9 BP 331 EP 339 DI 10.1016/j.tem.2008.07.009 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 373BC UT WOS:000260945000004 PM 18805703 ER PT J AU Basu, MK Rogozin, IB Koonin, EV AF Basu, Malay Kumar Rogozin, Igor B. Koonin, Eugene V. TI Primordial spliceosomal introns were probably U2-type SO TRENDS IN GENETICS LA English DT Article ID MINOR CLASS; SITES; U12; EUKARYOTES; SEQUENCES; ORIGIN AB The two types of eukaryotic spliceosomall introns, U2 and U12, possess different splice signals and are excised by distinct spliceosomes. The nature of the primordial introns remains uncertain. A comparison of the amino acid distributions at insertion sites of introns that retained their positions throughout eukaryotic evolution with the distributions for human and Arabidopsis thaliana U2 and U12 introns reveals close similarity with U2 but not U12. Thus, the primordial spliceosomall introns were, most likely, U2-type. C1 [Basu, Malay Kumar; Rogozin, Igor B.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU National Library of Medicine at the National Institutes of Health FX We thank Ravi Sachidanandam for providing the dump of the SpliceRack (http://k-atahdin.cshl.edu:9331/SpliceRack) dababase. The authors' research is supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health. NR 21 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD NOV PY 2008 VL 24 IS 11 BP 525 EP 528 DI 10.1016/j.tig.2008.09.002 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 381KB UT WOS:000261533700001 PM 18824272 ER PT J AU Belyakov, IM Ahlers, JD AF Belyakov, Igor M. Ahlers, Jeffrey D. TI Functional CD8(+) CTLs in mucosal sites and HIV infection: moving forward toward a mucosal AIDS vaccine SO TRENDS IN IMMUNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; NEUTRALIZING MONOCLONAL-ANTIBODIES; DENDRITIC CELLS; HIGH-AVIDITY; LYMPHOID-TISSUE; ANTIRETROVIRAL THERAPY; TYPE-1 INFECTION; EPITHELIAL-CELLS; RHESUS MACAQUES AB The gastrointestinal and vaginal mucosa are the major routes of natural HIV transmission, with the former being the primary reservoir for virus replication. The crucial need for a global HIV vaccine underscores the effort to develop vaccines capable of eliciting mucosal immune responses. Vaccines that induce high levels of effective mucosal immunity should impact viral replication rate and prevent dissemination of virus from the mucosa into the systemic circulation. In our opinion, the major effort for effective HIV vaccine should be concentrated on generating protective immunity at the site of viral entry (i.e. the gastrointestinal and vaginal mucosae). Here we examine the current information regarding the role of mucosal immunity in prevention of HIV transmission and discuss strategies for mucosal AIDS vaccine development. C1 [Belyakov, Igor M.] Midwest Res Inst, Frederick, MD 21702 USA. [Ahlers, Jeffrey D.] NIAID, Div Aids, NIH, Rockville, MD 20817 USA. RP Belyakov, IM (reprint author), Midwest Res Inst, Frederick, MD 21702 USA. EM ibelyakov@mriresearch.org NR 111 TC 27 Z9 31 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD NOV PY 2008 VL 29 IS 11 BP 574 EP 585 DI 10.1016/j.it.2008.07.010 PG 12 WC Immunology SC Immunology GA 374LM UT WOS:000261044900010 PM 18838298 ER PT J AU Schlander, M Schwarz, O Hakkaart-Van, RL Jensen, PS Persson, U Santosh, PJ Trott, GE AF Schlander, M. Schwarz, O. Hakkaart-van, Roijen L. Jensen, P. S. Persson, U. Santosh, P. J. Trott, G. E. CA MTA Cooperative Grp TI HOW MUCH SHOULD WE BE PREPARED TO PAY FOR PSYCHOSOCIAL INTERVENTIONS FOR PATIENTS WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)? SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Schlander, M.; Schwarz, O.] InnoVal HC, Eschborn, Germany. [Hakkaart-van, Roijen L.] Erasmus MC, Rotterdam, Netherlands. [Jensen, P. S.] Columbia Univ, New York, NY USA. [Persson, U.] Swedish Inst Hlth Econ, Lund, Sweden. [Santosh, P. J.] Great Ormond St Hosp Sick Children, Inst Child Hlth, London, England. [Trott, G. E.] Univ Wurzburg, Aschaffenburg, Germany. [MTA Cooperative Grp] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD NOV PY 2008 VL 11 IS 6 BP A339 EP A339 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 360JV UT WOS:000260054700013 ER PT J AU Patient, R Hourioux, C Roingeard, P AF Patient, R. Hourioux, C. Roingeard, P. TI Morphogenesis of the hepatitis B virus SO VIROLOGIE LA French DT Review DE hepatitis B; virion; envelope particle; morphogenesis ID SURFACE-ANTIGEN PARTICLES; SMALL ENVELOPE PROTEIN; HEPATOMA-CELL LINE; CAPSID PARTICLES; CORE-PROTEIN; S-DOMAIN; HBV-DNA; SECRETION; REPLICATION; INFECTION AB The human hepatitis B virus (HBV) is a small hepatotropic enveloped virus associated with chronic infection that can lead to cirrhosis and hepatocellular carcinoma. The HBV genome is a DNA molecule contained in an icosahedral capsid. Although HBV is not a retrovirus, the replication of its genome involves reverse transcription. Another distinctive feature of HBV is the production, in great excess over virions, of non-infectious subviral particles (SVP) consisting of membrane phospholipids and the three envelope proteins (small [S], medium [M] and large [L]). These empty non-infectious particles are highly immunogenic, and their in vitro production is at the basis of the current vaccine against hepatitis B. Despite numerous studies that lead to a better understanding of the HBV replication, little is known about the morphogenesis of the virion and its associated SVP. Recent approaches suggest that the mechanisms responsable for assembly of the virions and the SVP could be distinct. C1 [Patient, R.; Hourioux, C.; Roingeard, P.] Univ Tours, INSERM, U966, Tours, France. RP Patient, R (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM patientr@niddk.nih.gov NR 57 TC 0 Z9 0 U1 1 U2 1 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 1267-8694 J9 VIROLOGIE JI Virologie PD NOV-DEC PY 2008 VL 12 IS 6 BP 453 EP 464 DI 10.1684/vir.2008.0214 PG 12 WC Virology SC Virology GA 411SB UT WOS:000263669600006 ER PT J AU Kumar, S Nayak, B Collins, PL Samal, SK AF Kumar, Sachin Nayak, Baibaswata Collins, Peter L. Samal, Siba K. TI Complete genome sequence of avian paramyxovirus type 3 reveals an unusually long trailer region SO VIRUS RESEARCH LA English DT Article DE Avian paramyxovirus (APMV); Paramyxoviridae; Paramyxovirinae; Genome sequence ID NEWCASTLE-DISEASE VIRUS; COMPLETE NUCLEOTIDE-SEQUENCE; SUBFAMILY PARAMYXOVIRINAE; FAMILY PARAMYXOVIRIDAE; RNA REPLICATION; MATRIX PROTEIN; GREAT-BRITAIN; HENDRA VIRUS; V-PROTEIN; STRAIN AB The complete genome sequence was determined for prototype parakeet/Netherlands/449/75 strain of avian paramyxovirus (APMV) serotype 3. The genome is 16,272 nucleotides (nt) in length, consisting of six non-overlapping genes in the order of 3'-N-P/V/W-M-F-HN-L-5', with intergenic regions of 31-63 nt. APMV-3 genome follows the "rule of six" and is the largest among the avian paramyxoviruses reported to date, with a trailer region of 707 nt, the longest in the family Paramyxoviridae. The cleavage site of F protein, A-R-P-R-G-R L, does not conform to the preferred cleavage site of the ubiquitous cellular protease furin. Therefore, exogenous protease was needed for replication in vitro. Alignment and phylogenetic analysis of the predicted amino acid sequences of strain Netherlands proteins with the cognate proteins of viruses of all of the five genera of family Paramyxoviridae showed that APMV-3 strain Netherlands is more closely related to APMV-1 than APMV-6. (c) 2008 Elsevier B.V. All rights reserved. C1 [Kumar, Sachin; Nayak, Baibaswata; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU MAID [N01A060009]; NIH FX We thank Daniel Rockemann and all our laboratory members for their excellent technical assistance and help. We also thank Hamp Edwards for performing electron microscopy and Ireen Dryburgh-Barry for proofreading the manuscript. "This research was supported by MAID contract no. N01A060009 (85% support) and MAID, NIH Intramural Research Program (15% support). The views expressed herein neither necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government." NR 43 TC 39 Z9 39 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD NOV PY 2008 VL 137 IS 2 BP 189 EP 197 DI 10.1016/j.virusres.2008.07.012 PG 9 WC Virology SC Virology GA 374ML UT WOS:000261047600003 PM 18691616 ER PT J AU Duggal, P Gillanders, EM Holmes, TN Bailey-Wilson, JE AF Duggal, Priya Gillanders, Elizabeth M. Holmes, Taura N. Bailey-Wilson, Joan E. TI Establishing an adjusted p-value threshold to control the family-wide type 1 error in genome wide association studies SO BMC GENOMICS LA English DT Article ID HAPLOTYPE BLOCKS; COMPLEX TRAITS; RECOMBINATION; LINKAGE; HISTORY; LOCI; MAP AB Background: By assaying hundreds of thousands of single nucleotide polymorphisms, genome wide association studies (GWAS) allow for a powerful, unbiased review of the entire genome to localize common genetic variants that influence health and disease. Although it is widely recognized that some correction for multiple testing is necessary, in order to control the family-wide Type 1 Error in genetic association studies, it is not clear which method to utilize. One simple approach is to perform a Bonferroni correction using all n single nucleotide polymorphisms (SNPs) across the genome; however this approach is highly conservative and would "overcorrect" for SNPs that are not truly independent. Many SNPs fall within regions of strong linkage disequilibrium (LD) ("blocks") and should not be considered "independent". Results: We proposed to approximate the number of "independent" SNPs by counting 1 SNP per LD block, plus all SNPs outside of blocks (interblock SNPs). We examined the effective number of independent SNPs for Genome Wide Association Study (GWAS) panels. In the CEPH Utah (CEU) population, by considering the interdependence of SNPs, we could reduce the total number of effective tests within the Affymetrix and Illumina SNP panels from 500,000 and 317,000 to 67,000 and 82,000 "independent" SNPs, respectively. For the Affymetrix 500 K and Illumina 317 K GWAS SNP panels we recommend using 10(-5), 10(-7) and 10(-8) and for the Phase II HapMap CEPH Utah and Yoruba populations we recommend using 10(-6), 10(-7) and 10(-9) as "suggestive", "significant" and "highly significant" p-value thresholds to properly control the family-wide Type 1 error. Conclusion: By approximating the effective number of independent SNPs across the genome we are able to 'correct' for a more accurate number of tests and therefore develop 'LD adjusted' Bonferroni corrected p-value thresholds that account for the interdepdendence of SNPs on well-utilized commercially available SNP "chips". These thresholds will serve as guides to researchers trying to decide which regions of the genome should be studied further. C1 [Duggal, Priya; Gillanders, Elizabeth M.; Holmes, Taura N.; Bailey-Wilson, Joan E.] NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Duggal, P (reprint author), NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. EM pduggal@mail.nih.gov; lgilland@mail.nih.gov; tnholmes@mail.nih.gov; tnholmes@mail.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural Program at the National Human Genome Research Institute, National Institutes of Health; NHGRI's Bioinformatics; Scientific Programming Core FX We would like to acknowledge the programming support of NHGRI's Bioinformatics and Scientific Programming Core. Specifically we would like to recognize Suiyuan Zhang. NR 18 TC 75 Z9 76 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 31 PY 2008 VL 9 AR 516 DI 10.1186/1471-2164-9-516 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 403UI UT WOS:000263107100002 PM 18976480 ER PT J AU Wainberg, MA Jeang, KT AF Wainberg, Mark A. Jeang, Kuan-Teh TI 25 years of HIV-1 research - progress and perspectives SO BMC MEDICINE LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; PROTEIN BINDS; TAT PROTEIN; VIF PROTEIN; VIRAL LOAD; CYCLIN T1; INFECTION; RNA; TYPE-1 AB Twenty-five years after the discovery and isolation of the human immunodeficiency virus by French and American scientists, much progress has been made in basic research, clinical treatment, and public health prevention measures for acquired immunodeficiency syndrome. Here, we summarize, in brief, advances that have been achieved and provide some perspectives on future challenges. C1 [Jeang, Kuan-Teh] NIAID, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. [Wainberg, Mark A.] McGill Univ, Jewish Gen Hosp, AIDS Ctr, Montreal, PQ H3T 1E2, Canada. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. EM mark.wainberg@mcgill.ca; kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 FU Intramural NIH HHS NR 54 TC 28 Z9 32 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 31 PY 2008 VL 6 AR 31 DI 10.1186/1741-7015-6-31 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 378JS UT WOS:000261317600001 PM 18976462 ER PT J AU Reilly, KM Van Dyke, T AF Reilly, Karlyne M. Van Dyke, Terry TI It Takes a (Dysfunctional) Village to Raise a Tumor SO CELL LA English DT Editorial Material ID MICROENVIRONMENT; CANCER AB The tumor microenvironment is known to play an important role in tumorigenesis. In this issue, Yang et al. ( 2008) demonstrate that mast cells heterozygous for the Nf1 gene promote the growth of neurofibromas in a mouse model of neurofibromatosis and that genetic and pharmacological inhibition of these cells is sufficient to block tumor growth. C1 [Reilly, Karlyne M.; Van Dyke, Terry] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Van Dyke, Terry] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. RP Reilly, KM (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM kreilly@ncifcrf.gov; vandyket@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 6 TC 5 Z9 5 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 31 PY 2008 VL 135 IS 3 BP 408 EP 410 DI 10.1016/j.cell.2008.10.009 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 367EW UT WOS:000260536300009 PM 18984150 ER PT J AU Chou, YF Chen, HH Eijpe, M Yabuuchi, A Chenoweth, JG Tesar, P Lu, J McKay, RDG Geijsen, N AF Chou, Yu-Fen Chen, Hsu-Hsin Eijpe, Maureen Yabuuchi, Akiko Chenoweth, Joshua G. Tesar, Paul Lu, Jun Mckay, Ronald D. G. Geijsen, Niels TI The Growth Factor Environment Defines Distinct Pluripotent Ground States in Novel Blastocyst-Derived Stem Cells SO CELL LA English DT Article ID PRIMORDIAL GERM-CELLS; HUMAN SOMATIC-CELLS; E-CADHERIN; REGULATORY CIRCUITRY; MOUSE EMBRYOS; SELF-RENEWAL; FREE CULTURE; ES CELLS; LINES; DIFFERENTIATION AB Pluripotent stem cell lines can be derived from blastocyst embryos, which yield embryonic stem cell lines (ES cells), as well as the postimplantation epiblast, which gives rise to epiblast stem cell lines (EpiSCs). Remarkably, ES cells and EpiSCs display profound differences in the combination of growth factors that maintain their pluripotent state. Molecular and functional differences between these two stem cell types demonstrate that the tissue of origin and/or the growth factor milieu may be important determinants of the stem cell identity. We explored how developmental stage of the tissue of origin and culture growth factor conditions affect the stem cell pluripotent state. Our findings indicate that novel stem cell lines, with unique functional and molecular properties, can be generated from murine blastocyst embryos. We demonstrate that the culture growth factor environment and cell-cell interaction play a critical role in defining several unique and stable stem cell ground states. C1 [Chou, Yu-Fen; Chen, Hsu-Hsin; Geijsen, Niels] Massachusetts Gen Hosp, Harvard Stem Cell Inst, Ctr Regenerat Med, Boston, MA 02114 USA. [Eijpe, Maureen] Erasmus MC, Dept Cell Biol, NL-3015 GE Rotterdam, Netherlands. [Yabuuchi, Akiko] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Chenoweth, Joshua G.; Mckay, Ronald D. G.] Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Tesar, Paul] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Lu, Jun] Harvard Univ, Broad Inst, Cambridge, MA 02141 USA. [Lu, Jun] MIT, Cambridge, MA 02141 USA. RP Geijsen, N (reprint author), Massachusetts Gen Hosp, Harvard Stem Cell Inst, Ctr Regenerat Med, CPZN-4256,185 Cambridge St, Boston, MA 02114 USA. EM ngeijsen@mgh.harvard.edu RI Tesar, Paul/C-9848-2014 OI Tesar, Paul/0000-0003-1532-3155 FU National Institutes of Health [RO1HD048769-01A1]; Harvard Stem Cell Institute; Dutch Cancer Society (Koningin Wilhelmina Fonds) FX The authors thank Dr. George Daley for his review of our manuscript and help with the blastocyst injections; Dr. Paul Tesar for the EpiSC image; Dr. Roger Tsien for the use of the tdTomato fluorescent reporter; Dr. Keith Orford for critical review of the manuscript; Kelly Shea for providing technical support; and Laura Prickett and Kat Folz-Donahue at the HSCI/MGH Flow Cytometry Core Facility for help with cell purifications. This work was supported by grants from the National Institutes of Health (RO1HD048769-01A1) and the Harvard Stem Cell Institute. M. E. was supported by the Dutch Cancer Society (Koningin Wilhelmina Fonds). NR 56 TC 148 Z9 155 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 31 PY 2008 VL 135 IS 3 BP 449 EP 461 DI 10.1016/j.cell.2008.08.035 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 367EW UT WOS:000260536300016 PM 18984157 ER PT J AU Cui, YJ Costa, RM Murphy, GG Elgersma, Y Zhu, Y Gutmann, DH Parada, LF Mody, I Silva, AJ AF Cui, Yijun Costa, Rui M. Murphy, Geoffrey G. Elgersma, Ype Zhu, Yuan Gutmann, David H. Parada, Luis F. Mody, Istvan Silva, Alcino J. TI Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning SO CELL LA English DT Article ID LONG-TERM POTENTIATION; MORRIS WATER MAZE; ACTIVATED PROTEIN-KINASE; MOUSE MODEL; SYNAPTIC PLASTICITY; DOWN-SYNDROME; MEMORY; TYPE-1; DEFICITS; RATS AB We uncovered a role for ERK signaling in GABA release, long-term potentiation (LTP), and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for learning disabilities in neurofibromatosis type I (NF1). Our results demonstrate that neurofibromin modulates ERK/synapsin I-dependent GABA release, which in turn modulates hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased GABA release in the hippocampus, and this was reversed by pharmacological downregulation of ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a subthreshold dose of a GABAA antagonist. Accordingly, Cre deletions of Nf1 showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP, and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning. C1 [Cui, Yijun; Costa, Rui M.; Murphy, Geoffrey G.; Elgersma, Ype; Silva, Alcino J.] Univ Calif Los Angeles, Brain Res Inst, Dept Neurobiol, Los Angeles, CA 90095 USA. [Cui, Yijun; Costa, Rui M.; Murphy, Geoffrey G.; Elgersma, Ype; Silva, Alcino J.] Univ Calif Los Angeles, Brain Res Inst, Dept Psychiat, Los Angeles, CA 90095 USA. [Cui, Yijun; Costa, Rui M.; Murphy, Geoffrey G.; Elgersma, Ype; Silva, Alcino J.] Univ Calif Los Angeles, Brain Res Inst, Dept Psychol, Los Angeles, CA 90095 USA. [Costa, Rui M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20852 USA. [Murphy, Geoffrey G.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Elgersma, Ype] Erasmus MC, Dept Neurosci, NL-3000 CA Rotterdam, Netherlands. [Zhu, Yuan] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Zhu, Yuan] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Gutmann, David H.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Parada, Luis F.] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75235 USA. [Mody, Istvan] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. RP Silva, AJ (reprint author), Univ Calif Los Angeles, Brain Res Inst, Dept Neurobiol, Los Angeles, CA 90095 USA. EM silvaa@mednet.ucla.edu RI Parada, luis/B-9400-2014; OI Silva, Alcino/0000-0001-5525-0494; Costa, Rui/0000-0003-0495-8374 FU NIH [R01 NS38480]; Neurofibromatosis Inc.; Children's Tumor Foundation; United States Army [W81XWH-06-1-0174]; Coelho Endowment [NS30549] FX This work was supported by grants from the NIH (R01 NS38480), Neurofibromatosis Inc., the Children's Tumor Foundation, and United States Army (W81XWH-06-1-0174) to A.J.S. and NS30549 and the Coelho Endowment to I. M. This work was also supported by a generous donation from C. M. Spivak to A. J.S.Y.C. was supported by a fellowship from the Children's Tumor Foundation. We thank P. Greengard and J.N. Jovanovic for the generous gift of the phospho-Syn I antibodies. We are grateful to Steven Kushner, Brandon M. Stell, and Weizheng Wei for fruitful discussions. NR 43 TC 173 Z9 179 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 31 PY 2008 VL 135 IS 3 BP 549 EP 560 DI 10.1016/j.cell.2008.09.060 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 367EW UT WOS:000260536300024 PM 18984165 ER PT J AU Regard, JB Sato, IT Coughlin, SR AF Regard, Jean B. Sato, Isaac T. Coughlin, Shaun R. TI Anatomical Profiling of G Protein-Coupled Receptor Expression SO CELL LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NICOTINIC-ACID; FUNCTIONAL EXPRESSION; CHEMOKINE RECEPTOR; MICE LACKING; MOLECULAR-IDENTIFICATION; SACCHAROMYCES-CEREVISIAE; PARATHYROID-HORMONE; GABA(B) RECEPTOR; LYMPHOID ORGANS AB G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane signaling molecules and regulate a host of physiological and disease processes. To better understand the functions of GPCRs in vivo, we quantified transcript levels of 353 nonodorant GPCRs in 41 adult mouse tissues. Cluster analysis placed many GPCRs into anticipated anatomical and functional groups and predicted previously unidentified roles for less-studied receptors. From one such prediction, we showed that the Gpr91 ligand succinate can regulate lipolysis in white adipose tissue, suggesting that signaling by this citric acid cycle intermediate may regulate energy homeostasis. We also showed that pairwise analysis of GPCR expression across tissues may help predict drug side effects. This resource will aid studies to understand GPCR function in vivo and may assist in the identification of therapeutic targets. C1 [Regard, Jean B.; Sato, Isaac T.; Coughlin, Shaun R.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. RP Regard, JB (reprint author), NHGRI, NIH, Bldg 49,Room 4C60,49 Convent Dr,MSC 4472, Bethesda, MD 20892 USA. EM regardj@mail.nih.gov; shaun.coughlin@ucsf.edu FU National Institutes of Health; Sandler Family Foundation FX We thank the Coughlin lab for valuable discussions, Ivo Cornelissen, Gerard Honig, and Grant Li, for technical assistance in isolating mouse tissues, and Stuart Peirson for sharing qPCR efficiency transformations. We also thank Dale Webster and Joseph Derisi for help with informatics, Silvio Gutkind for providing the Adrb2 construct, and Bryan Roth for critical reading of the manuscript. This work was supported by the National Institutes of Health (S.R.C.) and Sandler Family Foundation (J.B.R.). NR 94 TC 195 Z9 200 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 31 PY 2008 VL 135 IS 3 BP 561 EP 571 DI 10.1016/j.cell.2008.08.040 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 367EW UT WOS:000260536300025 PM 18984166 ER PT J AU Cha, SW Lee, JW Hwang, YS Chae, JP Park, KM Cho, HJ Kim, DS Bae, YC Park, MJ AF Cha, Sang-wook Lee, Jong-Woo Hwang, Yoo-Seok Chae, Jeong-Pil Park, Kwon Moo Cho, Hee Jung Kim, Dong Sun Bae, Yong Chul Park, Mae Ja TI Spatiotemporal regulation of fibroblast growth factor signal blocking for endoderm formation in Xenopus laevis SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE embryonic development; endoderm; fibroblast growth factors; SU 5402; Xenopus ID MESODERM INDUCTION; CELL FATE; VERTEBRATE DEVELOPMENT; FGF; SPECIFICATION; VEGT; INHIBITION; COMPETENCE; ORGANIZER; BLASTULA AB We have previously shown that the inhibition of fibroblast growth factor (FGF) signaling induced endodermal gene expression in the animal cap and caused the expansion of the endodermal mass in Xenopus embryos. However, we still do not know whether or not the alteration of FGF signaling controls embryonic cell fate, or when FGF signal blocking is required for endoderm formation in Xenopus. Here, we show that FGF signal blocking in embryonic cells causes their descendants to move into the endodermal region and to express endodermal genes. It is also interesting that blocking FGF signaling between fertilization and embryonic stage 10.5 promotes endoderm formation, but persistent FGF signaling blocking after stage 10.5 restricts endoderm formation and differentiation. C1 [Cha, Sang-wook; Chae, Jeong-Pil; Park, Kwon Moo; Cho, Hee Jung; Kim, Dong Sun; Park, Mae Ja] Kyungpook Natl Univ, Sch Med, Dept Anat, Taegu 700412, South Korea. [Bae, Yong Chul] Kyungpook Natl Univ, Sch Dent, Dept Oral Anat, Taegu 700412, South Korea. [Lee, Jong-Woo] Gumi Cha Hosp, Dept Urol, Gumi 730728, South Korea. [Hwang, Yoo-Seok] NICHD, NIH, Mol Genet Lab, Bethesda, MD USA. RP Park, MJ (reprint author), Kyungpook Natl Univ, Sch Med, Dept Anat, Taegu 700412, South Korea. EM mjpark@knu.ac.kr FU Korean Government (MOEHRD) [R04-2004-000-10120-0, KRF: E00032]; Brain Korea 21 Project FX This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (R04-2004-000-10120-0, KRF: E00032) and by the Brain Korea 21 Project in 2006 (Sang-wook Cha). NR 26 TC 1 Z9 1 U1 0 U2 0 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD OCT 31 PY 2008 VL 40 IS 5 BP 550 EP 557 DI 10.3858/emm.2008.40.5.550 PG 8 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 370VJ UT WOS:000260790900009 PM 18985013 ER PT J AU Cabib, E Farkas, V Kosik, O Blanco, N Arroyo, J McPhie, P AF Cabib, Enrico Farkas, Vladimir Kosik, Ondrej Blanco, Noelia Arroyo, Javier McPhie, Peter TI Assembly of the Yeast Cell Wall Crh1p AND Crh2p ACT AS TRANSGLYCOSYLASES IN VIVO AND IN VITRO SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CHITIN; PROTEINS; POROSITY; BETA-1,6-GLUCAN; ENDOCHITINASE; BIOSYNTHESIS; LOCALIZATION; PURIFICATION; ARCHITECTURE AB The cross-linking of polysaccharides to assemble new cell wall in fungi requires mechanisms by which a preexisting linkage is broken for each new one made, to allow for the absence of free energy sources outside the plasma membrane. Previous work showed that Crh1p and Crh2p, putative transglycosylases, are required for the linkage of chitin to beta(1-3) glucose branches of beta(1-6) glucan in the cell wall of budding yeast. To explore the linking reaction in vivo and in vitro, we used fluorescent sulfor-hodamine-linked laminari-oligosaccharides as artificial chitin acceptors. In vivo, fluorescence was detected in bud scars and at a lower level in the cell contour, both being dependent on the CRH genes. The linking reaction was also shown in digitonin-permeabilized cells, with UDP-N-acetylglucosamine as the substrate for nascent chitin production. Both the nucleotide and the Crh proteins were required here. A gas1 mutant that overexpresses Crh1p showed very high fluorescence both in intact and permeabilized cells. In the latter, fluorescence was still incorporated in patches in the absence of UDP-GlcNAc. Isolated cell walls of this strain, when incubated with sulforhodamine-oligosaccharide, also showed Crhp-dependent fluorescence in patches, which were identified as bud scars. In all three systems, binding of the fluorescent material to chitin was verified by chitinase digestion. Moreover, the cell wall reaction was inhibited by chitooligosaccharides. These results demonstrate that the Crh proteins act by transferring chitin chains to beta(1-6) glucan, with a newly observed high activity in the bud scar. The importance of transglycosylation for cell wall assembly is thus firmly established. C1 [Cabib, Enrico; McPhie, Peter] NIDDK, Lab Biochem & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Farkas, Vladimir; Kosik, Ondrej] Slovak Acad Sci, Ctr Excellence GLYCOBIOS, Inst Chem, Bratislava 84538, Slovakia. [Blanco, Noelia; Arroyo, Javier] Univ Complutense Madrid, Fac Farm, Dept Microbiol 2, E-28040 Madrid, Spain. RP Cabib, E (reprint author), NIDDK, Lab Biochem & Genet, NIH, Dept Hlth & Human Serv, Bldg 8,Rm 403, Bethesda, MD 20892 USA. EM enricoc@bdg10.niddk.nih.gov RI Arroyo, Javier/E-9308-2016; OI Arroyo, Javier/0000-0002-1971-1721; Farkas, Vladimir/0000-0002-8219-4288 FU National Institutes of Health; European Commission [MRTN-CT-2004-512265]; Scientific Grant Agency VEGA, Slovakia [2/3158/25]; MEC (Spanish Government) [BIO2007-67821]; Comunidad de Madrid [S-SAL-0246/2006] FX This work was supported, in whole or in part, by a National Institutes of Health grant (Intramural Research Program, NIDDK). This work was also supported by Grant MRTN-CT-2004-512265 from the 6FP of the European Commission, by Grant 2/3158/25 from the Scientific Grant Agency VEGA, Slovakia, and by Projects BIO2007-67821 from the MEC (Spanish Government) and S-SAL-0246/2006 from Comunidad de Madrid. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 40 TC 49 Z9 49 U1 3 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 31 PY 2008 VL 283 IS 44 BP 29859 EP 29872 DI 10.1074/jbc.M804274200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 364WS UT WOS:000260366900030 PM 18694928 ER PT J AU Gavard, J Gutkind, JS AF Gavard, Julie Gutkind, J. Silvio TI Protein Kinase C-related Kinase and ROCK Are Required for Thrombin-induced Endothelial Cell Permeability Downstream from G alpha(12/13) and G alpha(11/q) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; LEUKEMIA-ASSOCIATED RHO; VE-CADHERIN; TYROSINE PHOSPHORYLATION; DEPENDENT ENDOCYTOSIS; VASCULAR-PERMEABILITY; ACTIN CYTOSKELETON; MYOSIN PHOSPHATASE; BARRIER FUNCTION; P115 RHOGEF AB Increase in vascular permeability occurs under many physiological conditions such as wound repair, inflammation, and thrombotic reactions and is central in diverse human pathologies, including tumor-induced angiogenesis, ocular diseases, and septic shock. Thrombin is a pro-coagulant serine protease, which causes the local loss of endothelial barrier integrity thereby enabling the rapid extravasation of plasma proteins and the local formation of fibrin-containing clots. Available information suggests that thrombin induces endothelial permeability by promoting actomyosin contractility through the Rho/ROCK signaling pathway. Here we took advantage of pharmacological inhibitors, knockdown approaches, and the emerging knowledge on how permeability factors affect endothelial junctions to investigate in detail the mechanism underlying thrombin-induced endothelial permeability. We show that thrombin signals through PAR-1 and its coupled G proteins G alpha(12/13) and G alpha(11/q) to induce RhoA activation and intracellular calcium elevation, and that these events are interrelated. In turn, this leads to the stimulation of ROCK, which causes actin stress-fiber formation. However, this alone is not sufficient to account for thrombin-induced permeability. Instead, we found that protein kinase C-related kinase, a Rho-dependent serine/threonine kinase, is activated in endothelial cells upon thrombin stimulation and that its expression is required for endothelial permeability and the remodeling of cell-extracellular matrix and cell-cell adhesions. Our results demonstrate that the signal initiated by thrombin bifurcates at the level of RhoA to promote changes in the cytoskeletal architecture through ROCK, and the remodeling of focal adhesion components through protein kinase C-related kinase. Ultimately, both pathways converge to cause cell-cell junction disruption and provoke vascular leakage. C1 [Gavard, Julie; Gutkind, J. Silvio] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gavard, J (reprint author), Univ Paris 05, CNRS, INSERM,U567, Inst Cochin,UMR8104, 22 Rue Mechain, F-75014 Paris, France. EM julie.gavard@inserm.fr RI Gutkind, J. Silvio/A-1053-2009; Gavard, Julie/I-5487-2012 OI Gavard, Julie/0000-0002-7985-9007 FU National Institutes of Health; CNRS; INSERM FX This work was supported, in whole or in part, by National Institutes of Health grant (Intramural Research Program of NIDCR). This work was also supported by CNRS and INSERM. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 59 TC 49 Z9 50 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 31 PY 2008 VL 283 IS 44 BP 29888 EP 29896 DI 10.1074/jbc.M803880200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 364WS UT WOS:000260366900033 PM 18713748 ER PT J AU Ehteshami, M Scarth, BJ Tchesnokov, EP Dash, C Le Grice, SFJ Hallenberger, S Jochmans, D Gotte, M AF Ehteshami, Maryam Scarth, Brian J. Tchesnokov, Egor P. Dash, Chandravanu Le Grice, Stuart F. J. Hallenberger, Sabine Jochmans, Dirk Goette, Matthias TI Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against "Nucleotide-competing Reverse Transcriptase Inhibitors" SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYMERASE TRANSLOCATION; DRUG-RESISTANCE; RT INHIBITORS; DNA-SYNTHESIS; SUBSTITUTIONS; MECHANISM; ABACAVIR; SUSCEPTIBILITY; REPLICATION; APHIDICOLIN AB Indolopyridones are potent inhibitors of reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1). Although the structure of these compounds differs from established nucleoside analogue RT inhibitors (NRTIs), previous studies suggest that the prototype compound INDOPY-1 may bind in close proximity to the polymerase active site. NRTI-associated mutations that are clustered around the active site confer decreased, e. g. M184V and Y115F, or increased, e. g. K65R, susceptibility to INDOPY-1. Here we have studied the underlying biochemical mechanism. RT enzymes containing the isolated mutations M184V and Y115F cause 2-3-fold increases in IC50 values, while the combination of the two mutations causes a > 15-fold increase. K65R can partially counteract these effects. Binding studies revealed that the M184V change reduces the affinity to INDOPY-1, while Y115F facilitates binding of the natural nucleotide substrate and the combined effects enhance the ability of the enzyme to discriminate against the inhibitor. Studies with other strategic mutations at residues Phe-61 and Ala-62, as well as the use of chemically modified templates shed further light on the putative binding site of the inhibitor and ternary complex formation. An abasic site residue at position n, i. e. opposite the 3'-end of the primer, prevents binding of INDOPY-1, while an abasic site at the adjacent position n + 1 has no effect. Collectively, our findings provide strong evidence to suggest that INDOPY-1 can compete with natural deoxynucleoside triphosphates (dNTPs). We therefore propose to refer to members of this class of compounds as "nucleotide-competing RT inhibitors" (NcRTIs). C1 [Ehteshami, Maryam; Scarth, Brian J.; Tchesnokov, Egor P.; Goette, Matthias] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Goette, Matthias] McGill Univ, Dept Med, Montreal, PQ H3A 2B4, Canada. [Goette, Matthias] McGill Univ, Dept Biochem, Montreal, PQ H3A 2B4, Canada. [Dash, Chandravanu; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Hallenberger, Sabine; Jochmans, Dirk] Tibotec BVBA, B-2800 Mechelen, Belgium. RP Gotte, M (reprint author), McGill Univ, Dept Microbiol & Immunol, Duff Med Bldg D-6,3775 Univ St, Montreal, PQ H3A 2B4, Canada. EM matthias.gotte@mcgill.ca OI JOCHMANS, DIRK/0000-0002-9265-6028 FU Center for Cancer Research, NCI, National Institutes of Health; Tibotec; Canadian Institutes of Health Research (CIHR) FX This work was supported, in whole or in part, by the intramural research program of the Center for Cancer Research, NCI, National Institutes of Health (to S. L. G.). This work was also funded in part by Tibotec and a grant from the Canadian Institutes of Health Research (CIHR) (to M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 32 TC 32 Z9 34 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 31 PY 2008 VL 283 IS 44 BP 29904 EP 29911 DI 10.1074/jbc.M804882200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 364WS UT WOS:000260366900035 PM 18728003 ER PT J AU Han, S McBride, DJ Losert, W Leikin, S AF Han, Sejin McBride, Daniel J. Losert, Wolfgang Leikin, Sergey TI Segregation of Type I Collagen Homo- and Heterotrimers in Fibrils SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE collagen; type I homotrimer; fibrillogenesis; segregation; osteoporosis ID EHLERS-DANLOS-SYNDROME; OSTEOGENESIS IMPERFECTA MURINE; COLIA1 SP1 POLYMORPHISM; OSTEOPOROTIC FRACTURE; BREAST-CARCINOMA; BINDING-SITE; BONE-DENSITY; CHAIN; HOMOTRIMER; CELLS AB Normal type I collagen is a heterotrimer of two alpha 1(I) and one alpha 2(I) chains, but various genetic and environmental factors result in synthesis of homotrimers that consist of three alpha 1(1) chains. The homotrimers completely replace the heterotrimers only in rare recessive disorders. In the general population, they may compose just a small fraction of type I collagen. Nevertheless, they may play a significant role in pathology; for example, synthesis of 10-15% homotrimers due to a polymorphism in the alpha 1(l) gene may contribute to osteoporosis. Homotrimer triple helices have different stability and less efficient fibrillogenesis than heterotrimers. Their fibrils have different mechanical properties. However, very little is known about their molecular interactions and fibrillogenesis in mixtures with normal heterotrimers. Here we studied the kinetics and thermodynamics of fibril formation in such mixtures by combining traditional approaches with 3D confocal imaging of fibrils, in which homo- and heterotrimers were labeled with different fluorescent colors. In a mixture, following a temperature-jump from 4 to 32 degrees C, we observed a rapid increase in turbidity most likely caused by formation of homotrimer aggregates. The aggregates promoted nucleation of homotrimer fibrils that served as seeds for mixed and heterotrimer fibrils. The separation of colors in confocal images indicated segregation of homo- and heterotrimers at a subfibrillar level throughout the process. The fibril color patterns continued to change slowly after the fibrillogenesis appeared to be complete, due to dissociation and reassociation of the pepsin-treated homo- and heterotrimers, but this remixing did not significantly reduce the segregation even after several days. Independent homo- and heterotrimer solubility measurements in mixtures confirmed that the subfibrillar segregation was an equilibrium property of intermolecular interactions and not just a kinetic phenomenon. We argue that the subfibrillar segregation may exacerbate effects of a small fraction of alpha 1(I) homotrimers on formation, properties, and remodeling of collagen fibers. (C) 2008 Published by Elsevier Ltd. C1 [Han, Sejin; Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Phys Biochem, NIH, DHHS, Bethesda, MD 20892 USA. [Han, Sejin; Losert, Wolfgang] Univ Maryland, Dept Phys, IPST, College Pk, MD 20742 USA. [Han, Sejin; Losert, Wolfgang] Univ Maryland, Dept Phys, IREAP, College Pk, MD 20742 USA. [McBride, Daniel J.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Leikin, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth, Sect Phys Biochem, NIH, DHHS, Bethesda, MD 20892 USA. EM leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 FU NICHD; National Institutes of Health (NIH) [R21-EB-00328501]; Department of Health and Human Services; Charitable and Research Foundation; Arthritis Foundation FX We are grateful to Natalia Kuznetsova and Elena Makareeva for valuable discussions and suggestions. Confocal microscopy was performed at the Microscopy and Imaging Core of the National Institute of Child Health and Human Development (NICHD) with the assistance of Dr. Vincent Schram. This work was supported in part by the Intramural Research Program of NICHD, National Institutes of Health (NIH), Department of Health and Human Services. Wolfgang Losert was partially supported by NIH grant R21-EB-00328501. Daniel McBride was supported by the Charitable and Research Foundation and the Arthritis Foundation. NR 40 TC 15 Z9 16 U1 2 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 31 PY 2008 VL 383 IS 1 BP 122 EP 132 DI 10.1016/j.jmb.2008.08.008 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362IN UT WOS:000260191500010 PM 18721810 ER PT J AU Enoch, MA Shen, PH Ducci, F Yuan, QP Liu, JX White, KV Albaugh, B Hodgkinson, CA Goldman, D AF Enoch, Mary-Anne Shen, Pei-Hong Ducci, Francesca Yuan, Qiaoping Liu, Jixia White, Kenneth V. Albaugh, Bernard Hodgkinson, Colin A. Goldman, David TI Common Genetic Origins for EEG, Alcoholism and Anxiety: The Role of CRH-BP SO PLOS ONE LA English DT Article AB The resting EEG is a dynamic index of cortical activation, cognitive function and consciousness and is therefore an intermediate phenotype for many behaviors in which arousal is implicated such as anxiety and alcoholism. We performed a dense whole genome linkage scan using 3878 unlinked SNPs in a large pedigree derived from a population isolate sample of 328 Plains American Indians. Alpha (8-13 Hz), theta (4-8 Hz) and beta (13-30 Hz) EEG power was heritable (0.58-0.27) and stable over a 2 year period (r = 0.82-0.53). Genetic correlations between frequency bands were high (0.75). Linkage peaks for EEG power in all three frequency bands converged on chromosome 5q13-14 with genome-wide significant LOD scores of 3.5 (empirical p<0.0001) for alpha and beta power. A logical candidate gene, corticotropin releasing hormone-binding protein (CRH-BP), was located at the apex of these convergent linkage peaks. CRH-BP was significantly associated with alpha power in the Plains Indians and also in a replication sample of 188 Caucasians. Moreover, the same SNPs and haplotypes, located within the CRH-BP haplotype block, were also associated with anxiety disorders in the Plains Indians and alcohol use disorders in the Caucasians. CRH-BP modulates CRH which influences cortical and hippocampal EEG activity and is the primary mediator of the neuroendocrine stress response. Our results suggest a likely role for CRH-BP in stress-related alcoholism and highlight the use of the resting EEG as an intermediate phenotype for arousal-related behaviors such as anxiety and addiction. C1 [Enoch, Mary-Anne; Shen, Pei-Hong; Ducci, Francesca; Yuan, Qiaoping; Liu, Jixia; White, Kenneth V.; Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. [Albaugh, Bernard] Ctr Human Behav Studies Inc, Weatherford, OK USA. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural Research Program of NIAAA, NIH; Office of Research on Minority Health FX This research was supported by the Intramural Research Program of NIAAA, NIH, and in part by the Office of Research on Minority Health. NR 58 TC 47 Z9 48 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 31 PY 2008 VL 3 IS 10 AR e3620 DI 10.1371/journal.pone.0003620 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432KK UT WOS:000265131700032 PM 18974851 ER PT J AU Keating, BJ Tischfield, S Murray, SS Bhangale, T Price, TS Glessner, JT Galver, L Barrett, JC Grant, SFA Farlow, DN Chandrupatla, HR Hansen, M Ajmal, S Papanicolaou, GJ Guo, YR Li, MY DerOhannessian, S de Bakker, PIW Bailey, SD Montpetit, A Edmondson, AC Taylor, K Gai, XW Wang, SS Fornage, M Shaikh, T Groop, L Boehnke, M Hall, AS Hattersley, AT Frackelton, E Patterson, N Chiang, CWK Kim, CE Fabsitz, RR Ouwehand, W Price, AL Munroe, P Caulfield, M Drake, T Boerwinkle, E Reich, D Whitehead, AS Cappola, TP Samani, NJ Lusis, AJ Schadt, E Wilson, JG Koenig, W McCarthy, MI Kathiresan, S Gabriel, SB Hakonarson, H Anand, SS Reilly, M Engert, JC Nickerson, DA Rader, DJ Hirschhorn, JN FitzGerald, GA AF Keating, Brendan J. Tischfield, Sam Murray, Sarah S. Bhangale, Tushar Price, Thomas S. Glessner, Joseph T. Galver, Luana Barrett, Jeffrey C. Grant, Struan F. A. Farlow, Deborah N. Chandrupatla, Hareesh R. Hansen, Mark Ajmal, Saad Papanicolaou, George J. Guo, Yiran Li, Mingyao DerOhannessian, Stephanie de Bakker, Paul I. W. Bailey, Swneke D. Montpetit, Alexandre Edmondson, Andrew C. Taylor, Kent Gai, Xiaowu Wang, Susanna S. Fornage, Myriam Shaikh, Tamim Groop, Leif Boehnke, Michael Hall, Alistair S. Hattersley, Andrew T. Frackelton, Edward Patterson, Nick Chiang, Charleston W. K. Kim, Cecelia E. Fabsitz, Richard R. Ouwehand, Willem Price, Alkes L. Munroe, Patricia Caulfield, Mark Drake, Thomas Boerwinkle, Eric Reich, David Whitehead, A. Stephen Cappola, Thomas P. Samani, Nilesh J. Lusis, A. Jake Schadt, Eric Wilson, James G. Koenig, Wolfgang McCarthy, Mark I. Kathiresan, Sekar Gabriel, Stacey B. Hakonarson, Hakon Anand, Sonia S. Reilly, Muredach Engert, James C. Nickerson, Deborah A. Rader, Daniel J. Hirschhorn, Joel N. FitzGerald, Garret A. TI Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies SO PLOS ONE LA English DT Article AB A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan'' tagging approach to capture the genetic diversity across similar to 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions. C1 [Keating, Brendan J.; Whitehead, A. Stephen; Reilly, Muredach; Rader, Daniel J.; FitzGerald, Garret A.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Tischfield, Sam; Farlow, Deborah N.; de Bakker, Paul I. W.; Patterson, Nick; Chiang, Charleston W. K.; Reich, David; Kathiresan, Sekar; Gabriel, Stacey B.; Hirschhorn, Joel N.] MIT, Broad Inst Harvard, Cambridge, MA 02139 USA. [Tischfield, Sam; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Endocrinol, Program Genom, Boston, MA USA. [Murray, Sarah S.] Scripps Genom Med, La Jolla, CA USA. [Bhangale, Tushar; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Price, Thomas S.] MRC SGDP Ctr, Inst Psychiat, London, England. [Glessner, Joseph T.; Grant, Struan F. A.; Gai, Xiaowu; Shaikh, Tamim; Frackelton, Edward; Kim, Cecelia E.; Hakonarson, Hakon] CHOP, Dept Pediat, Div Human Genet, Ctr Applied Genom, Philadelphia, PA USA. [Barrett, Jeffrey C.; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Chandrupatla, Hareesh R.; Ajmal, Saad; Li, Mingyao; DerOhannessian, Stephanie; Edmondson, Andrew C.; Cappola, Thomas P.; Reilly, Muredach; Rader, Daniel J.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Galver, Luana; Hansen, Mark] Illumina Inc, San Diego, CA USA. [Papanicolaou, George J.; Fabsitz, Richard R.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD USA. [Guo, Yiran] Beijing Genom Inst Shenzhen, Shenzhen, Peoples R China. [de Bakker, Paul I. W.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA USA. [Taylor, Kent] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA USA. [Wang, Susanna S.; Drake, Thomas; Lusis, A. Jake] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Fornage, Myriam] Univ Texas, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Groop, Leif] Lund Univ, Dept Clin Sci Malmoe, Diabetes & Endocrinol, S-22100 Lund, Sweden. [Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet, Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. [Hattersley, Andrew T.] Peninsula Med Sch, Inst Biomed & Clin Sci, Diabetes Genet Grp, Exeter, Devon, England. [Chiang, Charleston W. K.; Reich, David; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Munroe, Patricia] Barts & The London, Dept Clin Pharmacol, London, England. [Ouwehand, Willem] Univ Cambridge, NHS Blood & Transplant, Dept Haematol, Cambridge CB2 1TN, England. [Munroe, Patricia; Caulfield, Mark] Barts & The London, William Harvey Res Inst, London, England. [Boerwinkle, Eric] Univ Texas, Hlth Sci Ctr, Human Genet Ctr, Houston, TX USA. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England. [Schadt, Eric] Merck & Co Inc, Rosetta Inpharmat LLC, Seattle, WA USA. [Wilson, James G.] Univ Mississippi, Med Ctr, VA Med Ctr, University, MS 38677 USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiol Div, Boston, MA USA. [Anand, Sonia S.] McMaster Univ, Hamilton Gen Hosp, Hamilton Hlth Sci, Clin Epidemiol & Biostat, Populat Genom Program, Hamilton, ON L8S 4L8, Canada. [Bailey, Swneke D.; Engert, James C.] McGill Univ, Dept Med & Human Genet, Montreal, PQ H3A 2T5, Canada. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Cambridge, MA 02138 USA. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford Ctr Diabetes, Endocrinol & Metabolism, Oxford OX1 2JD, England. [Lusis, A. Jake] Univ Calif Los Angeles, Sch Med, Dept Microbiol, Immunol & Mol Genet, Los Angeles, CA 90024 USA. [Montpetit, Alexandre] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. RP Keating, BJ (reprint author), Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. EM garret@spirit.gcrc.upenn.edu RI FitzGerald, Garret/A-4222-2010; Price, Thomas/B-7372-2008; Guo, Yiran/H-4120-2011; de Bakker, Paul/B-8730-2009; OI Price, Thomas/0000-0001-7356-2109; Guo, Yiran/0000-0002-6549-8589; de Bakker, Paul/0000-0001-7735-7858; Barrett, Jeffrey/0000-0002-1152-370X; Chiang, Charleston/0000-0002-0668-7865 FU National Institute of Health Clinical and Translational Research Award [RR U54 RR023567]; University of Pennsylvania; National Heart, Lung and Blood Institute [N01-HC-65226, U01 HL66642] FX Supported by a National Institute of Health Clinical and Translational Research Award (RR U54 RR023567) to the University of Pennsylvania and National Heart, Lung and Blood Institute (N01-HC-65226). Tushar Bhangale's work was supported by the Program for Genomic Applications supported by the NHLBI (U01 HL66642). NR 39 TC 280 Z9 282 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 31 PY 2008 VL 3 IS 10 AR e3583 DI 10.1371/journal.pone.0003583 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432KK UT WOS:000265131700007 PM 18974833 ER PT J AU Ogurtsov, AY Marino-Ramirez, L Johnson, GR Landsman, D Shabalina, SA Spiridonov, NA AF Ogurtsov, Aleksey Y. Marino-Ramirez, Leonardo Johnson, Gibbes R. Landsman, David Shabalina, Svetlana A. Spiridonov, Nikolay A. TI Expression Patterns of Protein Kinases Correlate with Gene Architecture and Evolutionary Rates SO PLOS ONE LA English DT Article AB Background: Protein kinase (PK) genes comprise the third largest superfamily that occupy similar to 2% of the human genome. They encode regulatory enzymes that control a vast variety of cellular processes through phosphorylation of their protein substrates. Expression of PK genes is subject to complex transcriptional regulation which is not fully understood. Principal Findings: Our comparative analysis demonstrates that genomic organization of regulatory PK genes differs from organization of other protein coding genes. PK genes occupy larger genomic loci, have longer introns, spacer regions, and encode larger proteins. The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages. On average, PK genes evolve slower than other protein coding genes. Breadth of PK expression negatively correlates with rate of non-synonymous substitutions in protein coding regions. This rate is lower for high expression and ubiquitous PKs, relative to low expression PKs, and correlates with divergence in untranslated regions. Conversely, rate of silent mutations is uniform in different PK groups, indicating that differing rates of non-synonymous substitutions reflect variations in selective pressure. Brain and testis employ a considerable number of tissue-specific PKs, indicating high complexity of phosphorylation-dependent regulatory network in these organs. There are considerable differences in genomic organization between PKs up-regulated in the testis and brain. PK genes up-regulated in the highly proliferative testicular tissue are fast evolving and small, with short introns and transcribed regions. In contrast, genes up-regulated in the minimally proliferative nervous tissue carry long introns, extended transcribed regions, and evolve slowly. Conclusions/Significance: PK genomic architecture, the size of gene functional domains and evolutionary rates correlate with the pattern of gene expression. Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed. Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution. C1 [Ogurtsov, Aleksey Y.; Marino-Ramirez, Leonardo; Landsman, David; Shabalina, Svetlana A.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Johnson, Gibbes R.; Spiridonov, Nikolay A.] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Proteins, Bethesda, MD USA. RP Ogurtsov, AY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM shabalin@ncbi.nlm.nih.gov; nikolay.spiridonov@fda.hhs.gov RI Marino-Ramirez, Leonardo/I-5759-2013; Shabalina, Svetlana/N-8939-2013; Spiridonov, Nikolay/B-6287-2014; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Shabalina, Svetlana/0000-0003-2272-7473; Landsman, David/0000-0002-9819-6675 FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 9 Z9 9 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 31 PY 2008 VL 3 IS 10 AR e3599 DI 10.1371/journal.pone.0003599 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432KK UT WOS:000265131700020 PM 18974838 ER PT J AU Kobayashi, T Kai, N Kobayashi, K Fujiwara, T Akagawa, K Onda, M Kobayashi, K AF Kobayashi, Tomoko Kai, Nobuyuki Kobayashi, Kenta Fujiwara, Tomonori Akagawa, Kimio Onda, Masanori Kobayashi, Kazuto TI Transient silencing of synaptic transmitter release from specific neuronal types by recombinant tetanus toxin light chain fused to antibody variable region SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Cell targeting; Monoclonal antibody; Tetanus toxin light chain; Transmitter release; Striatum; Motor control ID BASAL GANGLIA FUNCTION; PSEUDOMONAS EXOTOXIN; NEURAL CIRCUITRY; TRANSGENIC MICE; IN-VIVO; MAMMALIAN NEURONS; RECEPTOR; CELLS; CHANNELRHODOPSIN-2; COORDINATION AB We developed a novel strategy for conditional silencing of synaptic transmission in specific neuronal types in transgenic animals. We generated a recombinant protein termed immuno-tetanus toxin (ITet), which contains a monoclonal antibody variable region for human interleukin-2 receptor alpha-subunit (IL-2R alpha) fused to tetanus toxin light chain. ITet was designed to transiently suppress transmitter release from target neurons genetically engineered to express human IL-2R alpha via proteolytic cleavage of vesicle-associated membrane protein-2 (VAMP-2). The in vivo actions of ITet were investigated by using mutant mice that express IL-2R alpha in striatal neurons under the control of the gene encoding dopamine D-2 receptor. Unilateral ITet injection into the striatum induced rotational behavior in the mutant mice and the rotations gradually reversed to the normal level. The behavioral alteration was accompanied by a transient decrease in the striatal VAMP-2 level and depolarization-evoked transmitter release in synaptic target region. However, ITet injection caused no structural change in striatal cells and nerve terminals in the mutants. These data indicate that ITet acts on striatal neurons bearing human IL-2R alpha and temporally reduces their VAMP-2 content, thereby causing the blockade of transmitter release. Our ITet technology provides a useful approach for inducible and reversible control of synaptic transmission in specific neuronal types in the brain. (C) 2008 Elsevier B.V. All rights reserved. C1 [Kobayashi, Tomoko; Kai, Nobuyuki; Kobayashi, Kenta; Kobayashi, Kazuto] Fukushima Med Univ, Sch Med, Inst Biomed Sci, Dept Mol Genet, Fukushima 9601295, Japan. [Kobayashi, Tomoko; Kobayashi, Kazuto] Japan Sci & Technol Cooperat, Core Res Evolut Sci & Technol, Kawaguchi, Saitama 3320012, Japan. [Fujiwara, Tomonori; Akagawa, Kimio] Kyorin Univ, Sch Med, Dept Cell Physiol, Mitaka, Tokyo 1818611, Japan. [Onda, Masanori] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, K (reprint author), Fukushima Med Univ, Sch Med, Inst Biomed Sci, Dept Mol Genet, Fukushima 9601295, Japan. EM kazuto@fmu.ac.jp FU Core Research for Evolutional Science and Technology, Japan Science and Technology Cooperation; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by a grant-in aid from Core Research for Evolutional Science and Technology, Japan Science and Technology Cooperation and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr. I. Pastan for providing the anti-Tac(Fv)-PE38 expression vector, Dr.J. Gogos for providing the tetanus toxin light chain cDNA, Drs. A. Morozov and Y. Yasoshima for valuable discussion, and T. Minakawa, M. Kikuchi, and N. Sato for their technical support in conducting the animal experiments. NR 30 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 30 PY 2008 VL 175 IS 1 BP 125 EP 132 DI 10.1016/j.jneumeth.2008.08.014 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 365ZA UT WOS:000260447500015 PM 18775748 ER PT J AU Monaco, A Menolascina, F Zhao, YD Tommasi, S Sabatino, M Fasano, R Paradiso, A Marincola, FM Wang, E AF Monaco, Alessandro Menolascina, Filippo Zhao, Yingdong Tommasi, Stefania Sabatino, Marianna Fasano, Ross Paradiso, Angelo Marincola, Francesco M. Wang, Ena TI "Sequencing-grade" screening for BRCA1 variants by oligo-arrays SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID MUTATIONAL ANALYSIS; CANCER; BREAST; STABILITY; GENOME AB The need for fast, efficient, and less costly means to screen genetic variants associated with disease predisposition led us to develop an oligo-nucleotide array-based process for gene-specific single nucleotide polymorphism (SNP) genotyping. This cost-effective, high-throughput strategy has high sensitivity and the same degree of accuracy as direct sequencing, the current gold standard for genetic screening. We used the BRCA1 breast and ovarian cancer predisposing gene model for the validation of the accuracy and efficiency of our strategy. This process could detect point mutations, insertions or deletions of any length, of known and unknown variants even in heterozygous conditions without affecting sensitivity and specificity. The system could be applied to other disorders and can also be custom-designed to include a number of genes related to specific clinical conditions. This system is particularly useful for the screening of long genomic regions with relatively infrequent but clinically relevant variants, while drastically cutting time and costs in comparison to high-throughput sequencing. C1 [Monaco, Alessandro; Sabatino, Marianna; Fasano, Ross; Marincola, Francesco M.; Wang, Ena] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Menolascina, Filippo] Univ Bari, Dept Bioinformat, I-70121 Bari, Italy. [Zhao, Yingdong] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Menolascina, Filippo; Tommasi, Stefania; Paradiso, Angelo] Ist Tumori IRCCS Giovanni Paolo II, Clin Expt Oncol Lab, Bari, Italy. RP Wang, E (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM monacoal@cc.nih.gov; f.menolascina@gmail.com; Zhaoy@mail.nih.gov; s.tommasi@oncologico.bari.it; sabatinom@cc.nih.gov; fasanor@cc.nih.gov; a.paradiso@oncologico.bari.it; fmarincola@cc.nih.gov; ewang@cc.nih.gov RI Tommasi, Stefania/J-6732-2012; Monaco, Alessandro/O-5338-2015 OI Tommasi, Stefania/0000-0002-2157-2978; Monaco, Alessandro/0000-0002-9941-7003 NR 18 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 30 PY 2008 VL 6 AR 64 DI 10.1186/1479-5876-6-64 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 380AF UT WOS:000261437200002 PM 18973698 ER PT J AU La Pean, A Jeffries, N Grow, C Ravina, B Di Prospero, NA AF La Pean, Alison Jeffries, Neal Grow, Chelsea Ravina, Bernard Di Prospero, Nicholas A. TI Predictors of Progression in Patients with Friedreich Ataxia SO MOVEMENT DISORDERS LA English DT Article DE Friedreich ataxia; genotype; phenotype; GAA expansion; medication ID MITOCHONDRIAL DYSFUNCTION; CLINICAL-FEATURES; REPEAT EXPANSION; PHENOTYPE; FRATAXIN AB Friedreich ataxia is an inherited, progressive, neurodegenerative disorder that is clinically heterogeneous. It is caused by a trinucleotide (GAA) repeat expansion resulting in frataxin loss and oxidative stress. We assessed clinical features including the development of cardiomyopathy and scoliosis and disease progression including loss of ambulation and interference with activities of daily living, relative to the length of the GAA repeal, age of onset. and age of diagnosis in a retrospective cohort study of 61 genetically confirmed patients. The use of antioxidants Such as vitamins, dietary supplements, and idebenone was also examined. Linear regression and Cox proportional hazard models assessed predictors to disease milestones. The shorter GAA allele accounted tor part of the variability in the age of diagnosis (46%) and less in the age of onset (27%). Multivariate analysis demonstrated that age at diagnosis, which may incorporate other genetic and environmental factors, is more important than GAA length in predicting cardiomyopathy, scoliosis. and disease progression. (C) 2008 Movement Disorder Society C1 [La Pean, Alison; Di Prospero, Nicholas A.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Jeffries, Neal] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Ravina, Bernard] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. RP La Pean, A (reprint author), NINDS, Neurogenet Branch, NIH, 35 Convent Dr,Bldg 35,Room 2A-114, Bethesda, MD 20892 USA. EM lapeana@ninds.nih.pov FU National Institute of Neurological Disorders and Stroke FX This Study was supported by intramural research funds from the National Institute of Neurological Disorders and Stroke. We thank the patients, their families, and the members of the Friedreich Ataxia Research Alliance for their time and support. We also thank Dr. Claudia Moy (NINDS) for advice and Dr. Kenneth Fischbeck (NINDS) for critical feedback and review of the manuscript. NR 24 TC 18 Z9 19 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD OCT 30 PY 2008 VL 23 IS 14 BP 2026 EP 2032 DI 10.1002/mds.22248 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 374DA UT WOS:000261021500010 PM 18759347 ER PT J AU Morris, BH Oh, W Tyson, JE Stevenson, DK Phelps, DL O'Shea, TM McDavid, GE Perritt, RL Van Meurs, KP Vohr, BR Grisby, C Yao, Q Pedroza, C Das, A Poole, WK Carlo, WA Duara, S Laptook, AR Salhab, WA Shankaran, S Poindexter, BB Fanaroff, AA Walsh, MC Rasmussen, MR Stoll, BJ Cotten, CM Donovan, EF Ehrenkranz, RA Guillet, R Higgins, RD AF Morris, Brenda H. Oh, William Tyson, Jon E. Stevenson, David K. Phelps, Dale L. O'Shea, T. Michael McDavid, Georgia E. Perritt, Rebecca L. Van Meurs, Krisa P. Vohr, Betty R. Grisby, Cathy Yao, Qing Pedroza, Claudia Das, Abhik Poole, W. Kenneth Carlo, Waldemar A. Duara, Shahnaz Laptook, Abbot R. Salhab, Walid A. Shankaran, Seetha Poindexter, Brenda B. Fanaroff, Avroy A. Walsh, Michele C. Rasmussen, Maynard R. Stoll, Barbara J. Cotten, C. Michael Donovan, Edward F. Ehrenkranz, Richard A. Guillet, Ronnie Higgins, Rosemary D. CA NICHD Neonatal Res Network TI Aggressive vs. conservative phototherapy for infants with extremely low birth weight SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BAYESIAN SUBSET ANALYSIS; PEAK SERUM BILIRUBIN; CLINICAL-TRIALS; NEONATAL HYPERBILIRUBINEMIA; NEURODEVELOPMENTAL OUTCOMES; INTRACRANIAL HEMORRHAGE; PRETERM INFANTS; AGE; KERNICTERUS; CHILDREN AB Background: It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less). Methods: We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments. Results: Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g. Conclusions: Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.). C1 [Morris, Brenda H.; Tyson, Jon E.; McDavid, Georgia E.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX 77030 USA. [Oh, William; Vohr, Betty R.; Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Providence, RI 02912 USA. [Stevenson, David K.; Van Meurs, Krisa P.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Phelps, Dale L.; Guillet, Ronnie] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [O'Shea, T. Michael] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Perritt, Rebecca L.; Yao, Qing; Poole, W. Kenneth] RTI Int, Res Triangle Pk, NC USA. [Grisby, Cathy; Donovan, Edward F.] Univ Cincinnati, Cincinnati, OH USA. [Pedroza, Claudia] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Carlo, Waldemar A.] Univ Alabama, Birmingham, AL USA. [Duara, Shahnaz] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Salhab, Walid A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Shankaran, Seetha] Wayne State Univ, Detroit, MI USA. [Poindexter, Brenda B.] Indiana Univ, James Whitcomb Riley Hosp Children, Indianapolis, IN 46204 USA. [Fanaroff, Avroy A.; Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Rasmussen, Maynard R.] Univ Calif San Diego, Sharp Mary Birch Hosp Women, San Diego, CA 92103 USA. [Stoll, Barbara J.] Emory Univ, Atlanta, GA 30322 USA. [Cotten, C. Michael] Duke Univ, Durham, NC USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, New Haven, CT USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Tyson, JE (reprint author), Univ Texas Houston, Sch Med, Dept Pediat, 6431 Fannin,MSB 3-226, Houston, TX 77030 USA. EM jon.e.tyson@uth.tmc.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Natus FX Supported by grants from the National Institutes of Health and from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which provided overall oversight for study conduct. All data analyses and interpretation were done independently of the funding agency. Natus Medical loaned light-emitting diode phototherapy lights to each center. These lights were used at the discretion of the attending neonatologist in treating infants in either treatment group. The lights were returned to Natus Medical or purchased at a prorated price after the study. Natus Medical played no role in the study design, data collection, data analysis, or manuscript preparation or revision.; Dr. Fanaroff reports receiving consulting fees, and Dr. Guillet grant support, from Natus. No other potential conflict of interest relevant to this article was reported.; We thank our medical and nursing colleagues and the infants and their parents. NR 42 TC 79 Z9 83 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 30 PY 2008 VL 359 IS 18 BP 1885 EP 1896 DI 10.1056/NEJMoa0803024 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 366BL UT WOS:000260454500005 PM 18971491 ER PT J AU Willis, MW Benson, BE Ketter, TA Kimbrell, TA George, MS Speer, AM Herscovitch, P Post, RM AF Willis, Mark W. Benson, Brenda E. Ketter, Terence A. Kimbrell, Tim A. George, Mark S. Speer, Andrew M. Herscovitch, Peter Post, Robert M. TI Interregional cerebral metabolic associativity during a continuous performance task (Part I): Healthy adults SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Positron emission tomography (PET); Cerebral glucose metabolism; FDG; Normal; Connectivity; Neural circuitry ID PHOTON-EMISSION-TOMOGRAPHY; FUNCTIONAL CONNECTIVITY; GLUCOSE-METABOLISM; MAJOR DEPRESSION; ALTERED INTERCORRELATIONS; UNIPOLAR DEPRESSION; BIPOLAR DISORDER; REGIONAL RATES; BRAIN-REGIONS; BLOOD-FLOW AB One emerging hypothesis regarding psychiatric illnesses is that they arise from the dysregulation of normal circuits or neuroanatomical patterns. In order to study mood disorders within this framework, we explored normal metabolic associativity patterns in healthy volunteers as a prelude to examining the same relationships in affectively ill patients (Part II). We applied, an auditory continuous performance task (CPT) in correlational analyses to regional brain activity as measured with FDG-PET during 66 healthy volunteers. This simple attention task controlled for brain activity that otherwise might vary amongst affective and cognitive states. There were highly significant positive correlations between homologous regions in the two hemispheres in thalamic, extrapyramidal, orbital frontal, medial temporal and cerebellar areas. Dorsal frontal, lateral temporal, cingulate, and especially insula, and inferior parietal areas showed less significant homologous associativity, suggesting more specific lateralized function. The medulla and bilateral thalami exhibited the most diverse interregional associations. A general pattern emerged of cortical regions covarying inversely with subcortical structures, particularly the frontal cortex with cerebellum, amygdala and thalamus. These analytical data may help to confirm known functional and neuroanatomical relationships, elucidate others as yet unreported, and serve as a basis for comparison to patients with psychiatric illness. Published by Elsevier Ireland Ltd. C1 [Benson, Brenda E.] NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bethesda, MD 20892 USA. [Willis, Mark W.] Uniformed Serv Univ Hlth Sci, US PHS, US Dept HHS, Bethesda, MD 20814 USA. [Ketter, Terence A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Kimbrell, Tim A.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [George, Mark S.] Med Univ S Carolina, Charleston, SC 29425 USA. [Herscovitch, Peter] Natl Inst Hlth Clin Ctr, PET Dept, Bethesda, MD 20892 USA. [Post, Robert M.] George Washington Univ, Washington, DC USA. [Post, Robert M.] Penn State Coll Med, Hershey, PA USA. [Post, Robert M.] Bipolar Collaborat Network, Bethesda, MD USA. RP Benson, BE (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bldg 9,Rm B1E04,10 Ctr Dr, Bethesda, MD 20892 USA. EM bbenson@mail.nih.gov FU NIMH; NIH; DHHS; Ted and Vada Stanley of the Stanley Foundation; Henry M. Jackson Foundation FX This work was supported by the intramural program of the NIMH, NIH, DHHS. The work of Mark Willis, Terence Ketter, and Mark George was Supported by Ted and Vada Stanley of the Stanley Foundation. Mark Willis also received salary support from the Henry M. Jackson Foundation for the Advancement of Military Medicine. The authors thank the PET technologists and cyclotron/radiochemistry staff of the NIH Clinical Center PET Department for their expertise. Software provided by Neil Weisenfeld and Jose M. Malsog, M.D. of the NIMH was used in the processing and analysis Of Our data. These data were presented in abstract and poster form at the Society of Biological Psychiatry 55th Annual Scientific Convention, May 11-13, 2000, Chicago, Illinois. NR 54 TC 1 Z9 2 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD OCT 30 PY 2008 VL 164 IS 1 BP 16 EP 29 DI 10.1016/j.pscychresns.2007.12.015 PG 14 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 374DV UT WOS:000261023800002 PM 18799294 ER PT J AU Benson, BE Willis, MW Ketter, TA Speer, A Kimbrell, TA George, MS Herscovitch, P Post, RM AF Benson, Brenda E. Willis, Mark W. Ketter, Terence A. Speer, Andrew Kimbrell, Tim A. George, Mark S. Herscovitch, Peter Post, Robert M. TI Interregional cerebral metabolic associativity during a continuous performance task (Part II) : Differential alterations in bipolar and unipolar disorders SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Associativity; Functional connectivity; Affective disorders; Metabolism; FDG; Neuroimaging; Depression; Mania; Bipolar; Unipolar ID MEDIAL PREFRONTAL CORTEX; GLUCOSE-METABOLISM; FUNCTIONAL CONNECTIVITY; MOOD DISORDERS; RHESUS-MONKEY; ALTERED INTERCORRELATIONS; MAJOR DEPRESSION; MACAQUE MONKEYS; REGIONAL RATES; RATING-SCALE AB Unipolar and bipolar disorders have often been reported to exhibit abnormal regional brain activity in prefrontal cortex and paralimbic structures compared with healthy controls. We Sought to ascertain how regions postulated to be abnormal in bipolar and unipolar disorders were functionally connected to the rest of the brain, and how this associativity differed from healthy controls. Thirty patients with bipolar disorder (Bps), 34 patients with Unipolar disorder (Ups), and 66 healthy volunteers (Willis, M.W., Benson, B. E., Ketter, T.A., Kimbrell, T.A., George, M.S., Speer, A.M., Herscovitch, P., Post, R.M., 2008. Interregional cerebral metabolic associativity during a continuous performance task in healthy adults. Psychiatry Research: Neuroimaging 164 (1)) were imaged using F-18-fluorodeoxyglucose and positron emission tomography (FDG-PET) while performing an auditory continuous performance task (CPT). Five bilateral regions of interest (ROIs), namely dorsolateral prefrontal cortex (DLPFC), insula, inferior parietal cortex (INFP), thalamus and cerebellum, were correlated with normalized cerebral metabolism in the rest of the brain while covarying out Hamilton Depression Rating Scale Scores. In bipolar patients compared with controls, metabolism in the left DLPFC and IN FP, and bilateral thalamus and insula had more positive and fewer negative metabolic correlations with other brain regions. In contrast, compared with controls, Unipolar patients had fewer significant correlative relationships, either positive or negative. In common, bipolar and unipolar patients lacked the normal inverse relationships between the DLPFC and cerebellum, as well as relationships between the primary ROIs and other limbic regions (medial prefrontal cortex, anterior cingulate, and temporal lobes) compared with controls. Associations of DLPFC and INFP with other brain areas were different in each hemisphere in patients and controls. Bipolar patients exhibited exaggerated positive coherence of activity throughout the brain, while unipolar patients showed a paucity of normal interrelationships compared with controls. These abnormal patterns of metabolic associativity suggest marked interregional neuronal dysregulation in bipolar and unipolar illness exists beyond that of mere absolute regional differences from control levels, and provides rationale for using acute and long-term therapies that may re-establish and maintain normal associativity in these devastating illnesses. Published by Elsevier Ireland Ltd. C1 [Benson, Brenda E.] NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bethesda, MD 20892 USA. [Willis, Mark W.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Ketter, Terence A.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Kimbrell, Tim A.] Vet Affairs Med Ctr, Little Rock, AR USA. [George, Mark S.] Med Univ S Carolina, Charleston, SC 29425 USA. [Herscovitch, Peter] NIH, Positron Emiss Tomog Dept, Bethesda, MD USA. [Post, Robert M.] George Washington Univ, Washington, DC USA. [Post, Robert M.] Penn State Coll Med, Hershey, PA USA. [Post, Robert M.] Bipolar Collaborat Network, Bethesda, MD USA. RP Benson, BE (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bldg 9,Rm B1E04,10 Ctr Dr, Bethesda, MD 20892 USA. EM bbenson@helix.nih.gov FU NIMH; NIH; DHHS; Stanley Foundation FX This work was supported by the intramural program of the NIMH, NIH, DHHS. The work of Mark Willis, Terence Ketter, and Mark George was Supported by Ted and Vada Stanley of the Stanley Foundation. The authors wish to thank the PET technologists and cyclotron/radiochernistry staff of the NIH Clinical Center PET Department for their expertise. Software provided by NeilWeisenfeld and Jose M. Maisog, M.D. of the NIMH was used in the processing and analysis of our data. These data were presented in abstract and poster form at the Society of Biological Psychiatry 55th Annual Scientific Convention, May 11 - 13, 2000, Chicago, Illinois. NR 88 TC 16 Z9 19 U1 4 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD OCT 30 PY 2008 VL 164 IS 1 BP 30 EP 47 DI 10.1016/j.pscychresns.2007.12.016 PG 18 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 374DV UT WOS:000261023800003 PM 18801648 ER PT J AU Alia-Klein, N Kriplani, A Pradhan, K Ma, JY Logan, J Williams, B Craig, IW Telang, F Tomasi, D Goldstein, RZ Wang, GJ Volkow, ND Fowler, JS AF Alia-Klein, Nelly Kriplani, Aarti Pradhan, Kith Ma, Jim Yeming Logan, Jean Williams, Benjamin Craig, Ian W. Telang, Frank Tomasi, Dardo Goldstein, Rita Z. Wang, Gene-Jack Volkow, Nora D. Fowler, Joanna S. TI The MAO-A genotype does not modulate resting brain metabolism in adults SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE MAO-A; FDG; Baseline ID MONOAMINE-OXIDASE; GENETIC-VARIATION; IMPULSIVITY; ATTENTION; PROMOTER; BEHAVIOR; VIOLENCE; HUMANS; RISK AB Variation in the monoamine-oxidase-A (MAO-A) gene has been associated with volumetric changes in corticolimbic regions with differences in their response to relevant emotional tasks. Here we show no changes in baseline regional brain metabolism as a function of genotype indicating that, unchallenged, corticolimbic activity is not modulated by the MAO-A genotype. Published by Elsevier Ireland Ltd. C1 [Alia-Klein, Nelly; Kriplani, Aarti; Pradhan, Kith; Ma, Jim Yeming; Logan, Jean; Telang, Frank; Tomasi, Dardo; Goldstein, Rita Z.; Wang, Gene-Jack; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Williams, Benjamin; Craig, Ian W.] Kings Coll London, Dept Psychiat, London SE5 8AF, England. [Wang, Gene-Jack; Fowler, Joanna S.] Mt Sinai Sch Med, New York, NY 10029 USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Alia-Klein, N (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM nellyklein@bnl.gov RI Tomasi, Dardo/J-2127-2015; OI Craig, Ian/0000-0002-4063-1005; Logan, Jean/0000-0002-6993-9994 FU Brookhaven National Laboratory [DE-AC-298CH 10886]; Office of Biological and Environmental Research; NIH-NIDA [K05DA020001]; NIH CGRC [MOIRR10710]; National Association for Research oil Schizophrenia and Depression (NARSAD) FX This work was carried out at Brookhaven National Laboratory under contract DE-AC-298CH 10886 with the U.S. Department of Energy and supported by its Office of Biological and Environmental Research and by NIH-NIDA (K05DA020001), NIH CGRC (MOIRR10710) and by the National Association for Research oil Schizophrenia and Depression (NARSAD). We thank the PET team for tile advice and assistance in different aspects of these studies. We are also grateful to the subjects who volunteered for these studies. NR 22 TC 9 Z9 10 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD OCT 30 PY 2008 VL 164 IS 1 BP 73 EP 76 DI 10.1016/j.pscychresns.2007.12.010 PG 4 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 374DV UT WOS:000261023800006 PM 18706791 ER PT J AU Zheng, G Meyer, M Li, WT Yang, YN AF Zheng, Gang Meyer, Mark Li, Wentian Yang, Yaning TI Comparison of two-phase analyses for case-control genetic association studies SO STATISTICS IN MEDICINE LA English DT Article DE adaptive approach; constrained likelihood ratio test; efficiency robustness; genetic model selection; MAX; two-phase analysis ID GENOME-WIDE ASSOCIATION; HARDY-WEINBERG EQUILIBRIUM; EFFICIENCY ROBUST-TESTS; SAMPLE-SIZE; TREND TESTS; MACULAR DEGENERATION; RISK; POLYMORPHISM; SURVIVAL; DISEASE AB To test for genetic association between a marker and a complex disease using a case-control design, Cochran-Armitage trend tests (CATFs) and Pearson's chi-square test are often employed. Both tests are genotype-based. Song and Elston (Statist. Med. 2006; 25:105-126) introduced the Hardy-Weinberg disequilibrium trend test and combined it with CAT-F to test for association. Compared to using a single statistic to test for case-control genetic association (referred to as single-phase analysis), two-phase analysis is a new strategy in that it employs two test statistics in one analysis framework, each statistic using all available case-control data. Two such two-phase analysis procedures were studied, in which Hardy-Weinberg equilibrium (HWE) in the population is a key assumption, although the procedures are robust to moderate departure from HWE. Our goal in this article is to study a new two-phase procedure and compare all three two-phase analyses and common single-phase procedures by extensive simulation studies. For illustration, the results are applied to real data from two case-control studies. On the basis of the results, we conclude that with an appropriate choice of significance level for the analysis in phase 1, some two-phase analyses could be more powerful than commonly used test statistics. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Zheng, Gang; Meyer, Mark] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Meyer, Mark] American Univ, Dept Math & Stat, Washington, DC 20016 USA. [Li, Wentian] Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA. [Yang, Yaning] Univ Sci & Technol China, Dept Stat & Finance, Hefei 230026, Anhui, Peoples R China. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Room 9200,6701 Rockledge Dr,MSC 7913, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov OI Li, Wentian/0000-0003-1155-110X FU China NSF [10671189]; Chinese Academy of Science [KJCX3-SYW-S02]; The Robert S Boas Center for Genomics and Human Genetics FX The work of Mark Meyer is completed when he is a summer intern at Office of Biostatistics Research, National Heart, Lung and Blood Institute. The research of Yaning Yang was supported by China NSF Grant 10671189 and Chinese Academy of Science Grant No. KJCX3-SYW-S02. Wentian Li acknowledges the support from The Robert S Boas Center for Genomics and Human Genetics at the Feinstein Institute for Medical Research. The views of this article only present those of the authors, not representing any of the National Heart, Lung and Blood Institute, National Institutes of Health. The authors Would like to thank three referees for their valuable comments and Suggestions which improved our presentations. NR 30 TC 11 Z9 12 U1 0 U2 1 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 OCT 30 PY 2008 VL 27 IS 24 BP 5054 EP 5075 DI 10.1002/sim.3336 PG 22 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 360MN UT WOS:000260061700013 PM 18570272 ER PT J AU Tanabe, S Cumming, BG AF Tanabe, Seiji Cumming, Bruce G. TI Mechanisms Underlying the Transformation of Disparity Signals from V1 to V2 in the Macaque SO JOURNAL OF NEUROSCIENCE LA English DT Article DE vision; binocular; receptive field; striate cortex; extrastriate; macaque ID STEREO CORRESPONDENCE PROBLEM; MONKEY VISUAL-CORTEX; BINOCULAR DISPARITY; HORIZONTAL DISPARITY; NEURAL MECHANISMS; TEMPORAL NEURONS; DEPTH-PERCEPTION; COMPLEX CELLS; AWAKE MONKEYS; PRIMATE V1 AB Stereo vision relies on cortical signals that encode binocular disparity. In V1, the disparity energy model explains many features of binocular interaction, but it overestimates the responses to anticorrelated images. Combining the outputs of two, or more, energy model-like subunits [two-subunit (2SU) model] can resolve this discrepancy and provides an alternative explanation for disparity signals previously thought to indicate phase disparity between the receptive fields (RFs) of each eye. The 2SU model naturally explains how "near/far" (odd-symmetric) tuning becomes dominant in extrastriate cortex. To compare the energy and the 2SU models, we used a broadband compound grating and applied a common interocular phase difference to all spatial frequency components (a stimulus phase disparity), combined with a common spatial displacement (a stimulus position disparity). This produces binocular images that never occur in natural viewing, for which the 2SU model and the energy model make distinctively different predictions. Responses of neurons recorded from both V1 and V2 of awake rhesus macaques systematically deviated from the predictions of the energy model, in accordance with the 2SU model. These deviations correlated with the symmetry of the tuning curve, indicating that the 2SU mechanism is exploited to produce odd symmetry. Nonetheless, individual subunits also contain RF phase disparity that contributes to odd symmetry. The results suggest that neurons in V2 probably inherit phase disparity signals from V1 neurons, but systematically combine input from V1 neurons with different position disparities, in a way that elaborates odd-symmetric tuning and extends the range of disparities encoded by single neurons. C1 [Tanabe, Seiji; Cumming, Bruce G.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Tanabe, S (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50, Bethesda, MD 20892 USA. EM tanabes@nei.nih.gov FU Intramural Program of the National Eye Institute-National Institutes of Health; Long-Term Fellowship of the Human Frontier Science Program FX This work was supported by the Intramural Program of the National Eye Institute-National Institutes of Health. We thank Denise Parker and Bethany Case for excellent animal care. S. T. was supported by the Long-Term Fellowship of the Human Frontier Science Program. NR 33 TC 15 Z9 17 U1 1 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 29 PY 2008 VL 28 IS 44 BP 11304 EP 11314 DI 10.1523/JNEUROSCI.3477-08.2008 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 366RZ UT WOS:000260502400021 PM 18971472 ER PT J AU Leenders, AGM Lin, L Huang, LD Gerwin, C Lu, PH Sheng, ZH AF Leenders, A. G. Miriam Lin, Lin Huang, Li-Dong Gerwin, Claudia Lu, Pei-Hua Sheng, Zu-Hang TI The Role of MAP1A Light Chain 2 in Synaptic Surface Retention of Ca(V)2.2 Channels in Hippocampal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium channels; presynaptic; surface expression; synaptic; axonal transport; microtubule; presynaptic regulation; actin ID MICROTUBULE-ASSOCIATED PROTEIN-1A; PRESYNAPTIC CALCIUM-CHANNELS; NEUROTRANSMITTER RELEASE; POTASSIUM CHANNEL; NERVE-TERMINALS; BINDING; RECEPTOR; TRANSMISSION; INHIBITION; COMPLEX AB Ca(v)2.2 channels are localized at nerve terminals where they play a critical role in neurotransmission. However, the determinant that controls surface retention of these channels has not been identified. Here, we report that presynaptic surface localization of Ca(v)2.2 is mediated through its interaction with light chain 2 (LC2) of microtubule-associated protein MAP1A. Deletion of a 23-residue binding domain within the Ca(v)2.2 C terminus resulted in reduced synaptic distribution of the mutant channels. Using an antibody generated against an extracellular epitope of Ca(v)2.2, we demonstrate that interfering the interaction with LC2 reduced surface expression of endogenous Ca(v)2.2 at presynaptic boutons. In addition, the disruption of LC2-Ca(v)2.2 coupling reduced Ca2+-influx into nerve terminals through Ca(v)2.2 and impaired activity-dependent FM4-64 uptake. The treatments of neurons with Latrunculin A to disrupt actin filaments resulted in reduced density of surface Ca(v)2.2-positive boutons. Furthermore, LC2NT, a LC2 truncated mutant lacking the actin-binding domain, could not rescue Ca(v)2.2 surface expression after suppressing LC2 expression with RNAi. Because actin filaments are major cytomatric components at the presynaptic boutons, these observations suggest a mechanism by which LC2 provides anchoring of surface Ca(v)2.2 to the actin cytoskeleton, thus contributing to presynaptic function. C1 [Leenders, A. G. Miriam; Gerwin, Claudia; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Lin, Lin; Huang, Li-Dong; Lu, Pei-Hua] Shanghai Jiao Tong Univ, Sch Med, Dept Neurobiol, Shanghai 200025, Peoples R China. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 3B203,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002946-11] NR 41 TC 15 Z9 16 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 29 PY 2008 VL 28 IS 44 BP 11333 EP 11346 DI 10.1523/JNEUROSCI.3078-08.2008 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 366RZ UT WOS:000260502400024 PM 18971475 ER PT J AU Mickey, BJ Ducci, F Hodgkinson, CA Langenecker, SA Goldman, D Zubieta, JK AF Mickey, Brian J. Ducci, Francesca Hodgkinson, Colin A. Langenecker, Scott A. Goldman, David Zubieta, Jon-Kar TI Monoamine Oxidase A Genotype Predicts Human Serotonin 1A Receptor Availability In Vivo SO JOURNAL OF NEUROSCIENCE LA English DT Article DE sex difference; polymorphism; positron emission tomography; serotonin; serotonergic 1A receptor; monoamine oxidase; imaging; genetics; human; depression ID POSITRON-EMISSION-TOMOGRAPHY; NATIONAL EPIDEMIOLOGIC SURVEY; COMORBIDITY-SURVEY; TREATMENT RESPONSE; PANIC DISORDER; GENE PROMOTER; BINDING; BRAIN; DEPRESSION; SEX AB The serotonergic system, including the serotonin 1A (5-HT1A) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data show substantial interindividual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT1A receptor expression. We used positron emission tomography and [C-11]WAY-100635 to quantify 5-HT1A receptors in a group of 31 healthy and unmedicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. ANOVA of 5-HT1A receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p < 0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT1A receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p < 0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT1A receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes. C1 [Mickey, Brian J.; Langenecker, Scott A.; Zubieta, Jon-Kar] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Mickey, Brian J.; Langenecker, Scott A.; Zubieta, Jon-Kar] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Ducci, Francesca; Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20892 USA. RP Zubieta, JK (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, 205 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM zubieta@umich.edu RI Langenecker, Scott/F-3548-2012; Mickey, Brian/J-1756-2014; Goldman, David/F-9772-2010 OI Langenecker, Scott/0000-0002-7932-5494; Mickey, Brian/0000-0002-7847-7680; Goldman, David/0000-0002-1724-5405 FU National Institute of Mental Health [P01 MH42251, R25 MH6374]; National Institute on Alcohol Abuse and Alcoholism Intramural Research Program; General Clinical Research Center at the University of Michigan (National Institutes of Health) [RR00042] FX This work was supported by National Institute of Mental Health Grants P01 MH42251 and R25 MH6374, National Institute on Alcohol Abuse and Alcoholism Intramural Research Program, and the General Clinical Research Center at the University of Michigan (National Institutes of Health Grant RR00042). We thank Virginia Murphy-Weinberg and the technologists of the PET Center at the University of Michigan for their assistance in the performance of the studies. NR 47 TC 29 Z9 30 U1 2 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 29 PY 2008 VL 28 IS 44 BP 11354 EP 11359 DI 10.1523/JNEUROSCI.2391-08.2008 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 366RZ UT WOS:000260502400026 PM 18971477 ER PT J AU Zhang, HL Pommier, Y AF Zhang, Hongliang Pommier, Yves TI Mitochondrial Topoisomerase I Sites in the Regulatory D-Loop Region of Mitochondrial DNA SO BIOCHEMISTRY LA English DT Article ID CLEAVAGE COMPLEXES; CAMPTOTHECIN; REPLICATION; DISEASE; CELLS; NUCLEOIDS; ORIGIN; CANCER; BREAKS AB Mitochondrial DNA (mtDNA) is required for mitochondrial activities because it encodes key proteins for oxidative phosphorylation and the production of cellular ATP. We previously reported the existence of a specific mitochondrial topoisomerase gene, Top1mt, in all vertebrates. The corresponding polypeptide contains an N-terminal mitochondrial targeting sequence and is otherwise highly homologous to the nuclear topoisomerase I (Top1). In this study, we provide biochemical evidence of the presence of an endogenous Top1mt polypeptide in human mitochondria. Using novel antibodies against Top1mt, we detected the corresponding 70 kDa polypeptide in mitochondria but not in nuclear fractions. This polypeptide could be trapped to form covalent complexes with mtDNA when mitochondria from human cells were treated with camptothecin. Mapping of Top1mt sites in the regulatory D-loop region of mtDNA in mitochondria revealed the presence of an asymmetric cluster of Top1mt sites confined to a 150 bp segment downstream from, and adjacent to, the site at which replication is prematurely terminated, generating an -base (7S DNA) product that forms the mitochondrial D-loop. Moreover, we show that inhibition of, 650 Top1mt by camptothecin reduces the level of formation of the 7S DNA. These results suggest novel roles for Top1mt in regulating mtDNA replication. C1 [Zhang, Hongliang; Pommier, Yves] Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Mol Pharmacol Lab, Bldg 10,Rm 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research (CCR); National Cancer Institute; National Institutes of Health FX These studies were supported by the Center for Cancer Research (CCR) of the National Cancer Institute, National Institutes of Health. NR 30 TC 23 Z9 25 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 28 PY 2008 VL 47 IS 43 BP 11196 EP 11203 DI 10.1021/bi800774b PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 363FZ UT WOS:000260254500006 PM 18826252 ER PT J AU Ranguelova, K Suarez, J Magliozzo, RS Mason, RP AF Ranguelova, Kalina Suarez, Javier Magliozzo, Richard S. Mason, Ronald P. TI Spin Trapping Investigation of Peroxide- and Isoniazid-Induced Radicals in Mycobacterium tuberculosis Catalase-Peroxidase SO BIOCHEMISTRY LA English DT Article ID HYDROGEN-PEROXIDE; CYTOCHROME-C; ORGANIC HYDROPEROXIDES; POTENTIAL MECHANISM; CRYSTAL-STRUCTURE; ELECTRON-TRANSFER; PROTEIN RADICALS; KATG; ACTIVATION; IDENTIFICATION AB A new approach, the immuno-spin trapping assay, used a novel rabbit polyclonal anti-DMPO (5,5-dimethyl-1-pyrroline N-oxide) antiserum to detect protein radical-derived DMPO nitrone adducts in the hemoprotein Mycobacterium tuberculosis catalase-peroxidase (KatG). This work demonstrates that the formation of protein nitrone adducts is dependent on the concentrations of tert-BuOOH and DMPO as shown by Western blotting and an enzyme-linked immunosorbent assay (ELISA). We have also detected protein-protein cross-links formed during turnover of Mtb KatG driven by tert-butyl peroxide (tert-BuOOH) or enzymatic generation of hydrogen peroxide. DMPO inhibits this dimerization due to its ability to trap the amino acid radicals responsible for the cross-linkage. Chemical modifications by tyrosine and tryptophan blockage suggest that tyrosine residues are one site of formation of the dimers. The presence of the tuberculosis drug isoniazid (INH) also prevented cross-linking as a result of its competition for the protein radical. Protein-DMPO nitrone adducts were also generated by a continuous flux of hydrogen peroxide. These findings demonstrated that the protein-based radicals were formed not only during Mtb KatG turnover with alkyl peroxides but also in the presence of hydrogen peroxide. Furthermore, the formation of protein-DMPO nitrone adducts was accelerated in the presence of isoniazid. C1 [Ranguelova, Kalina; Mason, Ronald P.] NIEHS, NIH, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Magliozzo, Richard S.] Brooklyn Coll, Dept Chem, Brooklyn, NY 11210 USA. [Suarez, Javier; Magliozzo, Richard S.] CUNY, Grad Ctr, Dept Biochem, New York, NY 10016 USA. RP Ranguelova, K (reprint author), 111 TW Alexander Dr,Bldg 101,MD F0-02, Res Triangle Pk, NC 27709 USA. EM ranguelovak@niehs.nih.gov FU National Institutes of Health; National Institute of Enviromnental Health Sciences; NIH [AI-43582, AI-060014] FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Enviromnental Health Sciences and NIH Grants AI-43582 and AI-060014 (National Institute of Allergy and Infections). NR 53 TC 23 Z9 23 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 28 PY 2008 VL 47 IS 43 BP 11377 EP 11385 DI 10.1021/bi800952b PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 363FZ UT WOS:000260254500024 PM 18831539 ER PT J AU Billemont, B Medioni, J Taillade, L Helley, D Meric, JB Rixe, O Oudard, S AF Billemont, B. Medioni, J. Taillade, L. Helley, D. Meric, J. B. Rixe, O. Oudard, S. TI Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib SO BRITISH JOURNAL OF CANCER LA English DT Article DE renal cell carcinoma; sunitinib; diabetes; glucose level; tyrosine-kinase inhibitor; VEGF AB Sunitinib, a multitargeted tyrosine-kinase inhibitor, extends survival of patients with metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumours. Between October 2005 and March 2007, we retrospectively reviewed blood glucose level variations associated with sunitinib therapy in patients treated for mRCC. Nineteen of the patients had type II diabetes. All 19 patients had a decrease in blood glucose level ( mean 1.77 mmol 1(-1)) after 4 weeks of treatment. This was followed by re-elevation in the 2-week rest period. After two cycles of sunitinib administration, two patients had stopped blood glucose-lowering drugs whereas five other patients had normalised their blood glucose level. On the basis of pre-clinical data, we hypothesise that several mechanisms could be involved in this process, such as capillary regression of pancreatic islets, IGF-1 modulation through HIF1-alpha or NF-kappa B activation. In addition, a decrease of glucose uptake in the context of concomitant gastrointestinal toxicity cannot be excluded. Glycaemic control should be carefully evaluated in diabetic patients treated with sunitinib, and routine monitoring is warranted. C1 [Billemont, B.; Taillade, L.; Meric, J. B.; Rixe, O.] Grp Hosp Pitie Salpetriere, Dept Med Oncol, F-75634 Paris, France. [Medioni, J.; Oudard, S.] Georges Pompidou Hosp, Dept Med Oncol, Paris, France. [Helley, D.] Georges Pompidou Hosp, Dept Biol, Paris, France. RP Rixe, O (reprint author), NCI, Bethesda, MD 20892 USA. EM rixeo@mail.nih.gov NR 12 TC 36 Z9 37 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 28 PY 2008 VL 99 IS 9 BP 1380 EP 1382 DI 10.1038/sj.bjc.6604709 PG 3 WC Oncology SC Oncology GA 366SE UT WOS:000260502900003 PM 18841151 ER PT J AU Lauer, M AF Lauer, Michael TI Screening for Coronary Artery Disease: Is It Too Soon to Think Clinically? SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Lauer, Michael] NHLBI, Bethesda, MD 20892 USA. RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP A23 EP A23 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500014 ER PT J AU Ahmet, I Talan, MI Lakatta, EG AF Ahmet, Ismayil Talan, Mark I. Lakatta, Edward G. TI Comparison of a Combination of beta 1-Adrenergic Receptor (AR) Blocker and beta 2AR Agonist vs. a Combination of beta 1AR Blocker and Angiotensin Converting Enzyme Inhibitor for the Treatment of Chronic Heart Failure SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Ahmet, Ismayil; Talan, Mark I.; Lakatta, Edward G.] NIA, NIH, Baltimore, MD 21224 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S799 EP S799 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502669 ER PT J AU Amar, MJ Demosky, S Stonick, J Voogt, J Turner, S Nigora, M Sviridov, D Remaley, AT AF Amar, Marcelo J. Demosky, Steve Stonick, John Voogt, Jason Turner, Scott Nigora, Mukhamedova Sviridov, Dmitri Remaley, Alan T. TI Mechanism for Atheroprotection in Mice by 5A, a bi-helical ApoA-I Mimetic Peptide SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Amar, Marcelo J.; Demosky, Steve; Stonick, John; Remaley, Alan T.] NIH, Bethesda, MD 20892 USA. [Nigora, Mukhamedova; Sviridov, Dmitri] Baker Heart Res Inst, Melbourne, Vic, Australia. [Voogt, Jason; Turner, Scott] Kinemed, Emeryville, CA USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S410 EP S410 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500633 ER PT J AU Asico, LD Zhang, XJ Jiang, JF Cabrera, D Escano, CS Armando, I Luo, YJ Sibley, D Mannon, R Jose, PA AF Asico, Laureano D. Zhang, Xiaojie Jiang, Jifu Cabrera, David Escano, Crisanto S. Armando, Ines Luo, Yingjin Sibley, David Mannon, Roslyn Jose, Pedro A. TI Cross-transplantation Studies Demonstrate the Role of Renal Dopamine D-5 Receptors in Hypertension SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Asico, Laureano D.; Escano, Crisanto S.; Armando, Ines; Luo, Yingjin; Jose, Pedro A.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Jiang, Jifu] Univ Western Ontario, London, ON N6A 3K7, Canada. [Sibley, David] NINDS, NIH, Bethesda, MD 20892 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 SU 2 BP S382 EP S382 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500508 ER PT J AU Cao, JJ Sigurdsson, S Kellman, P Aletras, AH Vincent, P Padmanabhan, S Shizukuda, Y Shizukuda, Y Shizukuda, Y Dyke, C Launer, L Eirksdottir, G Thorgeirsson, G Aspelund, T Gudnason, V Harris, T Arai, A AF Cao, Jie J. Sigurdsson, Sigurdur Kellman, Peter Aletras, Anthony H. Vincent, Pamela Padmanabhan, Shiram Shizukuda, Yukitaka Shizukuda, Yukitaka Shizukuda, Yukitaka Dyke, Christopher Launer, Lenore Eirksdottir, Gudny Thorgeirsson, Gudmundur Aspelund, Thor Gudnason, Vilmundur Harris, Tamara Arai, Andrew TI Prognostic Value of Myocardial Infarction and Left Ventricular Ejection Fraction In Elderly Subjects: Insights from the ICELAND-MI Substudy of AGES-Reykjavik SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Cao, Jie J.] St Francis Hosp, Roslyn, NY USA. [Sigurdsson, Sigurdur; Eirksdottir, Gudny; Thorgeirsson, Gudmundur; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Reykjavik, Ireland. [Kellman, Peter; Aletras, Anthony H.; Vincent, Pamela; Padmanabhan, Shiram; Shizukuda, Yukitaka; Shizukuda, Yukitaka; Shizukuda, Yukitaka; Dyke, Christopher; Launer, Lenore; Arai, Andrew] NIH, Bethesda, MD 20892 USA. [Harris, Tamara] NHLBI, Bethesda, MD 20892 USA. RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S839 EP S839 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104503075 ER PT J AU Chavakis, E Hain, A Orlandi, A Carmona, G Quertermous, T Chavalkis, T Dimmeler, S AF Chavakis, Emmanouil Hain, Andreas Orlandi, Alessia Carmona, Guillaume Quertermous, Thomas Chavalkis, Triantafyllos Dimmeler, Stefanie TI Del-1, A New beta 2-Integrin Ligand, Which Inhibits Adhesion and Homing of Progenitor Cells SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Chavakis, Emmanouil; Hain, Andreas; Orlandi, Alessia; Carmona, Guillaume; Dimmeler, Stefanie] Univ Frankfurt, Frankfurt, Germany. [Quertermous, Thomas] Stanford Sch Med, Stanford, CA USA. [Chavalkis, Triantafyllos] NCI, 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S502 EP S502 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104501228 ER PT J AU Des, S Wong, R Rajapakse, N Murphy, E Steenbergen, C AF Des, Samarjit Wong, Renee Rajapakse, Nishadi Murphy, Elizabeth Steenbergen, Charles TI Inhibition of GSK Can Produce Cardioprotection by Slowing Adenine Nucleotide Transport across the Outer Mitochondrial Membrane without Affecting the Mitochondrial Permeability Transition SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Des, Samarjit; Steenbergen, Charles] Johns Hopkins Univ, Baltimore, MD USA. [Wong, Renee; Murphy, Elizabeth] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. [Rajapakse, Nishadi] NIEHS, NIH, RTP, 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S355 EP S355 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500385 ER PT J AU Deschamps, AM Murphy, E AF Deschamps, Anne M. Murphy, Elizabeth TI Activation of a Novel Estrogen Receptor, GPR30, is Cardioprotective in the Rat SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Deschamps, Anne M.; Murphy, Elizabeth] NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S357 EP S358 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500396 ER PT J AU Dezfulian, C Shiva, S Pendyal, A Alekseyenko, A Anderson, SA Gladwin, MT AF Dezfulian, Cameron Shiva, Sruti Pendyal, Akshay Alekseyenko, Aleksey Anderson, Stasia A. Gladwin, Mark T. TI Nitrite Therapy upon Resuscitation from Cardiac Arrest Reversibly Inhibits Mitochondrial Complex I Reducing ROS Burst and Improving Cardiac Function and Survival SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Dezfulian, Cameron; Shiva, Sruti; Pendyal, Akshay; Alekseyenko, Aleksey; Anderson, Stasia A.; Gladwin, Mark T.] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1452 EP S1452 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504697 ER PT J AU Farasat, SM Valdes, C Shetty, V Muller, DC Egan, JM Ferrucci, L Najjar, SS AF Farasat, S. Morteza Valdes, Carolina Shetty, Veena Muller, Denis C. Egan, Josephine M. Ferrucci, Luigi Najjar, Samer S. TI Longitudinal Pulse Pressure is a Better Predictor of 24-Hour Urinary Albumin Excretion than Other Indices of Blood Pressure: The Baltimore Longitudinal Study of Aging SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Farasat, S. Morteza; Valdes, Carolina; Shetty, Veena; Muller, Denis C.; Egan, Josephine M.; Ferrucci, Luigi; Najjar, Samer S.] NIA, NIH, Baltimore, MD 21224 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S803 EP S803 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502688 ER PT J AU Fedorova, OV Zakharova, IO Bagrov, AY AF Fedorova, Olga V. Zakharova, Irina O. Bagrov, Alexei Y. TI Age-Dependent Increase in Salt Sensitivity is Associated with a Shift in ANP Modulation of the Effect of Marinobufagenin on Renal and Vascular Sodium Pump SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Fedorova, Olga V.; Zakharova, Irina O.; Bagrov, Alexei Y.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S348 EP S348 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500356 ER PT J AU Fox, CS Gona, P Hoffmann, U Salton, CJ Massaro, J Levy, D Larson, M D'Agostino, RB O'Donnell, CJ Manning, WJ AF Fox, Caroline S. Gona, Philimon Hoffmann, Udo Salton, Carol J. Massaro, Joseph Levy, Daniel Larson, Martin D'Agostino, Ralph B. O'Donnell, Christopher J. Manning, Warren J. TI Pericardial Fat, Intra-Thoracic Fat, and Left Ventricular Mass: The Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Fox, Caroline S.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [Gona, Philimon; Massaro, Joseph; Larson, Martin; D'Agostino, Ralph B.] Boston Univ, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Salton, Carol J.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1152 EP S1152 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504576 ER PT J AU Fox, CS Muntner, P Chen, AY Alexander, KP Roe, MT Saucedo, JF Wiviott, SD AF Fox, Caroline S. Muntner, Paul Chen, Anita Y. Alexander, Karen P. Roe, Matthew T. Saucedo, Jorge F. Wiviott, Stephen D. TI Short-Term Outcomes of STEMI and NSTEMI in Patients with Chronic Kidney Disease: A Report from the National Cardiovascular Data ACTION Registry SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Fox, Caroline S.] NHLBI, Framingham, MA USA. [Muntner, Paul] Mt Sinai Sch Med, New York, NY USA. [Chen, Anita Y.; Alexander, Karen P.; Roe, Matthew T.] Duke Clin Rsch Inst, Durham, NC USA. [Saucedo, Jorge F.] Univ Oklahoma Hlth Sci, Oklahoma City, OK USA. [Wiviott, Stephen D.] Brigham & Womens Hosp, Boston, MA 02115 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S966 EP S966 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104503579 ER PT J AU Franklin, SS Lopez, VA Wong, ND Mitchell, GF Larson, MG Vasan, RS Levy, D AF Franklin, Stanley S. Lopez, Victor A. Wong, Nathan D. Mitchell, Gary F. Larson, Martin G. Vasan, Romachandran S. Levy, Daniel TI Single Versus Paired Blood Pressure Components and Risk for Cardiovascular Disease: The Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Franklin, Stanley S.; Lopez, Victor A.; Wong, Nathan D.] Univ Calif Irvine, Irvine, CA USA. [Mitchell, Gary F.] Cardiovasc Engn, Waltham, MA USA. [Larson, Martin G.; Vasan, Romachandran S.; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Levy, Daniel] NHLBI, Framingham, MA USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S803 EP S803 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502686 ER PT J AU Garg, PK Liu, K Tian, L Guralnik, JM Ferrucci, LM Criqui, MH Tan, J McDermott, MM AF Garg, Parveen K. Liu, Kiang Tian, Lu Guralnik, Jack M. Ferrucci, Luigi M. Criqui, Michael H. Tan, Jin McDermott, Mary M. TI Physical Activity during Daily Life and Functional Decline in Peripheral Arterial Disease: A Prospective Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Garg, Parveen K.] NYU, New York, NY USA. [Liu, Kiang; Tian, Lu; Tan, Jin; McDermott, Mary M.] Northwestern Univ, Chicago, IL 60611 USA. [Guralnik, Jack M.; Ferrucci, Luigi M.] NIA, Bethesda, MD 20892 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S809 EP S810 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502713 ER PT J AU Georgiopoulou, VV Kalogeropoulos, AP de Rekeneire, N Rodondi, N Smith, AL Hoffmann, U Kanaya, A Newman, AB Kritchevsky, SB Vasan, RS Wilson, PW Harris, TB Butler, J AF Georgiopoulou, Vasiliki V. Kalogeropoulos, Andreas P. de Rekeneire, Nathalie Rodondi, Nicolas Smith, Andrew L. Hoffmann, Udo Kanaya, Alka Newman, Anne B. Kritchevsky, Stephen B. Vasan, Ramachandran S. Wilson, Peter W. Harris, Tamara B. Butler, Javed TI Serum Resistin Concentrations and Risk of New Onset Heart Failure in the Elderly SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Georgiopoulou, Vasiliki V.; Kalogeropoulos, Andreas P.; Smith, Andrew L.; Wilson, Peter W.; Butler, Javed] Emory Univ, Atlanta, GA 30322 USA. [de Rekeneire, Nathalie] EpiCntr, Paris, France. [Rodondi, Nicolas] Univ Lausanne, Lausanne, Switzerland. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kanaya, Alka] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1021 EP S1021 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504058 ER PT J AU Glaser, ND Ke, YB Zhu, WZ Zhao, AZ Solaro, RJ Lakatta, EG Xiao, RP AF Glaser, Nicole D. Ke, Yunbo Zhu, Weizhong Zhao, Aizhi Solaro, R. John Lakatta, Edward G. Xiao, Rui-Ping TI PKA Constitutes a Novel Activator of Cardiac Protective Pak1 Signaling SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Glaser, Nicole D.; Zhu, Weizhong; Zhao, Aizhi; Lakatta, Edward G.; Xiao, Rui-Ping] NIA, Baltimore, MD 21224 USA. [Ke, Yunbo; Solaro, R. John] Univ Illinois, Chicago, IL USA. NR 0 TC 1 Z9 1 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S319 EP S319 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500230 ER PT J AU Goldberger, JJ Borrow, R Cuffe, M Dyer, A Rosenberg, Y O'Rourke, R Shah, PK Smith, S AF Goldberger, Jeffrey J. Borrow, Robert Cuffe, Michael Dyer, Alan Rosenberg, Yves O'Rourke, Robert Shah, Prediman K. Smith, Sidney CA PACE MI Investigators TI Are Beta-blockers Underdosed Following Acute Myocardial Infarction? SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Goldberger, Jeffrey J.; Borrow, Robert; Dyer, Alan] NW Mem Hosp, Chicago, IL 60611 USA. [Cuffe, Michael] Duke Univ Hlth Syst, Durham, NC USA. [Rosenberg, Yves] NIH, Bethesda, MD 20892 USA. [O'Rourke, Robert] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Shah, Prediman K.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Smith, Sidney] Univ N Carolina, Chapel Hill Sch Med, Chapel Hill, NC USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S969 EP S969 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104503590 ER PT J AU Gorodeski, EZ Ishwaran, H Blackstone, EH Lauer, MS AF Gorodeski, Eiran Z. Ishwaran, Hemant Blackstone, Eugene H. Lauer, Michael S. TI Sub-Clinical Electrocardiographic Abnormalities Predict Mortality among Primary Prevention Exercise Test Patients with a Qualitatively Normal Electrocardiogram SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Gorodeski, Eiran Z.; Ishwaran, Hemant; Blackstone, Eugene H.] Cleveland Clin, Cleveland, OH 44106 USA. [Lauer, Michael S.] NHLBI, Bethesda, MD 20892 USA. RI Gorodeski, Eiran/D-5384-2009; Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1147 EP S1147 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504554 ER PT J AU Herrera, JE Yanek, LR Mathias, R Wilson, AF May, TF Becker, LC Becker, DM AF Herrera, J. E. Yanek, Lisa R. Mathias, Rasika Wilson, Alexander F. May, Taryn F. Becker, Lewis C. Becker, Diane M. TI Genome-Wide Association Study Identities Loci Associated with a Global Measure at Well-Being SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Herrera, J. E.; Yanek, Lisa R.; May, Taryn F.; Becker, Lewis C.; Becker, Diane M.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Mathias, Rasika; Wilson, Alexander F.] NIH, Baltimore, MD USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1143 EP S1144 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504541 ER PT J AU Howard, BV Devereux, RB Fleg, JL Howard, WJ Mete, M Otvos, JD Ratner, RE Roman, MJ Russell, M Umans, JG Weissman, NJ AF Howard, Barbara V. Devereux, Richard B. Fleg, Jerome L. Howard, Wm. James Mete, Mihriye Otvos, James D. Ratner, Robert E. Roman, Mary J. Russell, Marie Umans, Jason G. Weissman, Neil J. TI The SANDS Trial: Does Aggressive Lowering of LDL-C and Non-HDL-C in Diabetes Decrease the Plasma ApoB and LDL-C Particle Number? SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Howard, Barbara V.; Mete, Mihriye; Ratner, Robert E.; Umans, Jason G.; Weissman, Neil J.] MedStar Rsch Inst, Hyattsville, MD USA. [Devereux, Richard B.; Roman, Mary J.] Weill Cornell Med Coll, New York, NY USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Howard, Wm. James] Washington Hosp Cntr, Washington, DC USA. [Otvos, James D.] Liposci Inc, Raleigh, NC USA. [Russell, Marie] Phoenix Indian Med Cntr, Phoenix, AZ USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1136 EP S1136 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504509 ER PT J AU Huang, CC Fornage, M Lloyd-Jones, DM Wei, GS Boerwinkle, E Liu, K AF Huang, Chiang-Ching Fornage, Myriam Lloyd-Jones, Donald M. Wei, Gina S. Boerwinkle, Eric Liu, Kiang TI Association of PCSK9 Gene Variants with Longitudinal LDL-Cholesterol Levels: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Huang, Chiang-Ching; Lloyd-Jones, Donald M.; Liu, Kiang] Northwestern Univ, Chicago, IL 60611 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Houston, TX USA. [Wei, Gina S.] NHLBI, Bethesda, MD 20892 USA. RI Lloyd-Jones, Donald/C-5899-2009 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1101 EP S1102 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504374 ER PT J AU Kalogeropoulos, AP Georglopoulou, VV Kritchevsky, S Psaty, B Rodondi, N Smith, N Bauer, DC Bibbins-Domingo, K Satterfield, S Smith, AL Newman, AB Vasan, R Harris, TB Wilson, PW Butler, J AF Kalogeropoulos, Andreas P. Georglopoulou, Vasiliki V. Kritchevsky, Stephen Psaty, Bruce Rodondi, Nicolas Smith, Nicholas Bauer, Douglas C. Bibbins-Domingo, Kirsten Satterfield, Suzanne Smith, Andrew L. Newman, Anne B. Vasan, Ramachandran Harris, Tamara B. Wilson, Peter W. Butler, Javed TI Epidemiology of Incident Heart Failure in a Contemporary Elderly Population: The Health, Aging, and Body Composition (Health ABC) Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Kalogeropoulos, Andreas P.; Georglopoulou, Vasiliki V.] Emory Univ, Atlanta, GA 30322 USA. [Kritchevsky, Stephen] Wake Forest Univ, Winston Salem, NC 27109 USA. [Psaty, Bruce; Smith, Nicholas] Univ Washington, Seattle, WA 98195 USA. [Rodondi, Nicolas] Univ Lausanne, Lausanne, Switzerland. [Bauer, Douglas C.; Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Memphis, Memphis, TN 38152 USA. [Smith, Andrew L.] Emory Univ, Atlanta, GA 30322 USA. [Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Vasan, Ramachandran] Boston Univ, Boston, MA 02215 USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Wilson, Peter W.; Butler, Javed] Emory Univ, Atlanta, GA 30322 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S715 EP S715 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502330 ER PT J AU Kanda, T Orasanu, G Brown, J Gonzalez, F Plutzky, J AF Kanda, Takeshi Orasanu, Gabriela Brown, Jonathan Gonzalez, Frank Plutzky, Jorge TI Endothelial PPAR gamma Regulates Lipid Metabolism And Adiposity After High Fat Feeding SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Kanda, Takeshi; Orasanu, Gabriela; Brown, Jonathan; Plutzky, Jorge] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gonzalez, Frank] NCI, 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S424 EP S424 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500696 ER PT J AU Lan, HY Huang, XR Chung, AC Yang, FY Zhou, L Deng, CX Tse, HF Lau, CP AF Lan, Hui Y. Huang, Xiao R. Chung, Arthur C. Yang, Fuye Zhou, Li Deng, Chuxia Tse, Hung-Fat Lau, Chu Pak TI Mice Lacking Smad3 are Protected against Anglotensin II-Induced Cardiac Inflammation and Fibrosis SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Lan, Hui Y.; Huang, Xiao R.; Chung, Arthur C.; Yang, Fuye; Zhou, Li; Tse, Hung-Fat; Lau, Chu Pak] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Deng, Chuxia] NIDDK, NIH, Bethesda, MD USA. RI deng, chuxia/N-6713-2016 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S385 EP S385 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500521 ER PT J AU Lu, ZB Fassett, J Xu, X Hu, XL Zhu, GS Schnermann, J Bache, RJ Chen, YJ AF Lu, Zhongbing Fassett, John Xu, Xin Hu, Xinli Zhu, Guangshuo Schnermann, Jurgen Bache, Robert J. Chen, Yingjie TI Adenosine A3 Receptor Deficiency Exerts Unanticipated Protective Effects on Pressure Overloaded-Induced Left Ventricular Hypertrophy and Dysfunction In Mice SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Lu, Zhongbing; Fassett, John; Xu, Xin; Hu, Xinli; Zhu, Guangshuo; Bache, Robert J.; Chen, Yingjie] Univ Minnesota, Minneapolis, MN USA. [Schnermann, Jurgen] NIDDK, Bethesda, MD USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S351 EP S351 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500367 ER PT J AU McDermott, MM Dyer, A Liu, K Guralnik, JM Ades, P Ferrucci, L Nelson, M Llyod-Jones, D Pearce, WH Van Horn, L Criqui, MH AF McDermott, Mary M. Dyer, Alan Liu, Kiang Guralnik, Jack M. Ades, Philip Ferrucci, Luigi Nelson, Miriam Llyod-Jones, Donald Pearce, William H. Van Hom, Linda Criqui, Michael H. TI Benefits of Strength Training and Supervised Treadmill Exercise on Walking Performance for Persons with Peripheral Arterial Disease with and without Intermittent Claudlcation Symptoms SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [McDermott, Mary M.; Dyer, Alan; Liu, Kiang; Llyod-Jones, Donald; Pearce, William H.; Van Hom, Linda] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Guralnik, Jack M.; Ferrucci, Luigi] NIA, NIH, Bethesda, MD 20892 USA. [Ades, Philip] Univ Vermont, Burlington, VT USA. [Nelson, Miriam] Tufts Univ, Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S905 EP S906 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104503338 ER PT J AU Munoz, M Hoskote, A Chadwick, M Gadian, D Baldeweg, T de Haan, M Khambadkone, S Mishkin, M Vargha-Khadem, F AF Munoz, Monica Hoskote, Aparna Chadwick, Martin Gadian, David Baldeweg, Torsten de Haan, Michelle Khambadkone, Sachin Mishkin, Mortimer Vargha-Khadem, Faraneh TI Memory Impairment And Hippocampal Pathology In Survivors Of The Arterial Switch Operation For Transposition Of Great Arteries SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Munoz, Monica; Chadwick, Martin; Gadian, David; Baldeweg, Torsten; de Haan, Michelle; Vargha-Khadem, Faraneh] UCL, Inst Child Hlth, London, England. [Hoskote, Aparna; Khambadkone, Sachin] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Mishkin, Mortimer] NIMH, NIH, Bethesda, MD 20892 USA. RI Vargha-Khadem, Faraneh/C-2558-2008 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1057 EP S1057 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504199 ER PT J AU Ogedegbe, GO Boutin-Foster, C Wells, MT Allegrante, JP Jobe, JB Chalson, ME AF Ogedegbe, Gbenga O. Boutin-Foster, Carla Wells, Martin T. Allegrante, John P. Jobe, Jared B. Chalson, Mary E. TI The Healthy Habits Trials: Positive affect induction improves medication adherence in hypertensive African Americans SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Ogedegbe, Gbenga O.] NYU, Sch Med, New York, NY USA. [Boutin-Foster, Carla; Wells, Martin T.; Chalson, Mary E.] Weill Cornell Med Coll, New York, NY USA. [Allegrante, John P.] Columbia Univ, New York, NY USA. [Jobe, Jared B.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1148 EP S1148 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504558 ER PT J AU Pendyal, A Dezfulian, C Zhang, LH Munasinghe, J Gladwin, MT AF Pendyal, Akshay Dezfulian, Cameron Zhang, Luhua Munasinghe, Jeeva Gladwin, Mark T. TI Functional, Histologic, and Radiographic Characteristics of Global Ischemia-reperfusion Brain Injury in a Mouse Model Of Cardiac Arrest SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Pendyal, Akshay] Univ N Carolina, Chapel Hill, NC USA. [Dezfulian, Cameron; Gladwin, Mark T.] NHLBI, NIH, Bethesda, MD 20892 USA. [Zhang, Luhua] NCI, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S586 EP S586 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104501592 ER PT J AU Plehn, JF Hasbani, K Horton, K Ernst, I Arai, AE Di Prospero, NA AF Plehn, Jonathan F. Hasbani, Karen Horton, Ken Ernst, Inez Arai, Andrew E. Di Prospero, Nicholas A. TI Short-term Effects of High Dose Idebenone on Left Ventricular Mass and Function in a Pediatric Cohort with Friedreich's Ataxia SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Plehn, Jonathan F.; Hasbani, Karen; Arai, Andrew E.] NHLBI, Bethesda, MD 20892 USA. [Horton, Ken] Medstar Rsch Inst, Washington, DC USA. [Di Prospero, Nicholas A.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S799 EP S799 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502670 ER PT J AU Preis, SR Pencina, MJ Hwang, SJ D'Agostino, RB Savage, P Levy, D Fox, CS AF Preis, Sarah R. Pencina, Michael J. Hwang, Shih-Jen D'Agostino, Ralph B., Sr. Savage, Peter Levy, Daniel Fox, Caroline S. TI Trends in Cardiovascular Disease Risk Factors among Middle-Aged Individuals with and without Diabetes in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Preis, Sarah R.; Hwang, Shih-Jen; Levy, Daniel; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pencina, Michael J.; D'Agostino, Ralph B., Sr.] Boston Univ, Boston, MA 02215 USA. [Savage, Peter] NHLBI, Bethesda, MD 20892 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1082 EP S1082 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504297 ER PT J AU Reynolds, HR Tamis-Holland, JE Kronsbarg, SS Stag, PG Carvalho, AC Loboz-Grudzien, K Kruk, M Sopko, G Ruzyllo, W Pearle, CA Forman, SA Lamas, GA Hochman, JS AF Reynolds, Harmony R. Tamis-Holland, Jacqueline E. Kronsbarg, Shari Similo Stag, Philippe Gabriel Carvalho, Antonio C. Loboz-Grudzien, Krystyna Kruk, Mariusz Sopko, George Ruzyllo, Witold Pearle, Camille A. Forman, Sandra A. Lamas, Gervasio A. Hochman, Judith S. TI Sex Differences in Outcomes after Myocardial Infarction with Persistent Total Occlusion of the Infarct Artery: Analysis of the Occluded Artery Trial SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Reynolds, Harmony R.] NYU, Sch Med, New York, NY USA. [Tamis-Holland, Jacqueline E.] St Lukes Roosevelt Hosp, New York, NY USA. [Tamis-Holland, Jacqueline E.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Kronsbarg, Shari Similo; Forman, Sandra A.] Maryland Med Rsch Inst, Baltimore, MD USA. [Stag, Philippe Gabriel] Univ Paris 07, Cntr Hosp Bichat Claude Bernard, Paris, France. [Carvalho, Antonio C.] Hosp Sao Paulo, Sao Paulo, Brazil. [Loboz-Grudzien, Krystyna] Med Acad Wroclaw, T Marciniak Hosp, Wroclaw, Poland. [Kruk, Mariusz; Ruzyllo, Witold] Natl Inst Cardiol, Warsaw, Poland. [Sopko, George] NHLBI, Bethesda, MD 20892 USA. [Pearle, Camille A.; Hochman, Judith S.] NYU, Sch Med, New York, NY USA. [Lamas, Gervasio A.] Univ Miami, Miller Sch Med, Miami, FL 33136 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S967 EP S967 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104503582 ER PT J AU Rosenfield, KA White, CJ Jones, PG Spertus, JA Cates, CU Ho, KK Jeff, MA Kcroshetz, WJ Caldwell, SP Brindis, RG Anderson, HV AF Rosenfield, K. A. White, C. J. Jones, P. G. Spertus, J. A. Cates, C. U. Ho, K. K. Jeff, M. A. Kcroshetz, W. J. Caldwell, S. P. Brindis, R. G. Anderson, H. V. TI Relationship Between Procedure Indications and Outcomes of Carotid Artery Stenting: Preliminary Results from the CARE Registry SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Rosenfield, K. A.; Jeff, M. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [White, C. J.] Ochsner Clin & Alton Ochsner Med Fdn, New Orleans, LA USA. [Jones, P. G.; Spertus, J. A.] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Cates, C. U.] Emory Univ, Atlanta, GA 30322 USA. [Ho, K. K.] Beth Israel Hosp, Boston, MA USA. [Kcroshetz, W. J.] NINDS, Bethesda, MD 20892 USA. [Caldwell, S. P.] Amer Coll Cardiol, Washington, DC USA. [Brindis, R. G.] Kaiser Permanente, Oakland, CA USA. [Anderson, H. V.] Univ Texas HSC, Houston, TX USA. RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S907 EP S907 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104503343 ER PT J AU Schelbert, E Cao, JJ Kellman, P Haletras, A Sigurdsson, S Aspelund, T Eiriksdottir, G Launer, LJ Harris, TB Gudnason, V Arai, AE AF Schelbert, Erik Cao, Jie J. Kellman, Peter Haletras, Anthony Sigurdsson, Sigurdur Aspelund, Thor Eiriksdottir, Gudny Launer, Lenore J. Harris, Tamara B. Gudnason, Vilmundur Arai, Andrew E. TI Prevalence of Unrecognized and Recognized Myocardial Infarction in Older Individuals with Elevated NT-pro-BNP SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Schelbert, Erik; Cao, Jie J.; Kellman, Peter; Haletras, Anthony; Arai, Andrew E.] NHLBI, Bethesda, MD 20892 USA. [Sigurdsson, Sigurdur; Aspelund, Thor; Eiriksdottir, Gudny] Iceland Heart Assoc, Kopavogur, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Gudnason, Vilmundur] Iceland Heart Assoc, Reykjavik, Iceland. RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1105 EP S1105 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504387 ER PT J AU Schinzari, F Tesauro, M Rovella, V Di Daniell, N Mores, N Melina, D Quon, MJ Cardillo, C AF Schinzari, Francesca Tesauro, Manfredi Rovella, Valentina Di Daniell, Nicola Mores, Nadia Melina, Domenico Quon, Michael J. Cardillo, Carmine TI Leptin Stimulates both Endothelin and Nitric Oxide Activity in the Human Forearm Circulation SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Schinzari, Francesca; Mores, Nadia; Melina, Domenico; Cardillo, Carmine] Catholic Univ, Sch Med, Rome, Italy. [Tesauro, Manfredi; Rovella, Valentina; Di Daniell, Nicola] Tor Vergata Univ, Sch Med, Rome, Italy. [Quon, Michael J.] NCCAM, NIH, Bethesda, MD USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S730 EP S730 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502394 ER PT J AU Schnabel, RB Sullivan, LM Levy, D Pencina, MJ Massaro, JM D'Agostino, RB Newton-Cheh, C Magnani, JW Tadros, TM Kennel, W Wang, TJ Ellinor, PT Wolf, PA Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Sullivan, Lisa M. Levy, Daniel Pencina, Michael J. Massaro, Joseph M. D'Agostino, Ralph B. Newton-Cheh, Christopher Magnani, Jared W. Tadros, Thomas M. Kennel, William Wang, Thomas J. Ellinor, Patrick T. Wolf, Philip A. Vasan, Ramachandran S. Benjamin, Emella J. TI Development of a Risk Score for Incident Atrial Fibrillation in the Community; the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Schnabel, Renate B.; Pencina, Michael J.; Tadros, Thomas M.; Kennel, William; Wang, Thomas J.; Wolf, Philip A.; Vasan, Ramachandran S.; Benjamin, Emella J.] NHLBI, Framingham Heart Study, Boston, MA USA. [Sullivan, Lisa M.; D'Agostino, Ralph B.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Newton-Cheh, Christopher] Broad Inst Harvard, Cambridge, MA USA. [Newton-Cheh, Christopher] MIT, Cambridge, MA 02139 USA. [Magnani, Jared W.] Boston Univ, Dept Cardiol, Boston, MA 02215 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Rsch Ctr, Boston, MA 02114 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1089 EP S1090 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504328 ER PT J AU Sethi, AA Sampson, M Warrick, R Nordestgaard, B Tybjaerg-Hansen, A Remaley, AT AF Sethi, Amar A. Sampson, Maureen Warrick, Russel Nordestgaard, Boerge Tybjaerg-Hansen, Anne Remaley, Alan T. TI Pre-Beta HDL and Lecithin:Cholesterol Acyltransferase Levels Are Strong Positive Diagnostic Risk Markers for Ischemic Heart Disease in Subjects with Both High and Low HDL-C Levels in the Copenhagen City Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Sethi, Amar A.; Sampson, Maureen; Remaley, Alan T.] NIH, Bethesda, MD 20892 USA. [Warrick, Russel] Berkeley HeartLab Inc, Burlingame, CA USA. [Nordestgaard, Boerge] Herlev Univ Hosp, DK-2730 Herlev, Denmark. [Tybjaerg-Hansen, Anne] Univ Copenhagen Hosp, DK-2100 Copenhagen, Denmark. NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S370 EP S370 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500450 ER PT J AU Sirenko, S Li, Y Yang, DM Lukyanenko, Y Lakatta, EG Vinogradova, TM AF Sirenko, Syevda Li, Yue Yang, Dongmei Lukyanenko, Yevgenia Lakatta, Edward G. Vinogradova, Tatiana M. TI Basal Phosphorylation Of Ca2+ Cycling Proteins By Both PKA And CAMKII is Required For Robust Generation Of Local Subsarcolemmal Ca2+ Releases To Drive Sinoatrial Node Cell Automaticity SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Sirenko, Syevda; Li, Yue; Yang, Dongmei; Lukyanenko, Yevgenia; Lakatta, Edward G.; Vinogradova, Tatiana M.] NIA, Gerontol Rsch Cntr, LCS, NIH, Baltimore, MD 21224 USA. NR 0 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 SU 2 BP S346 EP S346 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500349 ER PT J AU Song, MJ Despres, DJ Anderson, S San, H Perry, TE Erdos, M Collins, FS Cannon, RO Orlic, D AF Song, Minjung Despres, Dayl J. Anderson, Stasia San, Hong Perry, Tashera E. Erdos, Michael Collins, Francis S. Cannon, Richard O., III Orlic, Donald TI Bone Marrow Progenitor Cells Repair the Endothelium Overlying Sites of Damaged Smooth Muscle Cells in the Ascending Aorta in a Mouse Model of Progeria SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Song, Minjung; Anderson, Stasia; Perry, Tashera E.; Cannon, Richard O., III; Orlic, Donald] NHLBI, NIH, Bethesda, MD 20892 USA. [Despres, Dayl J.] NINDS, NIH, Bethesda, MD 20892 USA. [San, Hong; Erdos, Michael; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S508 EP S508 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104501254 ER PT J AU Tsao, CW Gona, P Salton, CJ Danias, PG Levy, D O'Donnell, CJ Manning, WJ Yeon, SB AF Tsao, Connie W. Gona, Philimon Salton, Carol J. Danias, Peter G. Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. Yeon, Susan B. TI Wall Motion Abnormalities Detected by Cardiovascular Magnetic Resonance Are Associated with Electrocardiographic Q Waves in a Free-Living Population SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Tsao, Connie W.; Salton, Carol J.; Danias, Peter G.; Manning, Warren J.; Yeon, Susan B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tsao, Connie W.; Salton, Carol J.; Danias, Peter G.; Manning, Warren J.; Yeon, Susan B.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Gona, Philimon] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Gona, Philimon; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Boston, MA USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1082 EP S1082 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504298 ER PT J AU Tsao, CW Gona, P Salton, CJ Murabito, JM Oyama, N Danias, PG Levy, D O'Donnell, CJ Manning, WJ Yeon, SB AF Tsao, Connie W. Gona, Philimon Salton, Carol J. Murabito, Joanne M. Oyama, Noriko Danias, Peter G. Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. Yeon, Susan B. TI Aortic and Peripheral Atherosclerosis is Related to Wall Motion Abnormalities Detected by Cardiovascular Magnetic Resonance: The Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Tsao, Connie W.; Salton, Carol J.; Oyama, Noriko; Danias, Peter G.; Manning, Warren J.; Yeon, Susan B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Gona, Philimon] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Gona, Philimon; Murabito, Joanne M.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI Framingham Heart Study, Boston, MA USA. RI Oyama-Manabe, Noriko/A-5212-2012 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S686 EP S686 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502212 ER PT J AU Turkbey, EB McClelland, RL Kronmal, RA Bild, D Burke, GL Tracy, RP Wilkins, L Arai, A Bluemke, DA AF Turkbey, Evrim B. McClelland, Robyn L. Kronmal, Richard A. Bild, Diane Burke, Gregory L. Tracy, Russell P. Wilkins, Linda Arai, Andrew Bluemke, David A. TI Obesity is Related to Concentric Left Ventricular Hypertrophy: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Turkbey, Evrim B.; Wilkins, Linda; Bluemke, David A.] Johns Hopkins Univ, Baltimore, MD USA. [McClelland, Robyn L.; Kronmal, Richard A.] Univ Washington, Seattle, WA 98195 USA. [Bild, Diane; Arai, Andrew] NIH, Bethesda, MD 20892 USA. [Burke, Gregory L.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Tracy, Russell P.] Univ Vermont, Colchester, VT USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1154 EP S1154 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504583 ER PT J AU Vaisman, BL Knapper, CL Demosky, SJ Stonik, JA Amar, MJ Remaley, AT AF Vaisman, Boris L. Knapper, Catherine L. Demosky, Stephen J. Stonik, John A. Amar, Marcelo J. Remaley, Alan T. TI Expression of Human ABCA1 in Endothelium Protects Against Diet-induced Atherosclerosis in Mice SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Vaisman, Boris L.; Knapper, Catherine L.; Demosky, Stephen J.; Stonik, John A.; Amar, Marcelo J.; Remaley, Alan T.] NHLBI, Bethesda, MD 20892 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S558 EP S558 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104501466 ER PT J AU Vaisman, BL Wood, KC Demosky, SJ Knapper, CL Chin-Dusting, J Morris, SM Gladwin, MT Remaley, AT AF Vaisman, Boris L. Wood, Katherine C. Demosky, Stephen J. Knapper, Catherine L. Chin-Dusting, Jaye Morris, Sidney M. Gladwin, Mark T. Remaley, Alan T. TI The Effects of Arginase II Overexpression on Endothelial Function in Transgenic Mouse Model SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Vaisman, Boris L.; Wood, Katherine C.; Demosky, Stephen J.; Knapper, Catherine L.; Gladwin, Mark T.; Remaley, Alan T.] NHLBI, Bethesda, MD 20892 USA. [Chin-Dusting, Jaye] Baker Heart Res Inst, Melbourne, Vic, Australia. [Morris, Sidney M.] Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S455 EP S455 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104501021 ER PT J AU Velagaleti, RS Gona, P Chuang, ML Salton, CJ Fox, CS Blease, SJ Yeon, SB Manning, WJ O'Donnell, CJ AF Velagaleti, Raghava S. Gona, Philimon Chuang, Michael L. Salton, Carol J. Fox, Caroline S. Blease, Susan J. Yeon, Susan B. Manning, Warren J. O'Donnell, Christopher J. TI Associations of Insulin Metabolism and Diabetes with Cardiac Magnetic Resonance Measures of Ventricular Structure are Mediated by Clinical Risk Factors: the National Heart, Lung and Blood Institute's Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Velagaleti, Raghava S.; Gona, Philimon; Fox, Caroline S.; Blease, Susan J.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chuang, Michael L.; Salton, Carol J.; Yeon, Susan B.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S778 EP S778 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502587 ER PT J AU Wang, KL Cheng, HM Chuang, SY Spurgeon, HA Ting, CT Lakatta, EG Yin, FCP Chou, P Chen, CH AF Wang, Kang-Ling Cheng, Hao-Min Chuang, Shao-Yuan Spurgeon, Harold A. Ting, Chih-Tai Lakatta, Edward G. Yin, Frank C. P. Chou, Pesus Chen, Chen-Huan TI Central or Peripheral Systolic or Pulse Pressure: Which Best Predicts Target-Organ Damage and Mortality? SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Wang, Kang-Ling; Cheng, Hao-Min] Taipei Vet Gen Hosp, Taipei, Taiwan. [Chuang, Shao-Yuan] Acad Sinica, Taipei 115, Taiwan. [Spurgeon, Harold A.; Lakatta, Edward G.] NIH, Baltimore, MD USA. [Ting, Chih-Tai] Taichung Vet Gen Hosp, Taichung, Taiwan. [Yin, Frank C. P.] Washington Univ, St Louis, MO USA. [Chou, Pesus; Chen, Chen-Huan] Natl Yang Ming Univ, Taipei 112, Taiwan. RI Chuang, Shao-Yuan/B-3478-2011 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S804 EP S804 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104502690 ER PT J AU Wang, SN Zhou, YF Xu, XL Hunt, T Hoyt, RF Horvath, KA AF Wang, Suna Zhou, Yifu Xu, Xiuli Hunt, Timothy Hoyt, Robert F., Jr. Horvath, Keith A. TI Bioinformatic Profiling of the Transcriptional Response of Adult Porcine Bone Marrow Stem Cell during Exposure to Hypoxia SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Wang, Suna; Zhou, Yifu; Xu, Xiuli; Hunt, Timothy; Hoyt, Robert F., Jr.; Horvath, Keith A.] NHLBI, NIH, Bethesda, MD 20892 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S1476 EP S1476 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104504803 ER PT J AU Woo, AY Zeng, X Wang, TB Zhu, WZ Tran, TM Clark, RB Wainer, IW Xiao, RP AF Woo, Anthony Y. Zeng, Xiaokun Wang, Tian-Bing Zhu, Weizhong Tran, Tuan M. Clark, Richard B. Wainer, Irving W. Xiao, Rui-Ping TI Phosphorylation of beta(2)-Adrenoceptor by cAMP-Dependent Protein Kinase Is Neither Necessary nor Sufficient to Mediate the Receptor Coupling to G(i) Proteins SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Woo, Anthony Y.; Zeng, Xiaokun; Wang, Tian-Bing; Zhu, Weizhong; Wainer, Irving W.; Xiao, Rui-Ping] NIA, NIH, Baltimore, MD 21224 USA. [Tran, Tuan M.; Clark, Richard B.] Univ Texas Houston, Sch Med, Houston, TX USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 SU 2 BP S277 EP S277 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104500047 ER PT J AU Yang, XP Becker, LC Becker, DM Bocharov, AV Freeman, L Biesecker, L Remaley, AT AF Yang, Xiao Ping Becker, Lewis C. Becker, Diane M. Bocharov, Alexander V. Freeman, Lita Biesecker, Leslie Remaley, Alan T. TI Mutations In Scavenger Receptor-BI/II Result In a Novel Dyslipidemia, with Increased HDL and Lipoprotein(a) SO CIRCULATION LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Yang, Xiao Ping; Becker, Lewis C.; Becker, Diane M.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Bocharov, Alexander V.; Freeman, Lita; Biesecker, Leslie; Remaley, Alan T.] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 28 PY 2008 VL 118 IS 18 BP S559 EP S559 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 389ON UT WOS:000262104501469 ER PT J AU Mitchell, J Wang, XQ Zhang, GP Gentzsch, M Nelson, DJ Shears, SB AF Mitchell, Jennifer Wang, Xueqing Zhang, Guangping Gentzsch, Martina Nelson, Deborah J. Shears, Stephen B. TI An Expanded Biological Repertoire for Ins(3,4,5,6)P-4 through its Modulation of CIC-3 Function SO CURRENT BIOLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; CLC CHLORIDE CHANNELS; INOSITOL 3,4,5,6-TETRAKISPHOSPHATE; ENDOSOMAL ACIDIFICATION; EPITHELIAL-CELLS; CYSTIC-FIBROSIS; PLASMA-MEMBRANE; CALCIUM; CONDUCTANCE; LOCALIZATION AB Ins(3,4,5,6)P-4 inhibits plasma membrane Cl- flux in secretory epithelia [1]. However, in most other mammalian cells, receptor-dependent elevation of Ins(3,4,5,6)P-4 levels is an "orphan" response that lacks biological significance [2]. We set out to identify Cl- channel(s) and/or transporter(s) that are regulated by Ins(3,4,5,6)P-4 in vivo. Several candidates [3-5] were excluded through biophysical criteria, electro-physiological analysis, and confocal immunofluorescence microscopy. Then, we heterologously expressed CIC-3 in the plasma membrane of HEK293-tsA201 cells; whole-cell patch-clamp analysis showed Ins(3,4,5,6)P-4 to inhibit Cl- conductance through CIC-3. Next, we heterologously expressed CIC-3 in the early endosomal compartment of BHK cells; by fluorescence ratio imaging of endocytosed FITC-transferrin, we recorded intra-endosomal pH, an in situ biosensor for Cl- flux across endosomal membranes [6]. A cell-permeant, bioactivatable Ins(3,4,5,6)P-4 analog elevated endosomal pH from 6.1 to 6.6, reflecting inhibition of CIC-3. Finally, Ins(3,4,5,6)P-4 inhibited endogenous CIC-3 conductance in postsynaptic membranes of neonatal hippocampal neurones. Among other CIC-3 functions that could be regulated by Ins(3,4,5,6)P-4 are tumor cell migration [7], apoptosis [8], and inflammatory responses [9]. Ins(3,4,5,6)P-4 is a ubiquitous cellular signal with diverse biological actions. C1 [Mitchell, Jennifer; Shears, Stephen B.] NIEHS, Inositol Signaling Grp, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Wang, Xueqing; Zhang, Guangping; Nelson, Deborah J.] Univ Chicago, Dept Neurobiol Pharmacol & Physiol, Chicago, IL 60637 USA. [Gentzsch, Martina] Univ N Carolina, Dept Dev & Cell Biol, Chapel Hill, NC 27599 USA. [Gentzsch, Martina] Univ N Carolina, Cyst Fibrosis Res Ctr, Chapel Hill, NC 27599 USA. RP Shears, SB (reprint author), NIEHS, Inositol Signaling Grp, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov FU National Institutes of Health (NIH) [P50 HL60280, R01 GM36823, R56 DK080364]; National Institute of Environmental Health Sciences; Cystic Fibrosis Foundation FX We are grateful to Jeff Tucker for assistance with the confocal imaging. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) at the National Institute of Environmental Health Sciences, by an NIH grant supporting M.G. (P50 HL60280), and by the following grants to D.J.N: NIH R01 GM36823, NIH R56 DK080364, and Nelson07G0 awarded by the Cystic Fibrosis Foundation. NR 36 TC 24 Z9 24 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD OCT 28 PY 2008 VL 18 IS 20 BP 1600 EP 1605 DI 10.1016/j.cub.2008.08.073 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 367KR UT WOS:000260551400032 PM 18951024 ER PT J AU Fouche, G Cragg, GM Pillay, P Kolesnikova, N Maharaj, VJ Senabe, J AF Fouche, G. Cragg, G. M. Pillay, P. Kolesnikova, N. Maharaj, V. J. Senabe, J. TI In vitro anticancer screening of South African plants SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Anticancer; Asteraceae; Medicinal plants; Natural products; Plants; South Africa ID CYTOTOXICITY; AGENTS; CELL; DISCOVERY; CANCER AB Aim of the study: The purpose of the present study is to evaluate South African plants for their anticancer activity. Materials and methods: Plant species were collected throughout South Africa and voucher specimens were deposited and identified at the South African National Biodiversity Institute. Plant extracts were prepared and screened for in vitro anticancer activity against a panel of three human cell lines (breast MCF7, renal TK10 and melanoma LIACC62) at the CSIR. Plant extracts that exhibited anticancer activity against these three human cell lines were screened by the NO against sixty human cancer cell lines organized into sub-panels representing leukaemia, melanoma, cancer of the lung, colon, kidney, ovary, central nervous system, breast and prostate. Results: A total of 7500 plant extracts were screened for in vitro anticancer activity against breast MCF7, renal TK10 and melanoma UACC62 human cell lines between the period 1999 and 2006. Hits were classified into four categories based on their total growth inhibition of the cell lines. A hit rate of 5.9% was obtained for extracts which showed moderate activity and these were screened by the NCI against a panel of sixty human cancer cell lines. The extracts of plant species with limited published information for their anticancer properties were subjected to bioassay-guided fractionation and the active constituents isolated and identified. The largest number of plant specimens in this study was from the family Asteraceae, which is rich in sesquiterpene lactones. Conclusions: Although the extracts of the plants were randomly selected, 68% of these plant species which were hits in the screening programme are reported to be used medicinally. Based on our data, it appears that unrelated medicinal use of the source plants may serve as an initial guide to selection of plants for anticancer screening. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Fouche, G.; Pillay, P.; Kolesnikova, N.; Maharaj, V. J.; Senabe, J.] CSIR, ZA-0001 Pretoria, Gauteng, South Africa. [Cragg, G. M.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Fouche, G (reprint author), CSIR, POB 395, ZA-0001 Pretoria, Gauteng, South Africa. EM gfouche@csir.co.za FU Council for Scientific and Industrial Research FX The authors would like to thank the South African National Biodiversity Institute (SANBI) for the identification of plant specimens and the U.S. National Cancer Institute (NCI) for 60 human cell line testing. This work was financially supported by the Council for Scientific and Industrial Research. NR 20 TC 72 Z9 75 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD OCT 28 PY 2008 VL 119 IS 3 BP 455 EP 461 DI 10.1016/j.jep.2008.07.005 PG 7 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 372LU UT WOS:000260903900011 PM 18678239 ER PT J AU Khursigara, CM Wu, XW Zhang, PJ Lefman, J Subramaniam, S AF Khursigara, Cezar M. Wu, Xiongwu Zhang, Peijun Lefman, Jonathan Subramaniam, Sriram TI Role of HAMP domains in chemotaxis signaling by bacterial chemoreceptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cryo-electron tomography; molecular architecture; signal transduction ID LIGAND-BINDING DOMAIN; VIVO CROSS-LINKING; ASPARTATE RECEPTOR; ESCHERICHIA-COLI; CRYOELECTRON MICROSCOPY; CYTOPLASMIC DOMAIN; RESOLUTION; VISUALIZATION; ARRAYS; HELIX AB Bacterial chemoreceptors undergo conformational changes in response to variations in the concentration of extracellular ligands. These changes in chemoreceptor structure initiate a series of signaling events that ultimately result in regulation of rotation of the flagellar motor. Here we have used cryo-electron tomography combined with 3D averaging to determine the in situ structure of chemoreceptor assemblies in Escherichia coli cells that have been engineered to overproduce the serine chemoreceptor Tsr. We demonstrate that chemoreceptors are organized as trimers of receptor dimers and display two distinct conformations that differ principally in arrangement of the HAMP domains within each trimer. Ligand binding and methylation alter the distribution of chemoreceptors between the two conformations, with serine binding favoring the "expanded" conformation and chemoreceptor methylation favoring the "compact" conformation. The distinct positions of chemoreceptor HAMP domains within the context of a trimeric unit are thus likely to represent important aspects of chemoreceptor structural changes relevant to chemotaxis signaling. Based on these results, we propose that the compact and expanded conformations represent the "kinase-on" and "kinaseoff" states of chemoreceptor trimers, respectively. C1 [Khursigara, Cezar M.; Zhang, Peijun; Lefman, Jonathan; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wu, Xiongwu] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU National Cancer Institute; National Institutes of Health FX We thank Drs. Martin Kessel and Mario J. Borgnia for insightful comments and Ethan Tyler and Alan Hoofring for expert assistance with preparation of the figures. This work was supported by funds from the intramural research program of the National Cancer Institute, National Institutes of Health. NR 38 TC 52 Z9 52 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 28 PY 2008 VL 105 IS 43 BP 16555 EP 16560 DI 10.1073/pnas.0806401105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 372PM UT WOS:000260913500029 PM 18940922 ER PT J AU Hadj-Bouziane, F Bell, AH Ungerleider, LG Tootell, RBH AF Hadj-Bouziane, Fadila Bell, Andrew H. Ungerleider, Leslie G. Tootell, Roger B. H. TI Reply to Sterck and Goossens: Perception of facial expressions in rhesus macaques SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Hadj-Bouziane, Fadila; Bell, Andrew H.; Ungerleider, Leslie G.; Tootell, Roger B. H.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. RP Hadj-Bouziane, F (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM hadjf@mail.nih.gov RI Hadj-Bouziane, Fadila/A-1180-2013; OI Bell, Andrew/0000-0001-8420-4622 NR 7 TC 0 Z9 0 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 28 PY 2008 VL 105 IS 43 BP E72 EP E72 DI 10.1073/pnas.0807729105 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 372PM UT WOS:000260913500002 ER PT J AU Bahrarni, H Kronmal, R Bluemke, DA Olson, J Shea, S Liu, K Burke, GL Lima, JAC AF Bahrarni, Hossein Kronmal, Richard Bluemke, David A. Olson, Jean Shea, Steven Liu, Kiang Burke, Gregory L. Lima, Joao A. C. TI Differences in the Incidence of Congestive Heart Failure by Ethnicity - The Multi-Ethnic Study of Atherosclerosis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID QUALITY-OF-CARE; LEFT-VENTRICULAR FUNCTION; RISK-FACTORS; ASYMPTOMATIC INDIVIDUALS; CARDIOVASCULAR-DISEASE; RACIAL-DIFFERENCES; RACE; MESA; HYPERTENSION; OUTCOMES AB Background: The relationship between incident congestive heart failure (CHF) and ethnicity as well as racial/ethnic differences in the mechanisms leading to CHF have not been demonstrated in a multiracial, population-based study. Our objective was to evaluate the relationship between race/ethnicity and incident CHF. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study of 681.4 participants of 4 ethnicities: white (38.5%), African American (27.8%), Hispanic (21.9%), and Chinese American (11.8%). Participants with a history of cardiovascular disease at baseline were excluded. Cox proportional hazards models were used for data analysis. Results: During a median follow-up of 4.0 years, 79 participants developed CHF (incidence rate: 31 per 1000 person-years). African Americans had the highest incidence rate of CHF, followed by Hispanic, white, and Chinese American participants (incidence rates: 4.6, 3.5, 2.4, and 1.0 per 1000 person-years, respectively). Although risk of developing CHF was higher among African American compared with white participants (hazard ratio, 1.8; 95% confidence interval, 1.1-3.1), adding hypertension and/or diabetes mellitus to models including ethnicity eliminated statistical ethnic differences in incident CHF. Moreover, African Americans had the highest proportion of incident CHF not preceded by clinical myocardial infarction (75%) compared with other ethnic groups (P=.06). Conclusions: The higher risk of incident CHF among African Americans was related to differences in the prevalence of hypertension and diabetes mellitus as well as socioeconomic status. The mechanisms of CHF also differed by ethnicity interim myocardial infarction had the least influence among African Americans, and left ventricular mass increase had the greatest effect among Hispanic and white participants. C1 [Bahrarni, Hossein; Bluemke, David A.; Lima, Joao A. C.] Johns Hopkins Univ, Div Cardiol, Dept Med, Baltimore, MD 21287 USA. [Bahrarni, Hossein; Lima, Joao A. C.] Johns Hopkins Univ, Dept Epidemiol, Sch Publ Hlth, Baltimore, MD 21287 USA. [Bluemke, David A.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. [Kronmal, Richard] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [Olson, Jean] NHLBI, NIH, Bethesda, MD 20892 USA. [Shea, Steven] Columbia Univ, Dept Epidemiol & Med, New York, NY USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Sch Med, Chicago, IL USA. [Burke, Gregory L.] Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Dept Cardiol, 600 N Wolfe St,Blalock 524, Baltimore, MD 21287 USA. OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood institute [N01-HC-95159, N01-HC-95166, N01-HC-95168, N01-HC-9808, N01-HC95168]; [R01-HL-66075] FX This study was supported by grant R01-HL-66075 and contracts N01-HC-95159 through N01-HC-95166, N01-HC-95168, N01-HC-9808, and N01-HC95168 from the National Heart, Lung, and Blood institute. Additional Contributions: The other investigators, the staff, and the participants of the MESA study all made valuable contributions to this article. NR 50 TC 140 Z9 143 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 27 PY 2008 VL 168 IS 19 BP 2138 EP 2145 DI 10.1001/archinte.168.19.2138 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 364JQ UT WOS:000260332400012 PM 18955644 ER PT J AU Fredman, L Cauley, JA Satterfield, S Simonsich, E Spencer, SM Ayonayon, HN Harris, TB AF Fredman, Lisa Cauley, Jane A. Satterfield, Suzanne Simonsich, Eleanor Spencer, S. Melinda Ayonayon, Hilsa N. Harris, Tamara B. CA Hlth ABC Study Grp TI Caregiving, Mortality, and Mobility Decline - The Health, Aging, and Body Composition (Health ABC) Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; CHRONIC STRESS; OLDER-ADULTS; COMMUNITY POPULATION; PHYSICAL-ACTIVITY; WOMEN; LIMITATION; WHITE; RISK; EXPERIENCES AB Background: Although caregivers report more stress than noncaregivers, few studies have found greater health decline in older caregivers. We hypothesized that caregivers may be more physically active than noncaregivers, which may protect them from health decline. Methods: The sample included 3075 healthy adults from the Health, Aging, and Body Composition (Health ABC) Study. They were aged 70 to 79 years in April 1997 to June 1998 and resided in Memphis, Tennessee, or Pittsburgh, Pennsylvania. Caregivers (680 [22.1%]) were participants who provided regular care or assistance for a child or a disabled or sick adult. Outcomes included all-cause mortality and incident mobility limitation (defined as difficuity walking one-quarter mile or climbing 10 steps on 2 consecutive semiannual contacts) during 8 years. Total physical activity included daily routine, exercise, and caregiving activity. Results: Overall, 20.6% of caregivers died and 50.9% developed mobility limitations vs 22.0% and 48.9% of noncaregivers, respectively. Associations differed by race and sex. Mortality and mobility limitation rates were 1.5 times higher in white caregivers (eg, among white female caregivers, adjusted hazard ratio for mortality, 1.6; 95% confidence interval, 1.0-2.5) but not for black female caregivers vs noncaregivers (adjusted hazard ratio for mortality, 0.9; 95% confidence interval, 0.5-1.4). Physical activity mediated these associations in most race-sex groups. High-intensity caregivers (ie, caregiving >= 24 hours per week) had elevated rates of decline when adjusted for physical activity but lower rates when not adjusted for activity. Conclusion: Older white caregivers have poorer health outcomes than black female caregivers. Physical activity appears to mask the adverse effects of high-intensity caregiving in most race-sex groups. C1 [Fredman, Lisa] Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02118 USA. [Cauley, Jane A.; Spencer, S. Melinda] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simonsich, Eleanor] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Fredman, L (reprint author), Boston Univ, Dept Epidemiol, Sch Publ Hlth, 715 Albany St,Room TE329, Boston, MA 02118 USA. EM lfredman@bu.edu RI Newman, Anne/C-6408-2013; Cauley, Jane/N-4836-2015 OI Newman, Anne/0000-0002-0106-1150; Cauley, Jane/0000-0003-0752-4408 FU National Institutes of Health (NIH); National Institute on Aging (NIA) [N01-AG-6-2106, N01-AG-62101, N01-AG-6-2103]; NIH, NIA [R01 AG18037] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (NIA), by NIA contracts N01-AG-6-2106, N01-AG-62101, and N01-AG-6-2103, and by grant R01 AG18037 from the NIH, NIA. NR 24 TC 30 Z9 30 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 27 PY 2008 VL 168 IS 19 BP 2154 EP 2162 DI 10.1001/archinte.168.19.2154 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 364JQ UT WOS:000260332400014 PM 18955646 ER PT J AU Fox, CS Pencina, MJ Vasan, RS AF Fox, Caroline S. Pencina, Michael J. Vasan, Ramachandran S. TI Obesity and Hypothyroidism: Symbiotic Coexistence Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID NATIONAL-HEALTH; TSH C1 [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 27 PY 2008 VL 168 IS 19 BP 2168 EP 2168 DI 10.1001/archinte.168.19.2168-b PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 364JQ UT WOS:000260332400021 ER PT J AU Korn, EL Mooney, MM Abrams, JS AF Korn, Edward L. Mooney, Margaret M. Abrams, Jcffrey S. TI Treatment Success in Cancer SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN-18129, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 27 PY 2008 VL 168 IS 19 BP 2173 EP 2173 DI 10.1001/archinte.168.19.2173-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 364JQ UT WOS:000260332400031 PM 18955658 ER PT J AU Alves, G Ogurtsov, AY Yu, YK AF Alves, Gelio Ogurtsov, Aleksey Y. Yu, Yi-Kuo TI RAId_DbS: mass-spectrometry based peptide identification web server with knowledge integration SO BMC GENOMICS LA English DT Article ID DATABASE; ANNOTATION; SPECTRA; DISEASE; TEXT AB Background: Existing scientific literature is a rich source of biological information such as disease markers. Integration of this information with data analysis may help researchers to identify possible controversies and to form useful hypotheses for further validations. In the context of proteomics studies, individualized proteomics era may be approached through consideration of amino acid substitutions/modifications as well as information from disease studies. Integration of such information with peptide searches facilitates speedy, dynamic information retrieval that may significantly benefit clinical laboratory studies. Description: We have integrated from various sources annotated single amino acid polymorphisms, post-translational modifications, and their documented disease associations ( if they exist) into one enhanced database per organism. We have also augmented our peptide identification software RAId_DbS to take into account this information while analyzing a tandem mass spectrum. In principle, one may choose to respect or ignore the correlation of amino acid polymorphisms/modifications within each protein. The former leads to targeted searches and avoids scoring of unnecessary polymorphism/modification combinations; the latter explores possible polymorphisms in a controlled fashion. To facilitate new discoveries, RAId_DbS also allows users to conduct searches permitting novel polymorphisms as well as to search a knowledge database created by the users. Conclusion: We have finished constructing enhanced databases for 17 organisms. The web link to RAId_DbS and the enhanced databases is http://www.ncbi.nlm.nih.gov/CBBResearch/qmbp/RAId_DbS/index.html. The relevant databases and binaries of RAId_DbS for Linux, Windows, and Mac OS X are available for download from the same web page. C1 [Alves, Gelio; Ogurtsov, Aleksey Y.; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM alves@ncbi.nlm.nih.gov; ogurtsov@ncbi.nlm.nih.gov; yyu@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX We thank the administrative group of the NIH biowulf clusters, where all the computational tasks were carried out. We also thank Dr. David Landsman and Dr. Lewis Geer for helpful comments. This work was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 21 TC 10 Z9 11 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 27 PY 2008 VL 9 AR 505 DI 10.1186/1471-2164-9-505 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 390VV UT WOS:000262192700001 PM 18954448 ER PT J AU Junttila, IS Mizukami, K Dickensheets, H Meier-Schellersheim, M Yamane, H Donnelly, RP Paul, WE AF Junttila, Ilkka S. Mizukami, Kiyoshi Dickensheets, Harold Meier-Schellersheim, Martin Yamane, Hidehiro Donnelly, Raymond P. Paul, William E. TI Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4R alpha, IL-13R alpha 1, and gamma c regulates relative cytokine sensitivity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SIGNAL-TRANSDUCTION; MICE LACKING; RECEPTOR COMPLEX; GENE-EXPRESSION; CUTTING EDGE; INTERLEUKIN-13; ACTIVATION; CELLS; CHAIN; STAT6 AB Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4R alpha/common gamma-chain [gamma c]) and the type II (IL-4R alpha/-13R alpha 1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow-derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional gamma c made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of gamma c had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4R alpha, IL-13R alpha 1, and gamma c accounted for the distinct IL-4-IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine. C1 [Junttila, Ilkka S.; Mizukami, Kiyoshi; Meier-Schellersheim, Martin; Yamane, Hidehiro; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Dickensheets, Harold; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Junttila, IS (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM junttilai@niaid.nih.gov FU National Institute for Allergy and Infectious Diseases Intramural Program; Finnish Cultural Foundation; Finnish Medical Foundation; Emil Aaltonen Foundation FX This work was supported by National Institute for Allergy and Infectious Diseases Intramural Program, the Finnish Cultural Foundation, the Finnish Medical Foundation, and the Emil Aaltonen Foundation. NR 52 TC 79 Z9 81 U1 2 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 27 PY 2008 VL 205 IS 11 BP 2595 EP 2608 DI 10.1084/jem.20080452 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 368ED UT WOS:000260603200016 PM 18852293 ER PT J AU Andersson, ER Prakash, N Cajanek, L Minina, E Bryja, V Bryjova, L Yamaguchi, TP Hall, AC Wurst, W Arenas, E AF Andersson, Emma R. Prakash, Nilima Cajanek, Lukas Minina, Eleonora Bryja, Vitezslav Bryjova, Lenka Yamaguchi, Terry P. Hall, Anita C. Wurst, Wolfgang Arenas, Ernest TI Wnt5a Regulates Ventral Midbrain Morphogenesis and the Development of A9-A10 Dopaminergic Cells In Vivo SO PLOS ONE LA English DT Article AB Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9-10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E) 9.5, and was restricted to the VM floor and basal plate by E11.5-E13.5. Analysis of Wnt5a-/- mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a-/- mice also displayed a defect in (mid) brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors. C1 [Andersson, Emma R.; Cajanek, Lukas; Bryja, Vitezslav; Bryjova, Lenka; Wurst, Wolfgang; Arenas, Ernest] Karolinska Inst, Mol Neurobiol Lab, Dept Med Biochem & Biophys, Stockholm, Sweden. [Prakash, Nilima; Minina, Eleonora] Tech Univ Munich, Inst Dev Genet, German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Munich, Germany. [Bryja, Vitezslav; Bryjova, Lenka] Acad Sci Czech Republic, Inst Biophys, Dept Cytokinet, Brno, Czech Republic. [Bryja, Vitezslav; Bryjova, Lenka] Masaryk Univ, Fac Sci, Inst Expt Biol, Brno, Czech Republic. [Yamaguchi, Terry P.] Natl Canc Inst Frederick, Canc & Dev Biol Lab, Frederick, MD USA. [Hall, Anita C.] Imperial Coll London, Div Cell & Mol Biol, London, England. [Wurst, Wolfgang] Max Planck Inst Psychiat, Munich, Germany. RP Andersson, ER (reprint author), Karolinska Inst, Mol Neurobiol Lab, Dept Med Biochem & Biophys, Stockholm, Sweden. EM wurst@helmholtz-muenchen.de; ernest.arenas@ki.se RI Bryja, Vit?zslav/H-1925-2014; Andersson, Emma/J-4236-2012; OI Bryja, Vit?zslav/0000-0002-9136-5085; Andersson, Emma/0000-0002-8608-625X; Cajanek, Lukas/0000-0003-2914-8589; Arenas, Ernest/0000-0003-0197-6577 FU Swedish Foundation for Strategic Research; Swedish Royal Academy of Sciences; Knut and Alice Wallenberg Foundation; European Union (Eurostemcell); Swedish MRC; Karolinska Institutet; Federal Ministry of Education and Research (BMBF) [01GN0512]; National Genome Research Network (NGFN); Forderkennzeichen [01GS0476]; Deutsche Forschungsgemeinschaft (DFG) [WU 164/3-1, WU 164/3-2]; Bayerische Forschungsverbund ForNeuroCell; Helmholtz Virtual Institute of Neurodegeneration&Aging [VH-VI-252]; European Union (Eumorphia) FX This work was supported by the Swedish Foundation for Strategic Research, Swedish Royal Academy of Sciences, Knut and Alice Wallenberg Foundation, European Union (Eurostemcell), Swedish MRC and Karolinska Institutet (to EA), and by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), Forderkennzeichen 01GS0476, the BMBF Forderkennzeichen 01GN0512, the Deutsche Forschungsgemeinschaft (DFG) WU 164/3-1 and WU 164/3-2, the Bayerische Forschungsverbund ForNeuroCell, the Helmholtz Virtual Institute of Neurodegeneration&Aging (VH-VI-252) and by European Union (Eumorphia) (to WW). The authors are responsible for the contents of this publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 56 Z9 57 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2008 VL 3 IS 10 AR e3517 DI 10.1371/journal.pone.0003517 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432JY UT WOS:000265130500002 PM 18953410 ER PT J AU Dutton, JR Antonellis, A Carney, TJ Rodrigues, FSLM Pavan, WJ Ward, A Kelsh, RN AF Dutton, James R. Antonellis, Anthony Carney, Thomas J. Rodrigues, Frederico S. L. M. Pavan, William J. Ward, Andrew Kelsh, Robert N. TI An evolutionarily conserved intronic region controls the spatiotemporal expression of the transcription factor Sox10 SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID NEURAL CREST DEVELOPMENT; WAARDENBURG-HIRSCHSPRUNG-DISEASE; ENTERIC NERVOUS-SYSTEM; REGULATORY ELEMENTS; MOUSE MODEL; CELL FATE; MELANOCYTE DEVELOPMENT; OVERLAPPING FUNCTIONS; SIGNALING PATHWAY; PROGENITOR CELLS AB Background: A major challenge lies in understanding the complexities of gene regulation. Mutation of the transcription factor SOX10 is associated with several human diseases. The disease phenotypes reflect the function of SOX10 in diverse tissues including the neural crest, central nervous system and otic vesicle. As expected, the SOX10 expression pattern is complex and highly dynamic, but little is known of the underlying mechanisms regulating its spatiotemporal pattern. SOX10 expression is highly conserved between all vertebrates characterised. Results: We have combined in vivo testing of DNA fragments in zebrafish and computational comparative genomics to identify the first regulatory regions of the zebrafish sox10 gene. Both approaches converged on the 3' end of the conserved 1(st) intron as being critical for spatial patterning of sox10 in the embryo. Importantly, we have defined a minimal region crucial for this function. We show that this region contains numerous binding sites for transcription factors known to be essential in early neural crest induction, including Tcf/Lef, Sox and FoxD3. We show that the identity and relative position of these binding sites are conserved between zebrafish and mammals. A further region, partially required for oligodendrocyte expression, lies in the 5' region of the same intron and contains a putative CSL binding site, consistent with a role for Notch signalling in sox10 regulation. Furthermore, we show that beta-catenin, Notch signalling and Sox9 can induce ectopic sox10 expression in early embryos, consistent with regulatory roles predicted from our transgenic and computational results. Conclusion: We have thus identified two major sites of sox10 regulation in vertebrates and provided evidence supporting a role for at least three factors in driving sox10 expression in neural crest, otic epithelium and oligodendrocyte domains. C1 [Dutton, James R.; Carney, Thomas J.; Rodrigues, Frederico S. L. M.; Ward, Andrew; Kelsh, Robert N.] Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath BA2 7AY, Avon, England. [Antonellis, Anthony; Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Carney, Thomas J.] Max Planck Inst Immunol, Freiberg, Germany. [Dutton, James R.] Univ Minnesota, Stem Cell Inst, Minneapolis, MN USA. RP Kelsh, RN (reprint author), Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath BA2 7AY, Avon, England. EM dutto015@umn.edu; antonell@mail.nih.gov; carney@immunbio.mpg.de; F.S.L.Rodrigues@bath.ac.uk; bpavan@nhgri.nih.gov; a.ward@bath.ac.uk; bssrnk@bath.ac.uk RI Carney, Tom/H-4389-2011; Kelsh, Robert/B-6445-2008 OI Carney, Tom/0000-0003-2371-1924; Kelsh, Robert/0000-0002-9381-0066 FU Medical Research Council [G0000884]; Wellcome Trust [066326, 063998]; Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health (USA) FX We thank Kirsten Dutton for excellent technical support for several aspects of this study. We are grateful to C. Beck, R. Dorsky, A. Lekven, J. Postlethwait and J. Slack for reagents. We thank the NIH Intramural Sequencing Center (NISC) for generating genomic sequences used in this study. This research was supported in part by each of the Medical Research Council (G0000884), the Wellcome Trust (066326 and 063998), and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (USA). NR 80 TC 51 Z9 52 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD OCT 26 PY 2008 VL 8 AR 105 DI 10.1186/1471-213X-8-105 PG 20 WC Developmental Biology SC Developmental Biology GA 390QT UT WOS:000262179500001 PM 18950534 ER PT J AU Greenebaum, E Bozhok, YM Bogdanova, TI Zelinskaya, A Zurnadzhy, L Shpak, V Epstein, OV McConnell, RJ Brenner, A Robbins, J Zablotska, L Tronko, MD Hatch, M AF Greenebaum, Ellen Bozhok, Yuriy M. Bogdanova, Tetyana I. Zelinskaya, Anna Zurnadzhy, Lyudmyla Shpak, Victor Epstein, Ovsiy V. McConnell, Robert J. Brenner, Alina Robbins, Jacob Zablotska, Lydia Tronko, Mykola D. Hatch, Maureen TI A Cohort Study of Thyroid Cancer and Other Thyroid Diseases After the Chernobyl Accident. Cyto-Histopathologic Correlation and Accuracy of Fine Needle Aspiration Biopsy in Nodules Detected During the First Screening Cycle in Ukraine (1998-2000) SO CANCER CYTOPATHOLOGY LA English DT Meeting Abstract C1 [Greenebaum, Ellen; McConnell, Robert J.] Columbia U, Coll Phys & Surg, New York, NY USA. [Bozhok, Yuriy M.; Bogdanova, Tetyana I.; Zelinskaya, Anna; Zurnadzhy, Lyudmyla; Shpak, Victor; Epstein, Ovsiy V.; Tronko, Mykola D.] Inst Endocrinol & Metab, Kiev, Ukraine. [Brenner, Alina; Hatch, Maureen] NCI, Bethesda, MD 20892 USA. [Robbins, Jacob] NIDDK, Bethesda, MD USA. [Zablotska, Lydia] Columbia U, Mailman Sch Publ Hlth, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2008 VL 114 IS 5 SU S BP 436 EP 436 PG 1 WC Oncology; Pathology SC Oncology; Pathology GA 361PY UT WOS:000260140800146 ER PT J AU Martin, J Orlowski, R Bielekova, B AF Martin, Jayne Orlowski, Robert Bielekova, Bibiana TI Discordance between inhibitory effect of Rolipram on Th1/Th17T cells responses in MS and its lack of efficacy on brain inflammation SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract C1 [Martin, Jayne; Bielekova, Bibiana] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Orlowski, Robert] Univ Cincinnati, Waddell Ctr MS, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 25 PY 2008 VL 203 IS 2 BP 129 EP 129 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 377SJ UT WOS:000261270600011 ER PT J AU Mascaro-Blanco, A Alvarez, K Kirvan, K Heuser, J Leckman, J Swedo, S Grant, P Parke, J Cunningham, MW AF Mascaro-Blanco, A. Alvarez, K. Kirvan, K. Heuser, J. Leckman, J. Swedo, S. Grant, P. Parke, J. Cunningham, M. W. TI Anti-lysogangl ioside antibodies correlate with acute Sydenham chorea, PANDAS and Tics SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract C1 [Mascaro-Blanco, A.; Alvarez, K.; Heuser, J.; Cunningham, M. W.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Kirvan, K.] Calif State Univ Sacramento, Sacramento, CA 95819 USA. [Leckman, J.] Yale Univ, New Haven, CT USA. [Swedo, S.; Grant, P.] NIMH, Bethesda, MD 20892 USA. [Parke, J.] Childrens Hosp, OU Hlth Sci Ctr, Oklahoma City, OK USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 25 PY 2008 VL 203 IS 2 BP 185 EP 185 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 377SJ UT WOS:000261270600164 ER PT J AU Kirvan, C Swedo, S Cunningham, M AF Kirvan, Christine Swedo, Susan Cunningham, Madeleine TI Characterization of humoral responses in movement and behavior disorders associated with group a streptococcus SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract C1 [Kirvan, Christine] Calif State Univ Sacramento, Sacramento, CA 95819 USA. [Swedo, Susan] NIMH, Bethesda, MD 20892 USA. [Cunningham, Madeleine] Univ Oklahoma, HSC, Oklahoma City, OK USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 25 PY 2008 VL 203 IS 2 BP 186 EP 186 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 377SJ UT WOS:000261270600167 ER PT J AU Cunningham, MW Kirvan, C Brimberg, L Alvarez, K Blanco, A Heuser, J Parke, J Leckman, J Swedo, S Lombroso, P Joel, D AF Cunningham, M. W. Kirvan, C. Brimberg, L. Alvarez, K. Blanco, A. Heuser, J. Parke, J. Leckman, J. Swedo, S. Lombroso, P. Joel, D. TI Autoimmunity and behavior: Sydenham's chorea and related disorders SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract C1 [Cunningham, M. W.; Alvarez, K.; Blanco, A.; Heuser, J.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK USA. [Parke, J.] Univ Oklahoma, Hlth Sci Ctr, Dept Neurol, Oklahoma City, OK USA. [Kirvan, C.] Calif State Univ Sacramento, Dept Biol Sci, Sacramento, CA 95819 USA. [Brimberg, L.; Joel, D.] Tel Aviv Univ, Dept Psychol, IL-69978 Tel Aviv, Israel. [Leckman, J.; Lombroso, P.] Yale Univ, Sch Med, Dept Psychiat, Dept Child Study Ctr, New Haven, CT USA. [Swedo, S.] NIMH, Dept Pediat & Dev Neurosci Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 25 PY 2008 VL 203 IS 2 BP 204 EP 204 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 377SJ UT WOS:000261270600215 ER PT J AU Williams, E Stacy, S Krolick, K Infante, A Lenarclo, M Kraig, E AF Williams, Earlanda Stacy, Sue Krolick, Keith Infante, Anthony Lenarclo, Michael Kraig, Ellen TI Use of a novel transgenic model to unravel mechanisms of tolerance to AchR SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract C1 Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. NIAID, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 25 PY 2008 VL 203 IS 2 BP 206 EP 207 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 377SJ UT WOS:000261270600223 ER PT J AU Quandt, J Huh, J Baig, M Yao, K Kawamura, K Pinilla, C McFarland, H Martin, R Ito, K AF Quandt, Jacqueline Huh, Jaebong Baig, Mirza Yao, Karen Kawamura, Kazayuki Pinilla, Clemencia McFarland, Henry Martin, Roland Ito, Kouichi TI The multiple sclerosis-associated MHC DR2a gene drives disease in a humanized transgenic model of CNS autoimmunity SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract C1 [Quandt, Jacqueline; Huh, Jaebong; Baig, Mirza; Yao, Karen; Kawamura, Kazayuki; McFarland, Henry] NIH, Bethesda, MD 20892 USA. [Pinilla, Clemencia] Torrey Pines Inst Mol Studies, San Diego, CA USA. [Martin, Roland] Univ Hamburg, Hamburg, Germany. [Ito, Kouichi] UMDNJ, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 25 PY 2008 VL 203 IS 2 BP 211 EP 211 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 377SJ UT WOS:000261270600233 ER PT J AU Davidson, T Shevach, E AF Davidson, Todd Shevach, Ethan TI CD4+FOXP3+T regulatory cells inhibit experimental autoimmune encephalomyelitis via distinct IL-10 dependent and IL-10 independent mechanisms SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract C1 [Davidson, Todd; Shevach, Ethan] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 25 PY 2008 VL 203 IS 2 BP 266 EP 267 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 377SJ UT WOS:000261270600390 ER PT J AU Wu, XL Sambor, A Nason, MC Yang, ZY Wu, L Zolla-Pazner, S Nabel, GJ Mascola, JR AF Wu, Xueling Sambor, Anna Nason, Martha C. Yang, Zhi-Yong Wu, Lan Zolla-Pazner, Susan Nabel, Gary J. Mascola, John R. TI Soluble CD4 broadens neutralization of V3-directed monoclonal antibodies and guinea pig vaccine sera against HIV-1 subtype B and C reference viruses SO VIROLOGY LA English DT Article DE Neutralization; V3 antibodies and vaccine sera; Soluble CD4; HIV-1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; CORECEPTOR-BINDING-SITE; V3 LOOP; TYPE-1 ENVELOPE; SYNERGISTIC NEUTRALIZATION; CLADE-B; ALTERNATIVE CONFORMATIONS; 1-INFECTED INDIVIDUALS; V3-SPECIFIC ANTIBODIES AB To better understand the limits of antigenic reactivity and epitope accessibility of the V3 domain of primary HIV-1 isolates, we evaluated three human anti-V3 monoclonal antibodies (mAbs) and selected guinea pig vaccine sera for neutralization against reference panels of subtype B and C pseudoviruses derived from early stage infections. The mAbs and vaccine sera potently neutralized several prototype viruses, but displayed substantially less neutralization of most reference strains. In the presence of soluble CD4 (sCD4), the breadth of V3-mediated neutralization was increased; up to 80% and 77% of the subtype B and C viruses respectively were sensitive to V3-mediated neutralization. Unlike sCD4, the reaction of CD4-binding site mAbs b12 and F105 with native virus did not lead to full exposure of the V3 domain. These findings confirm that V3 antibodies recognize most primary viral strains, but that the epitope often has limited accessibility in the context of native envelope spike. Published by Elsevier Inc. C1 [Wu, Xueling; Sambor, Anna; Yang, Zhi-Yong; Wu, Lan; Nabel, Gary J.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Zolla-Pazner, Susan] NYU, New York Vet Affairs Med Ctr, New York, NY 10016 USA. [Zolla-Pazner, Susan] NYU, Sch Med, New York, NY 10016 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM jmascola@nih.gov FU Office of Clinical Research; Vaccine Research Center; MAID; NIH [AI 36085]; Department of Veterans Affairs FX We thank Peter Kwong, Tongqing Zhou and Richard Wyatt for helpful discussions of the data, and Stephen Schmidt for review of this manuscript. This research was supported by the Intramural Research Program of the Office of Clinical Research and the Vaccine Research Center, MAID, NIH and by NIH grants AI 36085, and research funds from the Department of Veterans Affairs. NR 82 TC 28 Z9 28 U1 0 U2 5 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 OCT 25 PY 2008 VL 380 IS 2 BP 285 EP 295 DI 10.1016/j.virol.2008.07.007 PG 11 WC Virology SC Virology GA 361SW UT WOS:000260148400014 PM 18804254 ER PT J AU Bok, K Cavanaugh, VJ Matson, DO Gonzalez-Molleda, L Chang, YO Zintz, C Smith, AW Iversen, P Green, KY Campbell, AE AF Bok, Karin Cavanaugh, Victoria J. Matson, David O. Gonzalez-Molleda, Lorenzo Chang, Yeong-Ok Zintz, Carmelann Smith, Alvin W. Iversen, Patrick Green, Kim Y. Campbell, Ann E. TI Inhibition of norovirus replication by morpholino oligomers targeting the 5 '-end of the genome SO VIROLOGY LA English DT Article DE Norovirus; Antisense; PMO; Antiviral ID MURINE NOROVIRUS; ANTISENSE OLIGODEOXYNUCLEOTIDES; VIRUS-REPLICATION; TISSUE-CULTURE; CELL-CULTURES; INFECTION; RNA; GASTROENTERITIS; EXPRESSION; DISEASE AB Noroviruses are an important cause of non-bacterial epidemic gastroenteritis, but no specific antiviral therapies are available. We investigated the inhibitory effect of phosphorodiamidiate morpholino oligomers (PMOs) targeted against norovirus sequences. A panel of peptide-conjugated PMOs (PPMOs) specific for the murine norovirus (MNV) genome was developed, and two PPMO compounds directed against the first AUG of the ORF1 coding sequence near the 5'-end of the genome proved effective in inhibiting MNV replication in cells. A consensus PPMO (designated Noro 1.1), designed to target the corresponding region of several diverse human norovirus genotypes, decreased the efficiency of protein translation in a cell-free luciferase reporter assay and inhibited Norwalk virus protein expression in replicon-bearing cells. Our data suggest that PPMOs directed against the relatively conserved 5'-end of the norovirus genome may show broad antiviral activity against this genetically diverse group of viruses. Published by Elsevier Inc. C1 [Bok, Karin; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Cavanaugh, Victoria J.; Matson, David O.; Zintz, Carmelann; Campbell, Ann E.] Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23507 USA. [Matson, David O.; Zintz, Carmelann] Eastern Virginia Med Sch, Dept Pediat, Norfolk, VA 23507 USA. [Matson, David O.; Zintz, Carmelann] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23507 USA. [Gonzalez-Molleda, Lorenzo] Univ Oviedo, Asturias Inst Biotechnol, Dept Biochem & Mol Biol, Oviedo, Spain. [Chang, Yeong-Ok] Kansas State Univ, Manhattan, KS 66506 USA. [Smith, Alvin W.] Oregon State Univ, Lab Calicivirus Studies, Corvallis, OR USA. [Iversen, Patrick] AVI BioPharma Inc, Corvallis, OR 97333 USA. RP Bok, K (reprint author), NIAID, Infect Dis Lab, NIH, DHHS, 50 South Dr,Bldg 50,Room 6316, Bethesda, MD 20892 USA. EM bokk@niaid.nih.gov FU Thrasher Research Fund, Salt Lake City, UT [02820-4]; NIH, MAID FX We acknowledge the generosity of Dr. Skip Virgin in providing MNV-1 stocks. The authors would like to thank Dr. Mary Staat and Dr. Parvin Azimi for their work in the calicivirus epidemiologic study. This work was supported by grant 02820-4 from the Thrasher Research Fund, Salt Lake City, UT, awarded to K.B, D.O.M, and A.E.C. This research was also supported [in part] by the intramural Research Program of the NIH, MAID. NR 39 TC 9 Z9 9 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 25 PY 2008 VL 380 IS 2 BP 328 EP 337 DI 10.1016/j.virol.2008.08.007 PG 10 WC Virology SC Virology GA 361SW UT WOS:000260148400019 PM 18783811 ER PT J AU Tsugawa, T Hoshino, Y AF Tsugawa, Takeshi Hoshino, Yasutaka TI Whole genome sequence and phylogenetic analyses reveal human rotavirus G3P[3] strains Ro1845 and HCR3A are examples of direct virion transmission of canine/feline rotaviruses to humans SO VIROLOGY LA English DT Article DE Rotavirus; Interspecies transmission; Human rotavirus; Canine rotavirus; Feline rotavirus; Sequence analysis ID GROUP-A ROTAVIRUSES; SEROTYPE-SPECIFIC NEUTRALIZATION; RNA-RNA HYBRIDIZATION; MOLECULAR CHARACTERIZATION; CANINE ROTAVIRUS; NUCLEOTIDE-SEQUENCE; NONSTRUCTURAL GLYCOPROTEIN; INTERSPECIES TRANSMISSION; ANIMAL ROTAVIRUSES; PORCINE ROTAVIRUS AB Rotaviruses, the major causative agents of infantile diarrhea worldwide, are, in general, highly species-specific. Interspecies virus transmission is thought to be one of the important contributors involved in the evolution and diversity of rotaviruses in nature. Human rotavirus (HRV) G3P[3] strains Ro1845 and HCR3A have been reported to be closely related genetically to certain canine and feline rotaviruses (RVs). Whole genome sequence and phylogenetic analyses of each of these 2 HRVs as well as 3 canine RVs (CU-1, K9 and A79-10, each with G3P[3] specificity) and 2 feline RVs (Cat97 with G3P[3] specificity and Cat2 with G3P[9] specificity) revealed that (i) each of 11 genes of the Ro1845 and HCR3A was of canine/feline origin; (ii) canine and feline rotaviruses with G3P[3] specificity bore highly conserved species-specific genomes; and (iii) the Cat2 strain may have evolved via multiple reassortment events involving canine, feline, human and bovine rotaviruses. Published by Elsevier Inc. C1 [Tsugawa, Takeshi; Hoshino, Yasutaka] NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bldg 50,Room 6308,50 South Dr,MSC 8026, Bethesda, MD 20892 USA. EM thoshino@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institutes of Health, USA FX We thank R. W. Jones for expert technical assistance; Y. Aboudy, H. F. Clark, I. D. Gust, R. W. Fulton and O. Nakagomi for providing us with rotavirus strains Ro1845, HCR3A, Cat97 and Cat2, K9 and AU-1, respectively; K. Wollenberg for phylogenetic analyses of the genes, and A. Z. Kapikian for continuing support. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. There is no conflict of interest to declare. NR 91 TC 68 Z9 70 U1 0 U2 2 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 OCT 25 PY 2008 VL 380 IS 2 BP 344 EP 353 DI 10.1016/j.virol.2008.07.041 PG 10 WC Virology SC Virology GA 361SW UT WOS:000260148400021 PM 18789808 ER PT J AU Nelson, GE Sisler, JR Chandran, D Moss, B AF Nelson, Gretchen E. Sisler, Jerry R. Chandran, Dev Moss, Bernard TI Vaccinia virus entry/fusion complex subunit A28 is a target of neutralizing and protective antibodies SO VIROLOGY LA English DT Article DE Vaccinia virus neutralization; Poxvirus immunity; Antibody protection ID CELL-CELL FUSION; SMALLPOX VACCINE; MEMBRANE-PROTEIN; ESSENTIAL COMPONENT; NONHUMAN-PRIMATES; ENVELOPE PROTEIN; VIRION MEMBRANE; POXVIRUS ENTRY; ANKARA MVA; MICE AB The vaccinia virus entry/fusion complex (EEC) is comprised of at least eight transmembrane proteins that are conserved in all poxviruses. However, neither the physical structure of the EEC nor the immunogenicity of the individual components has been determined. We prepared soluble forms of two EEC components, A28 and H2, by replacing the transmembrane domain with a signal peptide and adding a polyhistidine tail. The proteins were expressed by baculoviruses, secreted from insect cells, purified by affinity chromatography and used to raise antibodies in rabbits. The antibodies recognized the viral proteins but only the antibody to recombinant A28 bound intact virions and neutralized infectivity. Analyses with a set of overlapping peptides revealed a neutralizing epitope between residues 73 and 92 of A28. Passive immunization of mice with IgG purified from the anti-A28 serum provided partial protection against a vaccinia Virus intranasal challenge, whereas IgG from the anti-H2 serum did not. Published by Elsevier Inc. C1 [Nelson, Gretchen E.; Sisler, Jerry R.; Chandran, Dev; 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 National Institute of Allergy; Infectious Diseases of the National Institutes of Health FX We thank Norman Cooper and Catherine Cotter for their help with tissue culture, Patricia Earl and Jeffrey Americo for their advice on the neutralization assay, and Andrea Weisberg for assistance in preparing the figures. Mice were housed in the National Institutes of Health Building 50 Shared Animal Facility. GN was a student in the Johns Hopkins/National Institute of Health graduate training program and the research was submitted for partial fulfillment of the doctoral thesis. The research was Supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. NR 46 TC 24 Z9 25 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 OCT 25 PY 2008 VL 380 IS 2 BP 394 EP 401 DI 10.1016/j.virol.2008.08.009 PG 8 WC Virology SC Virology GA 361SW UT WOS:000260148400027 PM 18789472 ER PT J AU Das, S Wong, R Rajapakse, N Murphy, E Steenbergen, C AF Das, Samarjit Wong, Renee Rajapakse, Nishadi Murphy, Elizabeth Steenbergen, Charles TI Glycogen Synthase Kinase 3 Inhibition Slows Mitochondrial Adenine Nucleotide Transport and Regulates Voltage-Dependent Anion Channel Phosphorylation SO CIRCULATION RESEARCH LA English DT Article DE mitochondria; GSK-3; VDAC; adenine nucleotide transport ID PERMEABILITY TRANSITION PORE; OPIOID-INDUCED CARDIOPROTECTION; REPERFUSION INJURY; PROTEIN-KINASE; CYTOCHROME-C; ISCHEMIA; KINASE-3-BETA; RESPIRATION; EXPRESSION; MECHANISM AB Inhibition of glycogen synthase kinase (GSK)-3 reduces ischemia/reperfusion injury by mechanisms that involve the mitochondria. The goal of this study was to explore possible molecular targets and mechanistic basis of this cardioprotective effect. In perfused rat hearts, treatment with GSK inhibitors before ischemia significantly improved recovery of function. To assess the effect of GSK inhibitors on mitochondrial function under ischemic conditions, mitochondria were isolated from rat hearts perfused with GSK inhibitors and were treated with uncoupler or cyanide or were made anoxic. GSK inhibition slowed ATP consumption under these conditions, which could be attributable to inhibition of ATP entry into the mitochondria through the voltage-dependent anion channel (VDAC) and/or adenine nucleotide transporter (ANT) or to inhibition of the F(1)F(0)-ATPase. To determine the site of the inhibitory effect on ATP consumption, we measured the conversion of ADP to AMP by adenylate kinase located in the intermembrane space. This assay requires adenine nucleotide transport across the outer but not the inner mitochondrial membrane, and we found that GSK inhibitors slow AMP production similar to their effect on ATP consumption. This suggests that GSK inhibitors are acting on outer mitochondrial membrane transport. In sonicated mitochondria, GSK inhibition had no effect on ATP consumption or AMP production. In intact mitochondria, cyclosporin A had no effect, indicating that ATP consumption is not caused by opening of the mitochondrial permeability transition pore. Because GSK is a kinase, we assessed whether protein phosphorylation might be involved. Therefore, we performed Western blot and 1D/2D gel phosphorylation site analysis using phos-tag staining to indicate proteins that had decreased phosphorylation in hearts treated with GSK inhibitors. Liquid chromatographic-mass spectrometric analysis revealed 1 of these proteins to be VDAC2. Taken together, we found that GSK-mediated signaling modulates transport through the outer membrane of the mitochondria. Both proteomics and adenine nucleotide transport data suggest that GSK regulates VDAC and that VDAC may be an important regulatory site in ischemia/reperfusion injury. (Circ Res. 2008; 103:983-991.) C1 [Das, Samarjit; Steenbergen, Charles] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA. [Wong, Renee; Murphy, Elizabeth] NHLBI, Cardiac Physiol Sect, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Rajapakse, Nishadi] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Steenbergen, C (reprint author), Johns Hopkins Univ, Dept Pathol, 632N Ross Res Bldg,720 Rutland St, Baltimore, MD 21205 USA. EM csteenb1@jhmi.edu FU NIH [HL39752] FX Supported in part by NIH grant HL39752. R. W., N. R., and E. M. were supported by the NIH intramural program. NR 45 TC 106 Z9 108 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD OCT 24 PY 2008 VL 103 IS 9 BP 983 EP U186 DI 10.1161/CIRCRESAHA.108.178970 PG 19 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 364AL UT WOS:000260308500014 PM 18802025 ER PT J AU Pletnev, S Shcherbo, D Chudakov, DM Pletneva, N Merzlyak, EM Wlodawer, A Dauter, Z Pletnev, V AF Pletnev, Sergei Shcherbo, Dmitry Chudakov, Dmitry M. Pletneva, Nadezhda Merzlyak, Ekaterina M. Wlodawer, Alexander Dauter, Zbigniew Pletnev, Vladimir TI A Crystallographic Study of Bright Far-Red Fluorescent Protein mKate Reveals pH-induced cis-trans Isomerization of the Chromophore SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IN-VIVO; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; WHOLE-BODY; GREEN; MATURATION; CHROMOPROTEINS; RESOLUTION; MECHANISM; EXTENSION AB The far-red fluorescent protein mKate (lambda(ex), 588 nm; lambda(em), 635 nm; chromophore-forming triad Met(63)-Tyr(64)-Gly(65)), originating from wild-type red fluorescent progenitor eqFP578 (sea anemone Entacmaea quadricolor), is monomeric and characterized by the pronounced pH dependence of fluorescence, relatively high brightness, and high photostability. The protein has been crystallized at a pH ranging from 2 to 9 in three space groups, and four structures have been determined by x-ray crystallography at the resolution of 1.75-2.6 angstrom. The pH-dependent fluorescence of mKate has been shown to be due to reversible cis-trans isomerization of the chromophore phenolic ring. In the non-fluorescent state at pH 2.0, the chromophore of mKate is in the trans-isomeric form. The weakly fluorescent state of the protein at pH 4.2 is characterized by a mixture of trans and cis isomers. The chromophore in a highly fluorescent state at pH 7.0/9.0 adopts the cis form. Three key residues, Ser(143), Leu(174), and Arg(197) residing in the vicinity of the chromophore, have been identified as being primarily responsible for the far-red shift in the spectra. A group of residues consisting of Val(93), Arg(122), Glu(155), Arg(157), Asp(159), His(169), Ile(171), Asn(173), Val(192), Tyr(194), and Val(216), are most likely responsible for the observed monomeric state of the protein in solution. C1 [Pletnev, Sergei] SAIC Frederick Inc, Basic Res Program, Argonne, IL 60439 USA. [Pletnev, Sergei; Dauter, Zbigniew] NCI, Macromol Crystallog Lab, NIH, Argonne, IL 60439 USA. [Shcherbo, Dmitry; Chudakov, Dmitry M.; Pletneva, Nadezhda; Pletnev, Vladimir] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. [Merzlyak, Ekaterina M.] Evrogen JSC, Moscow 117997, Russia. [Wlodawer, Alexander] NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. RP Pletnev, S (reprint author), SAIC Frederick Inc, Basic Res Program, Argonne, IL 60439 USA. EM svp@ncifcrf.gov RI Chudakov, Dmitriy/G-7741-2014; Pletneva, Nadya/F-7839-2014; Pletnev, Vladimir/Q-6151-2016 OI Chudakov, Dmitriy/0000-0003-0430-790X; FU National Institutes of Health Intramural Research Program of the Center for Cancer Research; NCI [NO1-CO-12400]; Russian Foundation for Basic Research [07-04-00054, 07-04-12189]; Russian Federal Agency for Science and Innovations [02.513.12.3013] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the Center for Cancer Research, NCI, and with Federal funds from NCI Contract No. NO1-CO-12400. This work was also supported by the Russian Foundation for Basic Research (Grants 07-04-00054 and 07-04-12189), Russian Federal Agency for Science and Innovations (Grant 02.513.12.3013). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 48 TC 64 Z9 64 U1 2 U2 20 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 24 PY 2008 VL 283 IS 43 BP 28980 EP 28987 DI 10.1074/jbc.M800599200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362EB UT WOS:000260179900023 PM 18682399 ER PT J AU Chen, H Lin, AS Li, YH Reiter, CEN Ver, MR Quon, MJ AF Chen, Hui Lin, Alice Seraphina Li, Yunhua Reiter, Chad E. N. Ver, Maria R. Quon, Michael J. TI Dehydroepiandrosterone Stimulates Phosphorylation of FoxO1 in Vascular Endothelial Cells via Phosphatidylinositol 3-Kinase- and Protein Kinase A-dependent Signaling Pathways to Regulate ET-1 Synthesis and Secretion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CARDIOVASCULAR-DISEASE RISK; NITRIC-OXIDE; TRANSCRIPTION FACTOR; INSULIN SENSITIVITY; IN-VITRO; CIRCULATING DEHYDROEPIANDROSTERONE; SERUM CONCENTRATIONS; ESTROGEN-RECEPTORS; TUMOR SUPPRESSION; PLASMA-MEMBRANE AB Dehydroepiandrosterone (DHEA) is an endogenous adrenal steroid hormone with controversial actions in humans. We previously reported that DHEA has opposing actions in endothelial cells to stimulate phosphatidylinositol (PI) 3-kinase/Akt/endothelial nitric-oxide synthase leading to increased production of nitric oxide while simultaneously stimulating MAPK-dependent secretion of the vasoconstrictor ET-1. In the present study we hypothesized that DHEA may stimulate PI 3-kinase-dependent phosphorylation of FoxO1 in endothelial cells to help regulate endothelial function. In bovine or human aortic endothelial cells (BAEC and HAEC), treatment with DHEA(100 nM) acutely enhanced phosphorylation of FoxO1. DHEA-stimulated phosphorylation of FoxO1 was inhibited by pretreatment of cells with wortmannin (PI 3-kinase inhibitor) or H89 (protein kinase A (PKA) inhibitor) but not ICI182780 (estrogen receptor blocker), or PD98059 (MEK (MAPK/extracellular signal-regulated kinase kinase) inhibitor). Small interfering RNA knockdown of PKA inhibited DHEA-stimulated phosphorylation of FoxO1. DHEA promoted nuclear exclusion of FoxO1 that was blocked by pretreatment of cells with wortmannin, H89, or by small interfering RNA knockdown of PKA. DHEA treatment of endothelial cells increased PKA activity and intracellular cAMP concentrations. Transfection of BAEC with a constitutively nuclear FoxO1 mutant transactivated a co-transfected ET-1 promoter luciferase reporter. Treatment of BAEC with DHEA inhibited transactivation of the ET-1 promoter reporter in cells overexpressing FoxO1. ET-1 promoter activity and secretion in response to DHEA treatment was augmented by PI 3-kinase blockade and inhibited by MAPK blockade. We conclude that DHEA stimulates phosphorylation of FoxO1 via PI 3-kinase and PKA-dependent pathways in endothelial cells that negatively regulates ET-1 promoter activity and secretion. Balance between PI 3-kinase-dependent inhibition and MAPK-dependent stimulation of ET-1 secretion in response to DHEA may determine whether DHEA supplementation improves or worsens cardiovascular and metabolic function. C1 [Chen, Hui; Lin, Alice Seraphina; Li, Yunhua; Reiter, Chad E. N.; Ver, Maria R.; Quon, Michael J.] NIH, Diabet Unit, NCCAM, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), NIH, Diabet Unit, NCCAM, 9 Mem Dr,Bldg 9,Rm 1N-105, Bethesda, MD 20892 USA. EM quonm@nih.gov OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU National Institutes of Health; American Diabetes Association FX This work was supported, in part, by the National Institutes of Health (Intramural Research Program, NCCAM) and by a Mentor-based award from the American Diabetes Association (to M. J. Q.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 72 TC 25 Z9 25 U1 0 U2 3 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 OCT 24 PY 2008 VL 283 IS 43 BP 29228 EP 29238 DI 10.1074/jbc.M802906200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362EB UT WOS:000260179900050 PM 18718910 ER PT J AU Szabo, R Hobson, JP List, K Molinolo, A Lin, CY Bugge, TH AF Szabo, Roman Hobson, John P. List, Karin Molinolo, Alfredo Lin, Chen-Yong Bugge, Thomas H. TI Potent Inhibition and Global Co-localization Implicate the Transmembrane Kunitz-type Serine Protease Inhibitor Hepatocyte Growth Factor Activator Inhibitor-2 in the Regulation of Epithelial Matriptase Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL BARRIER FUNCTION; FUNCTIONAL-CHARACTERIZATION; PLACENTAL BIKUNIN; EXPRESSION; DOMAIN; IDENTIFICATION; CLONING; MOUSE; HAI-1; GENE AB Hepatocyte growth factor activator inhibitors (HAI)-1 and -2 are recently identified and closely related Kunitz-type transmembrane serine protease inhibitors. Whereas HAI-1 is well established as an inhibitor of the serine proteases matriptase and hepatocyte growth factor activator, the physiological targets of HAI-2 are unknown. Here we show that HAI-2 displays potent inhibitory activity toward matriptase, forms SDS-stable complexes with the serine protease, and blocks matriptase-dependent activation of its candidate physiological substrates pro-prostasin and cell surface-bound pro-urokinase plasminogen activator. To further explore the potential functional relationship between HAI-2 and matriptase, we generated a transgenic mouse strain with a promoterless beta-galactosidase marker gene inserted into the endogenous locus encoding HAI-2 protein and performed a global high resolution mapping of the expression of HAI-2, matriptase, and HAI-1 proteins in all adult tissues. This analysis showed striking co-localization of HAI-2 with matriptase and HAI-1 in epithelial cells of all major organ systems, thus strongly supporting a role of HAI-2 as a physiological regulator of matriptase activity, possibly acting in a redundant or partially redundant manner with HAI-1. Unlike HAI-1 and matriptase, however, HAI-2 expression was also detected in non-epithelial cells of brain and lymph nodes, suggesting that HAI-2 may also be involved in inhibition of serine proteases other than matriptase. C1 [Szabo, Roman; Hobson, John P.; List, Karin; Molinolo, Alfredo; Bugge, Thomas H.] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Lin, Chen-Yong] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Bugge, TH (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Rm 211, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU National Institutes of Health Intramural Program; Department of Defense [DAMD-17-02-1-0693] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Program. This work was also supported by a Grant DAMD-17-02-1-0693 from the Department of Defense (to T. H. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 36 TC 54 Z9 54 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 24 PY 2008 VL 283 IS 43 BP 29495 EP 29504 DI 10.1074/jbc.M801970200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362EB UT WOS:000260179900075 PM 18713750 ER PT J AU Lee, HH Elia, N Ghirlando, R Lippincott-Schwartz, J Hurley, JH AF Lee, Hyung Ho Elia, Natalie Ghirlando, Rodolfo Lippincott-Schwartz, Jennifer Hurley, James H. TI Midbody targeting of the ESCRT machinery by a noncanonical coiled coil in CEP55 SO SCIENCE LA English DT Article ID LATE DOMAINS; CYTOKINESIS; PROTEIN; HIV-1; ALIX; REQUIREMENTS; RECRUITMENT; RELEASE; PATHWAY; TSG101 AB The ESCRT (endosomal sorting complex required for transport) machinery is required for the scission of membrane necks in processes including the budding of HIV-1 and cytokinesis. An essential step in cytokinesis is recruitment of the ESCRT-I complex and the ESCRT-associated protein ALIX to the midbody (the structure that tethers two daughter cells) by the protein CEP55. Biochemical experiments show that peptides from ALIX and the ESCRT-I subunit TSG101 compete for binding to the ESCRT- and ALIX-binding region (EABR) of CEP55. We solved the crystal structure of EABR bound to an ALIX peptide at a resolution of 2.0 angstroms. The structure shows that EABR forms an aberrant dimeric parallel coiled coil. Bulky and charged residues at the interface of the two central heptad repeats create asymmetry and a single binding site for an ALIX or TSG101 peptide. Both ALIX and ESCRT-i are required for cytokinesis, which suggests that multiple CEP55 dimers are required for function. C1 [Lee, Hyung Ho; Ghirlando, Rodolfo; Hurley, James H.] NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. [Elia, Natalie; Lippincott-Schwartz, Jennifer] NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Ghirlando, Rodolfo/A-8880-2009 FU U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; NIH intramural suppor; NIDDK; NICHD; IATAP FX We thank B. Beach for generating DNA constructs, E. Freed and K. Kutsche for providing DNAs, T. Alber for discussions, and the staff of SER-CAT for user support at the Advanced Photon Source (APS). Use of the APS was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. Supported by NIH intramural support, NIDDK (J.H.H.), NICHD (J.L.), and IATAP (J.H.H. and J.L.). Crystallographic coordinates have been deposited in the RCSB Protein Data Bank with accession number 3E1R. NR 26 TC 113 Z9 117 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 24 PY 2008 VL 322 IS 5901 BP 576 EP 580 DI 10.1126/science.1162042 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363WV UT WOS:000260299100040 PM 18948538 ER PT J AU Ulucan, H Guel, D Sapp, JC Cockerham, J Johnston, JJ Biesecker, LG AF Ulucan, Hakan Guel, Davut Sapp, Julie C. Cockerham, John Johnston, Jennifer J. Biesecker, Leslie G. TI Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene SO BMC MEDICAL GENETICS LA English DT Article ID SINGLE ATRIUM AB Background: Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance. Methods: Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations. Results: We identified a c. 1868T > C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals. Conclusion: We conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome. C1 [Ulucan, Hakan; Sapp, Julie C.; Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Ulucan, Hakan] Adnan Menderes Univ, Fac Med, Dept Med Genet, Aydin, Turkey. [Guel, Davut] Gulhane Mil Med Acad, Dept Med Genet, Ankara, Turkey. [Cockerham, John] Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM ulucanh@mail.nih.gov; davutgul2001@yahoo.com; sappj@mail.nih.gov; jcockerh@cnmc.org; jjohnsto@mail.nih.gov; leslieb@helix.nih.gov FU National Human Genome Research Institute, NIH, Bethesda, USA FX The authors thank the subjects for participating in the study. Written consent was obtained from the patient or their relative for publication of the patient's details. This work was supported by funds from the Intramural Research Program of the National Human Genome Research Institute, NIH, Bethesda, USA. NR 15 TC 9 Z9 10 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD OCT 23 PY 2008 VL 9 AR 92 DI 10.1186/1471-2350-9-92 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 378JX UT WOS:000261318100001 PM 18947413 ER PT J AU Tilburt, JC Emanuel, EJ Kaptchuk, TJ Curlin, FA Miller, FG AF Tilburt, Jon C. Emanuel, Ezekiel J. Kaptchuk, Ted J. Curlin, Farr A. Miller, Franklin G. TI Prescribing "placebo treatments": results of national survey of US internists and rheumatologists SO BRITISH MEDICAL JOURNAL LA English DT Article ID QUESTIONNAIRE SURVEY; POWERFUL PLACEBO; PHYSICIANS; ATTITUDES; ETHICS AB Objective To describe the attitudes and behaviours regarding placebo treatments, defined as a treatment whose benefits derive from positive patient expectations and not from the physiological mechanism of the treatment itself. Design Cross sectional mailed survey. Setting Physicians' clinical practices. Participants 1200 practising internists and rheumatologists in the United States. Main outcome measures Investigators measured physicians' self reported behaviours and attitudes concerning the use of placebo treatments, including measures of whether they would use or had recommended a "placebo treatment," their ethical judgments about the practice, what they recommended as placebo treatments, and how they typically communicate with patients about the practice. Results 679 physicians ( 57%) responded to the survey. About half of the surveyed internists and rheumatologists reported prescribing placebo treatments on a regular basis ( 46- 58%, depending on how the question was phrased). Most physicians ( 399, 62%) believed the practice to be ethically permissible. Few reported using saline ( 18, 3%) or sugar pills ( 12, 2%) as placebo treatments, while large proportions reported using over the counter analgesics ( 267, 41%) and vitamins ( 243, 38%) as placebo treatments within the past year. A small but notable proportion of physicians reported using antibiotics ( 86, 13%) and sedatives ( 86, 13%) as placebo treatments during the same period. Furthermore, physicians who use placebo treatments most commonly describe them to patients as a potentially beneficial medicine or treatment not typically used for their condition ( 241, 68%); only rarely do they explicitly describe them as placebos ( 18, 5%). Conclusions Prescribing placebo treatments seems to be common and is viewed as ethically permissible among the surveyed US internists and rheumatologists. Vitamins and over the counter analgesics are the most commonly used treatments. Physicians might not be fully transparent with their patients about the use of placebos and might have mixed motivations for recommending such treatments. C1 [Tilburt, Jon C.; Emanuel, Ezekiel J.; Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Osher Inst, Boston, MA 02215 USA. [Curlin, Farr A.] Univ Chicago, Sect Internal Med, Chicago, IL 60637 USA. [Curlin, Farr A.] Univ Chicago, McClean Ctr Clin Med Eth, Chicago, IL 60637 USA. RP Tilburt, JC (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM tilburt.jon@mayo.edu FU NCCIH NIH HHS [K23 AT002749] NR 29 TC 87 Z9 89 U1 2 U2 12 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD OCT 23 PY 2008 VL 337 AR a1938 DI 10.1136/bmj.a1938 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 374FP UT WOS:000261028900001 PM 18948346 ER PT J AU Liang, FT Jain, N Hutchens, T Shock, DD Beard, WA Wilson, SH Chiarelli, MP Cho, BP AF Liang, Fengting Jain, Nidhi Hutchens, Troy Shock, David D. Beard, William A. Wilson, Samuel H. Chiarelli, M. Paul Cho, Bongsup P. TI alpha,beta-Methylene-2 '-deoxynucleoside 5 '-Triphosphates as Noncleavable Substrates for DNA Polymerases: Isolation, Characterization, and Stability Studies of Novel 2 '-Deoxycyclonucleosides, 3,5 '-Cyclo-dG, and 2,5 '-Cyclo-dT SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID INDUCED CONFORMATIONAL HETEROGENEITY; VIRUS-1 REVERSE-TRANSCRIPTASE; ADENOSINE 5'-TRIPHOSPHATE; THYMIDINE TRIPHOSPHATE; PHOSPHONATE ANALOGS; PURINE NUCLEOSIDES; ANTIVIRAL ACTIVITY; RNA-POLYMERASE; IN-PLACE; BETA AB We report synthesis and characterization of a complete set of alpha,beta-methylene-2'-dNTPs (alpha,beta-m-dNTP; N = A, C, T, G, 12-15) in which the alpha,beta-oxygen linkage of natural dNTP was replaced by a methylene group. These nucleotides were designed to be noncleavable substrates for DNA polymerases. Synthesis entails preparation of 2'-deoxynucleoside 5'-diphosphate precursors, followed by an enzymatic gamma-phosphorylation. All four synthesized alpha,beta-m-dNTPs were found to be potent inhibitors of polymerase beta, with K(i) values ranging 1-5 mu M. During preparation of the dG and dT derivatives of alpha,beta-methylene diphosphate, we also isolated significant amounts of 3,5'-cyclo-dG (16) and 2,5'-cyclo-dT (17), respectively. These novel 2'-deoxycyclonucleosides were formed via a base-catalyzed intramolecular cyclization (N3 -> C5' and O2 -> C5' respectively). In acidic solution, both 16 and 17 underwent glycolysis, followed by complete depurination. When exposed to alkaline conditions, 16 underwent an oxidative deamination to produce 3,5'-cyc1o-2'-deoxyxanthosine (19), whereas 17 was hydrolyzed exclusively to dT. C1 [Liang, Fengting; Jain, Nidhi; Hutchens, Troy; Cho, Bongsup P.] Univ Rhode Isl, Coll Pharm, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA. [Shock, David D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Chiarelli, M. Paul] Loyola Univ, Dept Chem, Chicago, IL 60626 USA. RP Cho, BP (reprint author), Univ Rhode Isl, Coll Pharm, Dept Biomed & Pharmaceut Sci, 41 Lower Coll Rd, Kingston, RI 02881 USA. EM bcho@uri.edu FU NIH [CA098296, 1U19CA105010]; NCRR/NIH [P20 RR016457, P4 1RR0954] FX This research was supported by the NIH grant CA098296 and the Intramural Research Program of the NIH, NIEHS,in association with the NIH grant 1U19CA105010. This research was also made possible in part by the use of the INBRE Research Core Facility, which is supported by the NCRR/NIH (P20 RR016457). Mass spectrometry was provided by Washington University Mass Spectrometry Resource with Support from the NCRR/NIH (P4 1RR0954). NR 54 TC 9 Z9 9 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 23 PY 2008 VL 51 IS 20 BP 6460 EP 6470 DI 10.1021/jm800692a PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 361BO UT WOS:000260102700022 PM 18811136 ER PT J AU Jeong, LS Pal, S Choe, SA Choi, WJ Jacobson, KA Gao, ZG Klutz, AM Hou, XY Kim, HO Lee, HW Lee, SK Tosh, DK Moon, HR AF Jeong, Lak Shin Pal, Shantanu Choe, Seung Ah Choi, Won Jun Jacobson, Kenneth A. Gao, Zhan-Guo Klutz, Athena M. Hou, Xiyan Kim, Hea Ok Lee, Hyuk Woo Lee, Sang Kook Tosh, Dilip K. Moon, Hyung Ryong TI Structure-Activity Relationships of Truncated D- and L-4 '-Thioadenosine Derivatives as Species-Independent A(3) Adenosine Receptor Antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SELECTIVE ANTAGONISTS; HIGHLY POTENT; IB-MECA; AGONISTS; LIGANDS; EFFICACY; CELLS; AFFINITY; SUBTYPES; DESIGN AB Novel D- and L-4'-thioadenosine derivatives lacking the 4'-hydroxymethyl moiety were synthesized, starting from D-mannose and D-gulonic gamma-lactone, respectively, as potent and selective species-independent A(3) adenosine receptor (AR) antagonists. Among the novel 4'-truncated 2-H nucleosides tested, a N-6-(3-chlorobenzyl) derivative 7c was the most potent at the human A(3) AR (K-i = 1.5 nM), but a N-6-(3-bromobenzyl) derivative 7d showed the optimal species-independent binding affinity. C1 [Jeong, Lak Shin; Pal, Shantanu; Choe, Seung Ah; Choi, Won Jun; Hou, Xiyan; Kim, Hea Ok; Lee, Hyuk Woo; Lee, Sang Kook; Tosh, Dilip K.] Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. [Jacobson, Kenneth A.; Gao, Zhan-Guo; Klutz, Athena M.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Moon, Hyung Ryong] Pusan Natl Univ, Coll Pharm, Pusan 609753, South Korea. RP Jeong, LS (reprint author), Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr OI Jacobson, Kenneth/0000-0001-8104-1493 FU Korea Research Foundation [KRF-2008-E00304]; NIDDK, NIH, Bethesda, MD FX This work was supported by the Korea Research Foundation grant (KRF-2008-E00304) and the Intramural Research Program of NIDDK, NIH, Bethesda, MD. NR 27 TC 26 Z9 26 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 23 PY 2008 VL 51 IS 20 BP 6609 EP 6613 DI 10.1021/jm8008647 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 361BO UT WOS:000260102700038 PM 18811138 ER PT J AU Chin, L Meyerson, M Aldape, K Bigner, D Mikkelsen, T VandenBerg, S Kahn, A Penny, R Ferguson, ML Gerhard, DS Getz, G Brennan, C Taylor, BS Winckler, W Park, P Ladanyi, M Hoadley, KA Verhaak, RGW Hayes, DN Spellman, PT Absher, D Weir, BA Ding, L Wheeler, D Lawrence, MS Cibulskis, K Mardis, E Zhang, JH Wilson, RK Donehower, L Wheeler, DA Purdom, E Wallis, J Laird, PW Herman, JG Schuebel, KE Weisenberger, DJ Baylin, SB Schultz, N Yao, J Wiedemeyer, R Weinstein, J Sander, C Gibbs, RA Gray, J Kucherlapati, R Lander, ES Myers, RM Perou, CM McLendon, R Friedman, A Van Meir, EG Brat, DJ Mastrogianakis, GM Olson, JJ Lehman, N Yung, WKA Bogler, O Berger, M Prados, M Muzny, D Morgan, M Scherer, S Sabo, A Nazareth, L Lewis, L Hall, O Zhu, YM Ren, YR Alvi, O Yao, JQ Hawes, A Jhangiani, S Fowler, G San Lucas, A Kovar, C Cree, A Dinh, H Santibanez, J Joshi, V Gonzalez-Garay, ML Miller, CA Milosavljevic, A Sougnez, C Fennell, T Mahan, S Wilkinson, J Ziaugra, L Onofrio, R Bloom, T Nicol, R Ardlie, K Baldwin, J Gabriel, S Fulton, RS McLellan, MD Larson, DE Shi, XQ Abbott, R Fulton, L Chen, K Koboldt, DC Wendl, MC Meyer, R Tang, YZ Lin, L Osborne, JR Dunford-Shore, BH Miner, TL Delehaunty, K Markovic, C Swift, G Courtney, W Pohl, C Abbott, S Hawkins, A Leong, S Haipek, C Schmidt, H Wiechert, M Vickery, T Scott, S Dooling, DJ Chinwalla, A Weinstock, GM O'Kelly, M Robinson, J Alexe, G Beroukhim, R Carter, S Chiang, D Gould, J Gupta, S Korn, J Mermel, C Mesirov, J Monti, S Nguyen, H Parkin, M Reich, M Stransky, N Garraway, L Golub, T Protopopov, A Perna, I Aronson, S Sathiamoorthy, N Ren, G Kim, H Kong, SK Xiao, YH Kohane, IS Seidman, J Cope, L Pan, F Van Den Berg, D Van Neste, L Yi, JM Li, JZ Southwick, A Brady, S Aggarwal, A Chung, T Sherlock, G Brooks, JD Jakkula, LR Lapuk, AV Marr, H Dorton, S Choi, YG Han, J Ray, A Wang, V Durinck, S Robinson, M Wang, NJ Vranizan, K Peng, V Van Name, E Fontenay, GV Ngai, J Conboy, JG Parvin, B Feiler, HS Speed, TP Socci, ND Olshen, A Lash, A Reva, B Antipin, Y Stukalov, A Gross, B Cerami, E Wang, WQ Qin, LX Seshan, VE Villafania, L Cavatore, M Borsu, L Viale, A Gerald, W Topal, MD Qi, Y Balu, S Shi, Y Wu, G Bittner, M Shelton, T Lenkiewicz, E Morris, S Beasley, D Sanders, S Sfeir, R Chen, J Nassau, D Feng, L Hickey, E Schaefer, C Madhavan, S Buetow, K Barker, A Vockley, J Compton, C Vaught, J Fielding, P Collins, F Good, P Guyer, M Ozenberger, B Peterson, J Thomson, E AF Chin, L. Meyerson, M. Aldape, K. Bigner, D. Mikkelsen, T. VandenBerg, S. Kahn, A. Penny, R. Ferguson, M. L. Gerhard, D. S. Getz, G. Brennan, C. Taylor, B. S. Winckler, W. Park, P. Ladanyi, M. Hoadley, K. A. Verhaak, R. G. W. Hayes, D. N. Spellman, Paul T. Absher, D. Weir, B. A. Ding, L. Wheeler, D. Lawrence, M. S. Cibulskis, K. Mardis, E. Zhang, Jinghui Wilson, R. K. Donehower, L. Wheeler, D. A. Purdom, E. Wallis, J. Laird, P. W. Herman, J. G. Schuebel, K. E. Weisenberger, D. J. Baylin, S. B. Schultz, N. Yao, Jun Wiedemeyer, R. Weinstein, J. Sander, C. Gibbs, R. A. Gray, J. Kucherlapati, R. Lander, E. S. Myers, R. M. Perou, C. M. McLendon, Roger Friedman, Allan Van Meir, Erwin G Brat, Daniel J Mastrogianakis, Gena Marie Olson, Jeffrey J Lehman, Norman Yung, W. K. Alfred Bogler, Oliver Berger, Mitchel Prados, Michael Muzny, Donna Morgan, Margaret Scherer, Steve Sabo, Aniko Nazareth, Lynn Lewis, Lora Hall, Otis Zhu, Yiming Ren, Yanru Alvi, Omar Yao, Jiqiang Hawes, Alicia Jhangiani, Shalini Fowler, Gerald San Lucas, Anthony Kovar, Christie Cree, Andrew Dinh, Huyen Santibanez, Jireh Joshi, Vandita Gonzalez-Garay, Manuel L. Miller, Christopher A. Milosavljevic, Aleksandar Sougnez, Carrie Fennell, Tim Mahan, Scott Wilkinson, Jane Ziaugra, Liuda Onofrio, Robert Bloom, Toby Nicol, Rob Ardlie, Kristin Baldwin, Jennifer Gabriel, Stacey Fulton, Robert S. McLellan, Michael D. Larson, David E. Shi, Xiaoqi Abbott, Rachel Fulton, Lucinda Chen, Ken Koboldt, Daniel C. Wendl, Michael C. Meyer, Rick Tang, Yuzhu Lin, Ling Osborne, John R. Dunford-Shore, Brian H. Miner, Tracie L. Delehaunty, Kim Markovic, Chris Swift, Gary Courtney, William Pohl, Craig Abbott, Scott Hawkins, Amy Leong, Shin Haipek, Carrie Schmidt, Heather Wiechert, Maddy Vickery, Tammi Scott, Sacha Dooling, David J. Chinwalla, Asif Weinstock, George M. O'Kelly, Michael Robinson, Jim Alexe, Gabriele Beroukhim, Rameen Carter, Scott Chiang, Derek Gould, Josh Gupta, Supriya Korn, Josh Mermel, Craig Mesirov, Jill Monti, Stefano Nguyen, Huy Parkin, Melissa Reich, Michael Stransky, Nicolas Garraway, Levi Golub, Todd Protopopov, Alexei Perna, Ilana Aronson, Sandy Sathiamoorthy, Narayan Ren, Georgia Kim, Hyunsoo Kong, Sek Won Xiao, Yonghong Kohane, Isaac S. Seidman, Jon Cope, Leslie Pan, Fei Van Den Berg, David Van Neste, Leander Yi, Joo Mi Li, Jun Z. Southwick, Audrey Brady, Shannon Aggarwal, Amita Chung, Tisha Sherlock, Gavin Brooks, James D. Jakkula, Lakshmi R. Lapuk, Anna V. Marr, Henry Dorton, Shannon Choi, Yoon Gi Han, Ju Ray, Amrita Wang, Victoria Durinck, Steffen Robinson, Mark Wang, Nicholas J. Vranizan, Karen Peng, Vivian Van Name, Eric Fontenay, Gerald V. Ngai, John Conboy, John G. Parvin, Bahram Feiler, Heidi S. Speed, Terence P. Socci, Nicholas D. Olshen, Adam Lash, Alex Reva, Boris Antipin, Yevgeniy Stukalov, Alexey Gross, Benjamin Cerami, Ethan Wang, Wei Qing Qin, Li-Xuan Seshan, Venkatraman E. Villafania, Liliana Cavatore, Magali Borsu, Laetitia Viale, Agnes Gerald, William Topal, Michael D. Qi, Yuan Balu, Sai Shi, Yan Wu, George Bittner, Michael Shelton, Troy Lenkiewicz, Elizabeth Morris, Scott Beasley, Debbie Sanders, Sheri Sfeir, Robert Chen, Jessica Nassau, David Feng, Larry Hickey, Erin Schaefer, Carl Madhavan, Subha Buetow, Ken Barker, Anna Vockley, Joseph Compton, Carolyn Vaught, Jim Fielding, Peter Collins, Francis Good, Peter Guyer, Mark Ozenberger, Brad Peterson, Jane Thomson, Elizabeth CA Canc Genome Atlas Res Network Tissue Source Sites Genome Sequencing Ctr Canc Genome Characterization Ctr Project Teams TI Comprehensive genomic characterization defines human glioblastoma genes and core pathways SO NATURE LA English DT Article ID NF1 GENE; MISMATCH REPAIR; NEUROFIBROMATOSIS TYPE-1; SOMATIC MUTATIONS; MALIGNANT GLIOMAS; ALKYLATING-AGENTS; HIGH-FREQUENCY; PIK3CA GENE; CELL-LINES; TUMORS AB Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer. C1 [Chin, L.; Meyerson, M.; Winckler, W.; Verhaak, R. G. W.; Weir, B. A.; Wiedemeyer, R.; Beroukhim, Rameen; Chiang, Derek; Mermel, Craig; Garraway, Levi] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chin, L.; Yao, Jun; Protopopov, Alexei; Perna, Ilana; Ren, Georgia; Xiao, Yonghong] Dana Farber Canc Inst, Ctr Appl Canc Sci, Belfer Inst innovat Canc Sci, Boston, MA 02115 USA. [Chin, L.; Robinson, Jim; Alexe, Gabriele; Carter, Scott] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Meyerson, M.; Getz, G.; Winckler, W.; Verhaak, R. G. W.; Weir, B. A.; Lawrence, M. S.; Lander, E. S.; O'Kelly, Michael; Beroukhim, Rameen; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd] Harvard Univ, Cambridge, MA 02142 USA. [Bigner, D.; McLendon, Roger] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Friedman, Allan] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Mikkelsen, T.] Henry Ford Hosp, Dept Neurol Surg, Detroit, MI 48202 USA. [VandenBerg, S.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Aldape, K.] Univ Texas Houston MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Yung, W. K. Alfred] Univ Texas Houston MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Bogler, Oliver] Univ Texas Houston MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. [Kahn, A.; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin] SRA Int, Fairfax, VA 22033 USA. NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD 20852 USA. [Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth] NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. [Gerhard, D. S.; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter] NCI, NIH, Bethesda, MD 20892 USA. [Penny, R.; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri] Int Genom Consortium, Phoenix, AZ 85004 USA. [Ferguson, M. L.] MLF Consulting, Arlington, MA 02474 USA. [Ding, L.; Mardis, E.; Wilson, R. K.; Wallis, J.; Fennell, Tim; Baldwin, Jennifer; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.] Washington Univ, Sch Med, Dept Genet, Genome Ctr, St Louis, MO 63108 USA. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21231 USA. [Park, P.; Aronson, Sandy; Sathiamoorthy, Narayan; Kim, Hyunsoo; Kohane, Isaac S.] Harvard Univ, Sch Med, Partners Healthcare Ctr Genet & Genom, Boston, MA 02115 USA. [Park, P.; Kucherlapati, R.; Kohane, Isaac S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Park, P.; Kong, Sek Won; Kohane, Isaac S.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Brennan, C.] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [Taylor, B. S.; Schultz, N.; Sander, C.; Socci, Nicholas D.; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Gerald, William] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Taylor, B. S.] Weill Cornell Grad Sch Med Sci, Dept Physiol & Biophys, New York, NY 10065 USA. [Ladanyi, M.; Borsu, Laetitia] Mem Sloan Kettering Canc Ctr, Dept Pathol, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Spellman, Paul T.; Gray, J.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Han, Ju; Ray, Amrita; Durinck, Steffen; Wang, Nicholas J.; Fontenay, Gerald V.; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. [Purdom, E.; Wang, Victoria; Speed, Terence P.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 95720 USA. [Choi, Yoon Gi; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Ngai, John] Univ Calif Berkeley, Dept Mol & Cellular Biol, Berkeley, CA 95720 USA. [Robinson, Mark; Speed, Terence P.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Brooks, James D.] Stanford Univ, Sch Med, Dept Urol, Stanford, CA 94305 USA. [Wheeler, D.; Donehower, L.; Wheeler, D. A.] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Perou, C. M.; Miller, Christopher A.; Milosavljevic, Aleksandar] Baylor Coll Med, Grad Program Struct & Computat Biol & Mol Biophys, Houston, TX 77030 USA. [Perou, C. M.; Milosavljevic, Aleksandar] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Univ N Carolina, Dept Genet, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Hoadley, K. A.; Topal, Michael D.] Univ N Carolina, Dept Pathol & Lab Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Qi, Yuan] Univ N Carolina, Dept Internal Med, Lineberger Comprehens Canc Ctr, Div Med Oncol, Chapel Hill, NC 27599 USA. [Hayes, D. N.; Herman, J. G.; Schuebel, K. E.; Baylin, S. B.; Yi, Joo Mi] Johns Hopkins Univ, Div Canc Biol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Cope, Leslie] Johns Hopkins Univ, Biometry & Clin Trials Div, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Van Neste, Leander] Univ Ghent, Fac Biosci & Engn, Dept Mol Biotechnol, B-9000 Ghent, Belgium. [Van Meir, Erwin G; Mastrogianakis, Gena Marie; Olson, Jeffrey J] Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA 30322 USA. [Van Meir, Erwin G; Olson, Jeffrey J] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Van Meir, Erwin G; Brat, Daniel J; Olson, Jeffrey J] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. [Brat, Daniel J] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Laird, P. W.; Weisenberger, D. J.; Pan, Fei; Van Den Berg, David] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90089 USA. [Lehman, Norman] Henry Ford Hosp, Dept Pathol, Detroit, MI 48202 USA. [Berger, Mitchel; Prados, Michael] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. [Cibulskis, K.; Sougnez, Carrie] MIT, Eli & Edythe L Broad Inst, Canc Genome Project, Cambridge, MA 02142 USA. [Sougnez, Carrie] MIT, Eli & Edythe L Broad Inst, Med Resequencing Project, Cambridge, MA 02142 USA. [Lander, E. S.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Lander, E. S.] Harvard Univ, Dept Syst Biol, Boston, MA 02115 USA. [Golub, Todd] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Seidman, Jon] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Absher, D.; Myers, R. M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Olshen, Adam; Qin, Li-Xuan; Seshan, Venkatraman E.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Villafania, Liliana; Cavatore, Magali; Viale, Agnes] Mem Sloan Kettering Canc Ctr, Genom Core Lab, New York, NY 10065 USA. [Bittner, Michael] Translat Genom Res Inst, Computat Biol Div, Phoenix, AZ 85004 USA. [Zhang, Jinghui; Schaefer, Carl; Madhavan, Subha; Buetow, Ken] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD 20852 USA. [Weinstein, J.] Univ Texas Houston MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Li, Jun Z.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Kong, Sek Won] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. RP Chin, L (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu; matthew_meyerson@dfci.harvard.edu RI Wendl, Michael/A-2741-2008; Speed, Terence /B-8085-2009; leng, xianwei/F-9073-2011; sander, chris/H-1452-2011; Meyerson, Matthew/E-7123-2012; Sherlock, Gavin/E-9110-2012; Miller, Christopher/A-1060-2009; Kohane, Isaac Kohane/K-3716-2012; Robinson, Mark/A-6432-2015; Laird, Peter/G-8683-2012; Lehman, Norman/A-7351-2015; Chiang, Daisy/C-9481-2011; Reva, Boris/B-6436-2014; OI Speed, Terence /0000-0002-5403-7998; Miller, Christopher/0000-0003-4266-6700; Kohane, Isaac Kohane/0000-0003-2192-5160; Robinson, Mark/0000-0002-3048-5518; Chiang, Daisy/0000-0002-8205-4285; Reva, Boris/0000-0002-8805-389X; Van Meir, Erwin G./0000-0003-2444-7707; Lehman, Norman/0000-0001-8394-2607; Bogler, Oliver/0000-0002-3700-0480; Brennan, Cameron/0000-0003-4064-8891; Lash, Alex/0000-0003-3787-1590; Hayes, D. Neil/0000-0001-6203-7771; Sherlock, Gavin/0000-0002-1692-4983; Perou, Charles/0000-0001-9827-2247 FU United States National Institutes of Health [U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563] FX We thank the members of TCGA's External Scientific Committee, the Glioblastoma Disease Working Group (http:// cancergenome.nih.gov/components) and D. N. Louis for discussions; A. Mirick, J. Melone and C. Collins for administrative coordination of TCGA activities; and L. Gaffney for graphic art. This work was supported by the following grants from the United States National Institutes of Health: U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561 and U24CA126563. NR 50 TC 2301 Z9 2332 U1 48 U2 314 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 23 PY 2008 VL 455 IS 7216 BP 1061 EP 1068 DI 10.1038/nature07385 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363FG UT WOS:000260252600035 ER PT J AU Ding, L Getz, G Wheeler, DA Mardis, ER McLellan, MD Cibulskis, K Sougnez, C Greulich, H Muzny, DM Morgan, MB Fulton, L Fulton, RS Zhang, QY Wendl, MC Lawrence, MS Larson, DE Chen, K Dooling, DJ Sabo, A Hawes, AC Shen, H Jhangiani, SN Lewis, LR Hall, O Zhu, YM Mathew, T Ren, YR Yao, JQ Scherer, SE Clerc, K Metcalf, GA Ng, B Milosavljevic, A Gonzalez-Garay, ML Osborne, JR Meyer, R Shi, XQ Tang, YZ Koboldt, DC Lin, L Abbott, R Miner, TL Pohl, C Fewell, G Haipek, C Schmidt, H Dunford-Shore, BH Kraja, A Crosby, SD Sawyer, CS Vickery, T Sander, S Robinson, J Winckler, W Baldwin, J Chirieac, LR Dutt, A Fennell, T Hanna, M Johnson, BE Onofrio, RC Thomas, RK Tonon, G Weir, BA Zhao, XJ Ziaugra, L Zody, MC Giordano, T Orringer, MB Roth, JA Spitz, MR Wistuba, II Ozenberger, B Good, PJ Chang, AC Beer, DG Watson, MA Ladanyi, M Broderick, S Yoshizawa, A Travis, WD Pao, W Province, MA Weinstock, GM Varmus, HE Gabriel, SB Lander, ES Gibbs, RA Meyerson, M Wilson, RK AF Ding, Li Getz, Gad Wheeler, David A. Mardis, Elaine R. McLellan, Michael D. Cibulskis, Kristian Sougnez, Carrie Greulich, Heidi Muzny, Donna M. Morgan, Margaret B. Fulton, Lucinda Fulton, Robert S. Zhang, Qunyuan Wendl, Michael C. Lawrence, Michael S. Larson, David E. Chen, Ken Dooling, David J. Sabo, Aniko Hawes, Alicia C. Shen, Hua Jhangiani, Shalini N. Lewis, Lora R. Hall, Otis Zhu, Yiming Mathew, Tittu Ren, Yanru Yao, Jiqiang Scherer, Steven E. Clerc, Kerstin Metcalf, Ginger A. Ng, Brian Milosavljevic, Aleksandar Gonzalez-Garay, Manuel L. Osborne, John R. Meyer, Rick Shi, Xiaoqi Tang, Yuzhu Koboldt, Daniel C. Lin, Ling Abbott, Rachel Miner, Tracie L. Pohl, Craig Fewell, Ginger Haipek, Carrie Schmidt, Heather Dunford-Shore, Brian H. Kraja, Aldi Crosby, Seth D. Sawyer, Christopher S. Vickery, Tammi Sander, Sacha Robinson, Jody Winckler, Wendy Baldwin, Jennifer Chirieac, Lucian R. Dutt, Amit Fennell, Tim Hanna, Megan Johnson, Bruce E. Onofrio, Robert C. Thomas, Roman K. Tonon, Giovanni Weir, Barbara A. Zhao, Xiaojun Ziaugra, Liuda Zody, Michael C. Giordano, Thomas Orringer, Mark B. Roth, Jack A. Spitz, Margaret R. Wistuba, Ignacio I. Ozenberger, Bradley Good, Peter J. Chang, Andrew C. Beer, David G. Watson, Mark A. Ladanyi, Marc Broderick, Stephen Yoshizawa, Akihiko Travis, William D. Pao, William Province, Michael A. Weinstock, George M. Varmus, Harold E. Gabriel, Stacey B. Lander, Eric S. Gibbs, Richard A. Meyerson, Matthew Wilson, Richard K. TI Somatic mutations affect key pathways in lung adenocarcinoma SO NATURE LA English DT Article ID HUMAN BREAST; MENDELIAN-INHERITANCE; HOMOZYGOUS DELETIONS; COLORECTAL CANCERS; EGFR MUTATIONS; TOBACCO-SMOKE; KRAS MUTATION; NEVER SMOKERS; RECEPTOR GENE; GEFITINIB AB Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment. C1 [Ding, Li; Mardis, Elaine R.; McLellan, Michael D.; Fulton, Lucinda; Fulton, Robert S.; Wendl, Michael C.; Larson, David E.; Chen, Ken; Dooling, David J.; Osborne, John R.; Meyer, Rick; Shi, Xiaoqi; Tang, Yuzhu; Koboldt, Daniel C.; Lin, Ling; Abbott, Rachel; Miner, Tracie L.; Pohl, Craig; Fewell, Ginger; Haipek, Carrie; Schmidt, Heather; Dunford-Shore, Brian H.; Crosby, Seth D.; Sawyer, Christopher S.; Vickery, Tammi; Sander, Sacha; Robinson, Jody; Weinstock, George M.; Wilson, Richard K.] Washington Univ, Sch Med, Dept Genet, Genome Ctr, St Louis, MO 63108 USA. [Getz, Gad; Cibulskis, Kristian; Sougnez, Carrie; Greulich, Heidi; Lawrence, Michael S.; Winckler, Wendy; Baldwin, Jennifer; Dutt, Amit; Fennell, Tim; Hanna, Megan; Onofrio, Robert C.; Weir, Barbara A.; Zhao, Xiaojun; Ziaugra, Liuda; Zody, Michael C.; Gabriel, Stacey B.; Lander, Eric S.; Meyerson, Matthew] Broad Inst Harvard & MIT, Canc Program, Genome Biol Program, Cambridge, MA 02142 USA. [Wheeler, David A.; Muzny, Donna M.; Morgan, Margaret B.; Sabo, Aniko; Hawes, Alicia C.; Shen, Hua; Jhangiani, Shalini N.; Lewis, Lora R.; Hall, Otis; Zhu, Yiming; Mathew, Tittu; Ren, Yanru; Yao, Jiqiang; Scherer, Steven E.; Clerc, Kerstin; Metcalf, Ginger A.; Ng, Brian; Milosavljevic, Aleksandar; Gonzalez-Garay, Manuel L.; Gibbs, Richard A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Greulich, Heidi; Winckler, Wendy; Dutt, Amit; Hanna, Megan; Johnson, Bruce E.; Tonon, Giovanni; Weir, Barbara A.; Zhao, Xiaojun; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhang, Qunyuan; Kraja, Aldi; Province, Michael A.] Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA. [Chirieac, Lucian R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chirieac, Lucian R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Chirieac, Lucian R.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Thomas, Roman K.] Max Planck Soc, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany. [Thomas, Roman K.] Univ Cologne, Fac Med, D-50931 Cologne, Germany. [Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol, D-50931 Cologne, Germany. [Thomas, Roman K.] Univ Cologne, Dept Internal Med 1, D-50931 Cologne, Germany. [Giordano, Thomas] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Orringer, Mark B.; Chang, Andrew C.; Beer, David G.] Univ Michigan, Thorac Surg Sect, Dept Surg, Ann Arbor, MI 48109 USA. [Roth, Jack A.; Wistuba, Ignacio I.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA. [Spitz, Margaret R.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Wistuba, Ignacio I.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Ozenberger, Bradley; Good, Peter J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Watson, Mark A.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63108 USA. [Ladanyi, Marc; Broderick, Stephen; Yoshizawa, Akihiko; Travis, William D.; Pao, William] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Ladanyi, Marc; Broderick, Stephen; Yoshizawa, Akihiko; Travis, William D.; Pao, William] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Ladanyi, Marc; Broderick, Stephen; Yoshizawa, Akihiko; Travis, William D.; Pao, William] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Ladanyi, Marc; Broderick, Stephen; Yoshizawa, Akihiko; Travis, William D.; Pao, William] Mem Sloan Kettering Canc Ctr, Dept Computat Biol, New York, NY 10065 USA. [Ladanyi, Marc; Pao, William] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Varmus, Harold E.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. RP Wilson, RK (reprint author), Washington Univ, Sch Med, Dept Genet, Genome Ctr, St Louis, MO 63108 USA. EM matthew_meyerson@dfci.harvard.edu; rwilson@wustl.edu RI Wendl, Michael/A-2741-2008; Chen, Ken/A-1074-2009; Meyerson, Matthew/E-7123-2012; Dutt, Amit/I-1911-2013; OI Dutt, Amit/0000-0002-1119-4774; Chang, Andrew/0000-0001-9506-0425; Giordano, Thomas/0000-0003-0641-8873 FU National Human Genome Research Institute FX We thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W. NR 50 TC 1294 Z9 1335 U1 29 U2 151 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 23 PY 2008 VL 455 IS 7216 BP 1069 EP 1075 DI 10.1038/nature07423 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363FG UT WOS:000260252600036 PM 18948947 ER PT J AU Gavathiotis, E Suzuki, M Davis, ML Pitter, K Bird, GH Katz, SG Tu, HC Kim, H Cheng, EHY Tjandra, N Walensky, LD AF Gavathiotis, Evripidis Suzuki, Motoshi Davis, Marguerite L. Pitter, Kenneth Bird, Gregory H. Katz, Samuel G. Tu, Ho-Chou Kim, Hyungjin Cheng, Emily H. -Y. Tjandra, Nico Walensky, Loren D. TI BAX activation is initiated at a novel interaction site SO NATURE LA English DT Article ID MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; STABILIZED ALPHA-HELICES; BCL-X-L; BH3-ONLY PROTEINS; CELL-DEATH; INTRACELLULAR-LOCALIZATION; PROAPOPTOTIC ACTIVITY; BH3 DOMAINS; APOPTOSIS; FAMILY AB BAX is a pro- apoptotic protein of the BCL- 2 family that is stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Anti- apoptotic proteins such as BCL- 2 counteract BAX- mediated cell death. Although an interaction site that confers survival functionality has been defined for anti- apoptotic proteins, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown. We previously developed stabilized alpha- helix of BCL- 2 domains ( SAHBs) that directly initiate BAX- mediated mitochondrial apoptosis. Here we demonstrate by NMR analysis that BIM SAHB binds BAX at an interaction site that is distinct from the canonical binding groove characterized for anti- apoptotic proteins. The specificity of the human BIM- SAHB - BAX interaction is highlighted by point mutagenesis that disrupts functional activity, confirming that BAX activation is initiated at this novel structural location. Thus, we have now defined a BAX interaction site for direct activation, establishing a new target for therapeutic modulation of apoptosis. C1 [Suzuki, Motoshi; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Tu, Ho-Chou; Kim, Hyungjin; Cheng, Emily H. -Y.] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Tu, Ho-Chou; Kim, Hyungjin; Cheng, Emily H. -Y.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Gavathiotis, Evripidis; Davis, Marguerite L.; Pitter, Kenneth; Bird, Gregory H.; Katz, Samuel G.; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Gavathiotis, Evripidis; Suzuki, Motoshi; Davis, Marguerite L.; Pitter, Kenneth; Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. [Gavathiotis, Evripidis; Davis, Marguerite L.; Pitter, Kenneth; Bird, Gregory H.; Katz, Samuel G.; Walensky, Loren D.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Gavathiotis, Evripidis; Davis, Marguerite L.; Pitter, Kenneth; Bird, Gregory H.; Katz, Samuel G.; Walensky, Loren D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov; loren_walensky@dfci.harvard.edu FU National Cancer Institute [5P01CA92625, 5RO1CA50239, 5RO1CA125562]; Burroughs Wellcome Fund Career Award; Culpeper Scholarship in Medical Science; American Society of Hematology Junior Faculty Scholar Award; William Lawrence Children's Foundation; Intramural Research Program of the National Heart, Lung and Blood Institute; Searle Scholars Program FX We thank E. Smith for editorial and graphics assistance, W. Beavers for amino acid analyses, A. Perry for technical assistance, C. Turner and A. Bielecki of the MIT/Harvard Center for Magnetic Resonance for NMR technical advice, and R. Youle for feedback on the manuscript. We acknowledge the indelible contributions of the late S.J. Korsmeyer, who inspired this work. L.D.W. is supported by National Cancer Institute (NCI) grant 5P01CA92625, a Burroughs Wellcome Fund Career Award in the Biomedical Sciences, a Culpeper Scholarship in Medical Science from the Goldman Philanthropic Partnerships, an American Society of Hematology Junior Faculty Scholar Award, and a grant from the William Lawrence Children's Foundation. This research was also supported by NCI grant 5RO1CA50239. N.T. is supported by the Intramural Research Program of the National Heart, Lung and Blood Institute, NIH. E.H.-Y.C. is supported by the Searle Scholars Program and NCI grant 5RO1CA125562. NR 50 TC 374 Z9 384 U1 5 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 23 PY 2008 VL 455 IS 7216 BP 1076 EP U6 DI 10.1038/nature07396 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363FG UT WOS:000260252600037 PM 18948948 ER PT J AU Gao, SY Takemura, SY Ting, CY Huang, SL Lu, ZY Luan, HJ Rister, J Thum, AS Yang, ML Hong, ST Wang, JW Odenwald, WF White, BH Meinertzhagen, IA Lee, CH AF Gao, Shuying Takemura, Shin-ya Ting, Chun-Yuan Huang, Songling Lu, Zhiyuan Luan, Haojiang Rister, Jens Thum, Andreas S. Yang, Meiluen Hong, Sung-Tae Wang, Jing W. Odenwald, Ward F. White, Benjamin H. Meinertzhagen, Ian A. Lee, Chi-Hon TI The Neural Substrate of Spectral Preference in Drosophila SO NEURON LA English DT Article ID CHLORIDE CHANNEL SUBUNITS; STARBURST AMACRINE CELLS; RETINAL GANGLION-CELLS; VISUAL-SYSTEM; COLOR-VISION; OPTIC LOBE; TARGET SPECIFICITY; LIGHT RESPONSE; WILD-TYPE; MELANOGASTER AB Drosophila vision is mediated by inputs from three types of photoreceptor neurons; R1-R6 mediate achromatic motion detection, while R7 and R8 constitute two chromatic channels. Neural circuits for processing chromatic information are not known. Here, we identified the first-order interneurons downstream of the chromatic channels. Serial EM revealed that small-field projection neurons Tm5 and Tm9 receive direct synaptic input from R7 and R8, respectively, and indirect input from R1-R6, qualifying them to function as color-opponent neurons. Wide-field Dm8 amacrine neurons receive input from 13-16 UV-sensing R7s and provide output to projection neurons. Using a combinatorial expression system to manipulate activity in different neuron subtypes, we determined that Dm8 neurons are necessary and sufficient for flies to exhibit phototaxis toward ultraviolet instead of green light. We propose that Dm8 sacrifices spatial resolution for sensitivity by relaying signals from multiple R7s to projection neurons, which then provide output to higher visual centers. C1 [Gao, Shuying; Ting, Chun-Yuan; Huang, Songling; Yang, Meiluen; Lee, Chi-Hon] NICHHD, Unit Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Takemura, Shin-ya; Lu, Zhiyuan; Meinertzhagen, Ian A.] Dalhousie Univ, Life Sci Ctr, Halifax, NS B3H 4J1, Canada. [Luan, Haojiang; White, Benjamin H.] NIMH, Unit Neural Funct, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Rister, Jens; Thum, Andreas S.] Univ Wurzburg, Lehrstuhl Genet & Neurobiol, D-97074 Wurzburg, Germany. [Wang, Jing W.] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92093 USA. [Odenwald, Ward F.] NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD 20892 USA. [Hong, Sung-Tae] Korea Adv Inst Sci & Technol, Dept Biol Sci, Lab Neural Network Cognit, Taejon 305701, South Korea. RP Meinertzhagen, IA (reprint author), Dalhousie Univ, Life Sci Ctr, Halifax, NS B3H 4J1, Canada. EM i.a.meinertzhagen@dal.ca; leechih@mail.nih.gov RI Wang, Jing/C-3885-2008; Gao, Shuying/D-8183-2011; Lee, Chi-Hon/G-9190-2012; Thum, Andreas/B-1083-2013; Ting, chun-yuan/F-6448-2013; Marion-Poll, Frederic/D-8882-2011; OI Wang, Jing/0000-0001-6291-5802; Marion-Poll, Frederic/0000-0001-6824-0180; Takemura, Shin-ya/0000-0003-2400-6426; Thum, Andreas/0000-0002-3830-6596; Meinertzhagen, Ian/0000-0002-6578-4526 FU NIH; National Institute of Child Health and Human Development [HD008748-03]; German Science Foundation [1156, SFB 554]; NIH [EY-03592] FX We thank Drs. William Pak, Liquin Luo. Christopher Potter, Martin Heisenberg, Tzumin Lee, Robert White. Akinao Nose, Howard Nash, Jaeseob Kim, Gero Miesenbock, and Alan Wong for reagents. We thank Drs. Claude Desplan and Javier Morante for communicating results prior to publication. We thank Dr. Howard Nash and Robert Scott for helping with ERG recordings and for providing the optomotor equipment. We thank Tom Polhida and Randall Pursley for optimizing the pattern recognition software and Jimmie Powell and Howard Metger for instrument fabrication. We thank Mr. Louis Dye and Dr. James Russell at NICHD's Microscopy and Image Core for assistance with EM image collection. We thank Drs. Alan Hinnebusch, Mark Stopfer, and Henry Levin for helpful discussion and Margaret Dieringer and Laura Lee for editing and manuscript handling. This work was supported by the Intramural Research Program of the NIH, National Institute of Child Health and Human Development (grant HD008748-03 to C.-H.L.), by the German Science Foundation (GRK 1156 and SFB 554 to J.R.), and by a grant from National Eye Institute of the NIH (EY-03592 to I.A.M.). NR 56 TC 116 Z9 116 U1 0 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 23 PY 2008 VL 60 IS 2 BP 328 EP 342 DI 10.1016/j.neuron.2008.08.010 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 367JW UT WOS:000260549300015 PM 18957224 ER PT J AU Overk, CR Guo, J Chadwick, LR Lantvit, DD Minassi, A Appendino, G Chen, SN Lankin, DC Farnsworth, NR Pauli, GF van Breemen, RB Bolton, JL AF Overk, Cassia R. Guo, Jian Chadwick, Lucas R. Lantvit, Daniel D. Minassi, Alberto Appendino, Giovanni Chen, Shao-Nong Lankin, David C. Farnsworth, Norman R. Pauli, Guido F. van Breemen, Richard B. Bolton, Judy L. TI In vivo estrogenic comparisons of Trifolium pratense (red clover) Humulus lupulus (hops), and the pure compounds isoxanthohumol and 8-prenylnaringenin SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE 8-Prenylnaringenin; Estrogen; Humulus lupulus; Isoxanthohumol; Menopause; Trifolium pratense ID HEALTHY POSTMENOPAUSAL WOMEN; POTENT PHYTOESTROGEN; MENOPAUSAL SYMPTOMS; PHYTO-ESTROGEN; RATS; L.; IDENTIFICATION; METABOLISM; FLAVONOIDS; EXTRACT AB The lack of a safe and reliable alternative to hormone therapy (HT) for treating menopausal symptoms underscores the need for alternative therapies. Objective: The purpose of this study was to assess the in vivo estrogenic effects of the botanical dietary supplements Trifolium pratense (red clover) and Humulus lupulus (hops), and two compounds obtained from H. lupulus, isoxanthohumol and 8-prenylnaringenin (8-PN) using the ovariectomized uterotrophic adult rat model. A H. lupulus extract and a 30% isoflavone extract of T. pratense were tested at three escalating doses as was one dose of isoxanthohumol for 21 d. 8-Prenylnaringenin, the major estrogen in H. lupulus, was also tested at three relevant escalating doses. In order to determine the in vivo metabolism of 8-PN, the major phases I and 11 metabolites were also identified. The primary outcome measure, uterus weight gain, indicated that H. lupulus and T pratense did not have an estrogenic effect on the uterus, and none of the secondary outcome measures were positive. In contrast, there was a clear dose response when 8-PN was evaluated where the middle and high doses of 8-PN were active. 8-Prenylnaringenin in rat plasma, liver, and mammary gland was measured and the major phases I and II 8-PN metabolites were detected. Our findings suggest that while both the H. lupulus and T pratense extracts do not have an effect on the rat uterus, 8-PN at equivalent doses to those previously used in humans did have an effect, and may therefore have a deleterious effect in women. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Overk, Cassia R.; Guo, Jian; Lantvit, Daniel D.; Chen, Shao-Nong; Lankin, David C.; Farnsworth, Norman R.; Pauli, Guido F.; van Breemen, Richard B.; Bolton, Judy L.] Univ Illinois, Coll Pharm, UIC, NIH,Ctr Bot Dietary Supplements Res,PCRPS, Chicago, IL 60612 USA. [Overk, Cassia R.; Guo, Jian; Lantvit, Daniel D.; Chen, Shao-Nong; Lankin, David C.; Farnsworth, Norman R.; Pauli, Guido F.; van Breemen, Richard B.; Bolton, Judy L.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Chadwick, Lucas R.] Kalsec Inc, Kalamazoo, MI 49006 USA. [Minassi, Alberto; Appendino, Giovanni] Univ Piemonte Orientale, Dipartimento Sci Chm Alimentari Farmaceut & Farma, I-28100 Novara, Italy. RP Bolton, JL (reprint author), Univ Illinois, Coll Pharm, UIC, NIH,Ctr Bot Dietary Supplements Res,PCRPS, 833 S Wood St,M-C 781, Chicago, IL 60612 USA. EM judy.bolton@uic.edu RI Appendino, Giovanni/O-4832-2015; OI Appendino, Giovanni/0000-0002-4170-9919; Pauli, Guido/0000-0003-1022-4326; minassi, alberto/0000-0002-3640-2912 FU Office of Dietary Supplements (ODS) [AT00155]; National Center for Complementary and Alternative Medicine (NCCAM); Office for Research on Women's Health (ORWH); National Institute of General Medicine (NIGMS); National Institutes of Health (NIH); NRSA NCCAM Predoctoral fellowship [AT24232] FX Funding: This work was supported, in part, by Grant P50 AT00155 provided jointly by the Office of Dietary Supplements (ODS), National Center for Complementary and Alternative Medicine (NCCAM), the Office for Research on Women's Health (ORWH), and the National Institute of General Medicine (NIGMS) of the National Institutes of Health (NIH). CRO is grateful for a Ruth L. Kirschstein NRSA NCCAM Predoctoral fellowship F31 AT24232. NR 44 TC 32 Z9 34 U1 1 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD OCT 22 PY 2008 VL 176 IS 1 BP 30 EP 39 DI 10.1016/j.cbi.2008.06.005 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 369AI UT WOS:000260664500004 PM 18619951 ER PT J AU Kryndushkin, DS Shewmaker, F Wickner, RB AF Kryndushkin, Dmitry S. Shewmaker, Frank Wickner, Reed B. TI Curing of the [URE3] prion by Btn2p, a Batten disease-related protein SO EMBO JOURNAL LA English DT Article DE amyloid; Hook homologue; Ypr158p ID BETA-SHEET STRUCTURE; SACCHAROMYCES-CEREVISIAE; YEAST PRION; PSI+ PRION; CYTOSOLIC HSP70; GENE DELETION; PROPAGATION; HSP104; PSI(+); MODEL AB [URE3] is a prion (infectious protein), a self-propagating amyloid form of Ure2p, a regulator of yeast nitrogen catabolism. We find that overproduction of Btn2p, or its homologue Ypr158 (Cur1p), cures [URE3]. Btn2p is reported to be associated with late endosomes and to affect sorting of several proteins. We find that double deletion of BTN2 and CUR1 stabilizes [URE3] against curing by several agents, produces a remarkable increase in the proportion of strong [URE3] variants arising de novo and an increase in the number of [URE3] prion seeds. Thus, normal levels of Btn2p and Cur1p affect prion generation and propagation. Btn2p-green fluorescent protein (GFP) fusion proteins appear as a single dot located close to the nucleus and the vacuole. During the curing process, those cells having both Ure2p-GFP aggregates and Btn2p-RFP dots display striking colocalization. Btn2p curing requires cell division, and our results suggest that Btn2p is part of a system, reminiscent of the mammalian aggresome, that collects aggregates preventing their efficient distribution to progeny cells. C1 [Kryndushkin, Dmitry S.; Shewmaker, Frank; Wickner, Reed B.] Natl Inst Diabet & Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank H Edskes, MD Ter-Avanesyan, J Gerst, D Klionsky, M Sherman and J Campbell for plasmids and strains; P Needham for the Ydj1p purified protein; K O'Connell and A Golden for the help with microscopy; members of our lab for a critical reading of the paper. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 52 TC 40 Z9 41 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD OCT 22 PY 2008 VL 27 IS 20 BP 2725 EP 2735 DI 10.1038/emboj.2008.198 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 366RM UT WOS:000260501100009 PM 18833194 ER PT J AU Emanuel, E Wyden, R AF Emanuel, Ezekiel Wyden, Ron TI A new federal-state partnership in health care - Real power for states SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Emanuel, Ezekiel] NIH, Dept Clin Bioeth, NIH Clin Ctr, Dept Bioeth, Bethesda, MD 20892 USA. [Wyden, Ron] US Senate, Washington, DC 20510 USA. RP Emanuel, E (reprint author), NIH, Dept Clin Bioeth, NIH Clin Ctr, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@cc.nih.gov NR 13 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 22 PY 2008 VL 300 IS 16 BP 1931 EP 1934 DI 10.1001/jama.2008.536 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 362UR UT WOS:000260223100025 PM 18940982 ER PT J AU Dahlhaus, M Hermans, JM Van Woerden, LH Saiepour, MH Nakazawa, K Mansvelder, HD Heimel, JA Levelt, CN AF Dahlhaus, Martijn Hermans, Josephine M. Van Woerden, Leonard H. Saiepour, M. Hadi Nakazawa, Kazu Mansvelder, Huibert D. Heimel, J. Alexander Levelt, Christiaan N. TI Notch1 Signaling in Pyramidal Neurons Regulates Synaptic Connectivity and Experience-Dependent Modifications of Acuity in the Visual Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE visual; cortex; acuity; plasticity; connectivity; dendritic spine ID EARLY MONOCULAR DEPRIVATION; NEURITE OUTGROWTH; REVERSE OCCLUSION; DENDRITIC SPINES; OCULAR DOMINANCE; ADULT RATS; IN-VIVO; PLASTICITY; MOUSE; DISEASE AB How the visual cortex responds to specific stimuli is strongly influenced by visual experience during development. Monocular deprivation, for example, changes the likelihood of neurons in the visual cortex to respond to input from the deprived eye and reduces its visual acuity. Because these functional changes are accompanied by extensive reorganization of neurite morphology and dendritic spine turnover, genes regulating neuronal morphology are likely to be involved in visual plasticity. In recent years, Notch1 has been shown to mediate contact inhibition of neurite outgrowth in postmitotic neurons and implicated in the pathogenesis of various degenerative diseases of the CNS. Here, we provide the first evidence for the involvement of neuronal Notch1 signaling in synaptic morphology and plasticity in the visual cortex. By making use of the Cre/Lox system, we expressed an active form of Notch1 in cortical pyramidal neurons several weeks after birth. We show that neuronal Notch1 signals reduce dendritic spine and filopodia densities in a cell-autonomous manner and limit long-term potentiation in the visual cortex. After monocular deprivation, these effects of Notch1 activity predominantly affect responses to visual stimuli with higher spatial frequencies. This results in an enhanced effect of monocular deprivation on visual acuity. C1 [Dahlhaus, Martijn; Hermans, Josephine M.; Van Woerden, Leonard H.; Saiepour, M. Hadi; Heimel, J. Alexander; Levelt, Christiaan N.] Royal Netherlands Acad Arts & Sci, Netherlands Inst Neurosci, Dept Mol Visual Plast, NL-1105 BA Amsterdam, Netherlands. [Van Woerden, Leonard H.; Mansvelder, Huibert D.] Vrije Univ Amsterdam, Ctr Neurogenom & Cognit Res, Dept Expt Neurophysiol, NL-1081 HV Amsterdam, Netherlands. [Nakazawa, Kazu] NIMH, Genet Cognit & Behav Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Levelt, CN (reprint author), Royal Netherlands Acad Arts & Sci, Netherlands Inst Neurosci, Dept Mol Visual Plast, Meibergdreef 47, NL-1105 BA Amsterdam, Netherlands. EM c.levelt@nin.knaw.nl RI Heimel, J.Alexander/F-5782-2012; Nakazawa, Kazutoshi/J-6195-2015; OI Nakazawa, Kazutoshi/0000-0001-5699-9093; Mansvelder, Huib/0000-0003-1365-5340 FU Netherlands Organization for Health Research and Development (ZonMW); Netherlands Academy of Arts and Sciences; SenterNovem FX This work was supported by a research support grant and a Vidi Grant from the Netherlands Organization for Health Research and Development (ZonMW). H.D.M. and C.N.L. are supported by the Netherlands Academy of Arts and Sciences and ZonMW. J.M.H.,J.A.H.,L.H.V.W., and C.N.L. are supported by a "Bsik" grant from SenterNovem. We thank Sean Perry, Hans Lodder, Svetlana Skulj, and Sitha Scheltinga for technical assistance, Dr. Susumu Tonegawa for supplying the G35-3-Cre mice, and Dr. Chris de Zeeuw for critical reading of this manuscript. NR 53 TC 25 Z9 26 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 22 PY 2008 VL 28 IS 43 BP 10794 EP 10802 DI 10.1523/JNEUROSCI.1348-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 363KH UT WOS:000260265700003 PM 18945887 ER PT J AU Comabella, M Craig, DW Camina-Tato, M Morcillo, C Lopez, C Navarro, A Rio, J Montalban, X Martin, R AF Comabella, Manuel Craig, David W. Camina-Tato, Montse Morcillo, Carlos Lopez, Cristina Navarro, Arcadi Rio, Jordi Montalban, Xavier Martin, Roland CA BiomarkerMS Study Grp TI Identification of a Novel Risk Locus for Multiple Sclerosis at 13q31.3 by a Pooled Genome-Wide Scan of 500,000 Single Nucleotide Polymorphisms SO PLOS ONE LA English DT Article AB Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort. The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation. The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy. The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility. This region of chromosome 13 has not been previously identified in MS linkage genome screens and represents a novel risk locus for the disease. C1 [Comabella, Manuel; Camina-Tato, Montse; Lopez, Cristina; Rio, Jordi; Montalban, Xavier] HUVH, CEM Cat, UNIC, Barcelona, Spain. [Craig, David W.] Translat Genom Res Inst TGen, Neurogenom Div, Phoenix, AZ USA. [Morcillo, Carlos; Navarro, Arcadi] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona, Spain. [Morcillo, Carlos] Natl Inst Bioinformat INB, Barcelona, Spain. [Navarro, Arcadi; Martin, Roland] Inst Catalana Recerca Estudis Avancats ICREA, Barcelona, Spain. NINDS, NIH, Bethesda, MD USA. RP Comabella, M (reprint author), HUVH, CEM Cat, UNIC, Barcelona, Spain. EM mcomabel@ir.vhebron.net RI Navarro, Arcadi/F-1592-2011; OI Navarro, Arcadi/0000-0003-2162-8246; Rio, Jordi/0000-0003-4546-7627 FU Spain's National Institute for Bioinformatics FX The Institute for Neuroimmunology and Clinical MS Research is supported by the Gemeinnutzige Hertie Foundation. This work has been supported by Spain's National Institute for Bioinformatics, a platform of Genoma Espana. NR 22 TC 56 Z9 58 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 22 PY 2008 VL 3 IS 10 AR e3490 DI 10.1371/journal.pone.0003490 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432IG UT WOS:000265126100021 PM 18941528 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Review: 64-slice computed tomography coronary angiography accurately diagnoses coronary artery disease SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 1 TC 0 Z9 0 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 21 PY 2008 VL 149 IS 8 AR JC4-13 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 367XJ UT WOS:000260585600031 ER PT J AU Chan, MP Dolinska, M Sergeev, YV Wingfield, PT Hejtmancik, JF AF Chan, May P. Dolinska, Monika Sergeev, Yuri V. Wingfield, Paul T. Hejtmancik, J. Fielding TI Association properties of beta B1- and beta A3-crystallins: Ability to form heterotetramers SO BIOCHEMISTRY LA English DT Article ID LENS BETA-CRYSTALLIN; AGE-RELATED-CHANGES; MASS-SPECTROMETRY; SEQUENCE; DIMER; AGGREGATION; RESOLUTION; BEHAVIOR; CDNA; B1 AB As major constituents of the mammalian lens, beta-crystallins associate into dimers, tetramers, and higher-order complexes to maintain lens transparency and refractivity. A previous study has shown that dimerization of beta B2- and beta A3-crystallins is energetically highly favored and entropically driven. While heterodimers further associate into higher-order complexes in vivo, a significant level of reversibly associated tetrameric crystallin has not been previously observed in vitro. To enhance our understanding of the interactions between beta-crystallins, we characterized the association of beta B1-crystallin, a major component of large beta-crystallin complexes (beta-high), with itself and with beta A3-crystallin. Mouse beta B1-crystallin and human beta A3-crystallin were expressed in Escherichia coli and purified chromatographically. Their association was then characterized using size-exclusion chromatography, native gel electrophoresis, isoelectric focusing, and analytical sedimentation equilibrium centrifugation. When present alone, each beta-crystallin associates into homodimers; however, no tetramer formation is seen. Once mixing has taken place, formation of a heterocomplex between beta B1- and beta A3-crystallins is observed using size-exclusion chromatography, native gel electrophoresis, isoelectric focusing, and sedimentation equilibrium. In contrast to results previously obtained after beta B2- and beta A3-crystallins had been mixed, mixed beta B1- and beta A3-crystallins show a dimer-tetramer equilibrium with a K(d) of 1.1 mu M, indicating that these two beta-crystallins associate predominantly into heterotetramers in vitro. Thus, while each purified beta-crystallin associates only into homodimers and under the conditions studied mixed beta B2- and beta A3-crystallins form a mixture of homo- and heterodimers, mixed beta B1- and beta A3-crystallins associate predominantly into heterotetramers in equilibrium with heterodimers. These findings suggest a unique role for beta B1-crystallin in promoting higher-order crystallin association in the lens. C1 [Hejtmancik, J. Fielding] NEI, OGVFB, NIH, Bethesda, MD 20892 USA. [Wingfield, Paul T.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Hejtmancik, JF (reprint author), NEI, OGVFB, NIH, 10-10B 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM f3h@nei.nih.gov FU Howard Hughes Medical Institute FX M.P.C. was supported by the Howard Hughes Medical Institute Research Scholars Program. NR 24 TC 16 Z9 16 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 21 PY 2008 VL 47 IS 42 BP 11062 EP 11069 DI 10.1021/bi8012438 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 359LL UT WOS:000259988100006 PM 18823128 ER PT J AU Oh, ECT Cheng, H Hao, H Jia, L Khan, NW Swaroop, A AF Oh, Edwin C. T. Cheng, Hong Hao, Hong Jia, Lin Khan, Naheed Wali Swaroop, Anand TI Rod differentiation factor NRL activates the expression of nuclear receptor NR2E3 to suppress the development of cone photoreceptors SO BRAIN RESEARCH LA English DT Article DE Retina; Development; Transcription factor; Maf; Gene regulation; Cell fate determination ID TRANSCRIPTION FACTOR NRL; CELL FATE SPECIFICATION; NRL(-/-) MOUSE RETINA; LEUCINE-ZIPPER; RAT RETINA; NEURONAL DIVERSITY; NERVOUS-SYSTEM; AXON GUIDANCE; GENE; CRX AB Neural developmental programs require a high level of coordination between the decision to exit cell cycle and acquisition of cell fate. The Maf-family transcription factor NRL is essential for rod photoreceptor specification in the mammalian retina as its loss of function converts rod precursors to functional cones. Ectopic expression of NRL or a photoreceptor-specific orphan nuclear receptor NR2E3 completely suppresses cone development while concurrently directing the post-mitotic photoreceptor precursors towards rod cell fate. Given that NRL and NR2E3 have overlapping functions and NR2E3 expression is abolished in the Nrl(-/-) retina, we wanted to clarify the distinct roles of NRL and NR2E3 during retinal differentiation. Here, we demonstrate that NRL binds to a sequence element in the Nr2e3 promoter and enhances its activity synergistically with the homeodomain protein CRX. Using transgenic mice, we show that NRL can only partially suppress cone development in the absence of NR2E3. Gene profiling of retinas from transgenic mice that ectopically express NR2E3 or NRL in cone precursors reveals overlapping and unique targets of these two transcription factors. Together with previous reports, our findings establish the hierarchy of transcriptional regulators in determining rod versus cone cell fate in photoreceptor precursors during the development of mammalian retina. (C) 2008 Elsevier B.V. All rights reserved. C1 [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Oh, Edwin C. T.; Swaroop, Anand] Univ Michigan, Program Neurosci, Ann Arbor, MI 48109 USA. [Oh, Edwin C. T.; Cheng, Hong; Hao, Hong; Jia, Lin; Khan, Naheed Wali; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Swaroop, Anand] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bldg 10-10B11,MSC 1864, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Institutes of Health [EY011115, EY007003]; Foundation Fighting Blindness [T-32-HD007505]; Rackham Predoctoral Fellowship FX We thank Matthew Brooks and Ritu Khanna for assistance with microarray analysis, Thom Saunders for advice with transgenic mice, and Hemant Khanna for discussions and comments on the manuscript. We acknowledge S. Lentz, M. Gillett, and M. Van Keuren for technical assistance and S. Ferrara for administrative support. This research was supported by grants from the National Institutes of Health (EY011115, EY007003; NEI intramural support), The Foundation Fighting Blindness, Research to Prevent Blindness, Organogenesis Training Program (T-32-HD007505), and a Rackham Predoctoral Fellowship. The core facilities of the Michigan Diabetes Research and Training Center (NIH5P60 DK20572) were also used for this work. NR 63 TC 59 Z9 60 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 21 PY 2008 VL 1236 BP 16 EP 29 DI 10.1016/j.brainres.2008.01.028 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 368JD UT WOS:000260616500003 PM 18294621 ER PT J AU Lu, ZB Fassett, J Xu, X Hu, XL Zhu, GS French, J Zhang, P Schnermann, J Bache, RJ Chen, YJ AF Lu, Zhongbing Fassett, John Xu, Xin Hu, Xinli Zhu, Guangshuo French, Joel Zhang, Ping Schnermann, Jurgen Bache, Robert J. Chen, Yingjie TI Adenosine A(3) Receptor Deficiency Exerts Unanticipated Protective Effects on the Pressure-Overloaded Left Ventricle SO CIRCULATION LA English DT Article DE adenosine; free radicals; heart failure; hypertrophy; oxidative stress ID INTRACELLULAR SIGNALING PATHWAYS; CARDIAC-HYPERTROPHY; HEART-FAILURE; TUBULOGLOMERULAR FEEDBACK; RAT CARDIOMYOCYTES; OXIDATIVE STRESS; ACTIVATION; MICE; A(1); GENE AB Background-Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A(1) receptors (A(1)R) and A(3) receptors (A(3)R) is not known. Methods and Results-To test the hypothesis that A1R and A3R can protect the heart against systolic overload, we exposed A3R gene-deficient (A3R knockout [KO]) mice and A1R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A(3)R KO attenuated 5-week TAC-induced left ventricular hypertrophy (ratio of ventricular mass/body weight increased to 7.6 +/- 0.3 mg/g in wild-type mice compared with 6.3 +/- 0.4 mg/g in KO mice), fibrosis, and dysfunction (left ventricular ejection fraction decreased to 43 +/- 2.5% and 55 +/- 4.2% in wild-type and KO mice, respectively). A3R KO also attenuated the TAC-induced increases of myocardial atrial natriuretic peptide and the oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal. In contrast, A1R KO increased TAC-induced mortality but did not alter ventricular hypertrophy or dysfunction compared with wild-type mice. In mice in which extracellular adenosine production was impaired by CD73 KO, TAC caused greater hypertrophy and dysfunction and increased myocardial 3'-nitrotyrosine. In neonatal rat cardiomyocytes induced to hypertrophy with phenylephrine, the adenosine analogue 2-chloroadenosine reduced cell area, protein synthesis, atrial natriuretic peptide, and 3'-nitrotyrosine. Antagonism of A(3)R significantly potentiated the antihypertrophic effects of 2-chloroadenosine. Conclusions-Adenosine exerts protective effects on the overloaded heart, but the A3R acts counter to the protective effect of adenosine. The data suggest that selective attenuation of A3R activity might be a novel approach to treat pressure overload-induced left ventricular hypertrophy and dysfunction. (Circulation. 2008; 118: 1713-1721.) C1 [Lu, Zhongbing; Xu, Xin; Hu, Xinli; Zhu, Guangshuo; Chen, Yingjie] Univ Minnesota, Ctr Vasc Biol, Minneapolis, MN 55455 USA. [Fassett, John; Hu, Xinli; Zhu, Guangshuo; French, Joel; Zhang, Ping; Bache, Robert J.; Chen, Yingjie] Univ Minnesota, Div Cardiovasc, Dept Med, Minneapolis, MN 55455 USA. [Schnermann, Jurgen] NIDDK, NIH, Bethesda, MD USA. RP Chen, YJ (reprint author), Univ Minnesota, Ctr Vasc Biol, Mayo Mail Cod 508,420 Delaware St SE, Minneapolis, MN 55455 USA. EM chenx106@umn.edu OI Lu, Zhongbing/0000-0002-2717-4698; Fassett, John/0000-0003-4591-6875 FU National Heart, Lung, and Blood Institute [HL71790, HL21872]; National Institutes of Health; American Heart Association; American Heart Association Scientist Development Awards FX This study was supported by National Heart, Lung, and Blood Institute grants HL71790 (Dr Chen) and HL21872 (Dr Bache) from the National Institutes of Health. Dr Xu is a recipient of an American Heart Association Postdoctoral Fellowship. Drs Fassett and Zhang are recipients of American Heart Association Scientist Development Awards. NR 44 TC 28 Z9 28 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 21 PY 2008 VL 118 IS 17 BP 1713 EP 1721 DI 10.1161/CIRCULATIONAHA.108.788307 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 362HQ UT WOS:000260189200005 PM 18838560 ER PT J AU Wu, XW Brooks, BR AF Wu, Xiongwu Brooks, Bernard R. TI Using the isotropic periodic sum method to calculate long-range interactions of heterogeneous systems SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DYNAMICS; WATER AB Isotropic periodic sum (IPS) is a method for the calculation of long-range interactions in molecular simulation based on the homogeneity of simulation systems. Three IPS models, 3D IPS, 2D IPS, and 1D IPS have been developed for three common types of homogeneous systems. Based on the fact that 3D IPS can well describe the long-range interactions of a heterogeneous system if a local region larger than the homogeneity scale is used, this work presents a method based on 3D IPS to calculate long-range interactions for all kinds of simulation systems, including homogeneous, heterogeneous, and finite systems. Unlike the original 3D IPS method that uses a local region defined by the cutoff distance, this method uses a local region larger than that defined by the cutoff distance to reach the homogeneity scale. To efficiently calculate interactions within such a large local region, this method split long-range interactions into two parts, a cutoff part and a long-range part. The cutoff part is calculated by summing over atom pairs within a cutoff range (about 10 A), and the long-range part is calculated using the discrete fast Fourier transform (DFFT) technique. This method is applied to electrostatic and van der Waals interactions for both periodic and non-periodic systems. Example simulations demonstrate that this method can accurately and efficiently calculate long-range interactions for molecular simulation. (C) 2008 American Institute of Physics. [DOI: 10.1063/1.2992601] C1 [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. RP Wu, XW (reprint author), NHLBI, NIH, Lab Computat Biol, Bldg 10, Bethesda, MD 20892 USA. EM wuxw@nhlbi.nih.gov NR 11 TC 41 Z9 41 U1 0 U2 9 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 21 PY 2008 VL 129 IS 15 AR 154115 DI 10.1063/1.2992601 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 363QA UT WOS:000260280600015 PM 19045184 ER PT J AU Yin, DW Horkay, F Douglas, JF de Pablo, JJ AF Yin, De-Wei Horkay, Ferenc Douglas, Jack F. de Pablo, Juan J. TI Molecular simulation of the swelling of polyelectrolyte gels by monovalent and divalent counterions SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID PHYSIOLOGICAL SALT-SOLUTIONS; DISCONTINUOUS VOLUME TRANSITIONS; PRIMITIVE MODEL ELECTROLYTES; MONTE-CARLO-SIMULATION; POLYACRYLATE HYDROGELS; FLEXIBLE POLYELECTROLYTES; EQUILIBRIUM STRUCTURE; PHASE-EQUILIBRIA; REPULSIVE FORCES; SIMPLE LIQUIDS AB Permanently crosslinked polyelectrolyte gels are known to undergo discontinuous first-order volume phase transitions, the onset of which may be caused by a number of factors. In this study we examine the volumetric properties of such polyelectrolyte gels in relation to the progressive substitution of monovalent counterions by divalent counterions as the gels are equilibrated in solvents of different dielectric qualities. We compare the results of coarse-grained molecular dynamics simulations of polyelectrolyte gels with previous experimental measurements by others on polyacrylate gels. The simulations show that under equilibrium conditions there is an approximate cancellation between the electrostatic contribution and the counterion excluded-volume contribution to the osmotic pressure in the gel-solvent system; these two contributions to the osmotic pressure have, respectively, energetic and entropic origins. The finding of such a cancellation between the two contributions to the osmotic pressure of the gel-solvent system is consistent with experimental observations that the swelling behavior of polyelectrolyte gels can be described by equations of state for neutral gels. Based on these results, we show and explain that a modified form of the Flory-Huggins model for nonionic polymer solutions, which accounts for neither electrostatic effects nor counterion excluded-volume effects, fits both experimental and simulated data for polyelectrolyte gels. The Flory-Huggins interaction parameters obtained from regression to the simulation data are characteristic of ideal polymer solutions, whereas the experimentally obtained interaction parameters, particularly that associated with the third virial coefficient, exhibit a significant departure from ideality, leading us to conclude that further enhancements to the simulation model, such as the inclusion of excess salt, the allowance for size asymmetric electrolytes, or the use of a distance-dependent solvent dielectricity model, may be required. Molecular simulations also reveal that the condensation of divalent counterions onto the polyelectrolyte network backbone occurs preferentially over that of monovalent counterions. (c) 2008 American Institute of Physics. C1 [Yin, De-Wei; de Pablo, Juan J.] Univ Wisconsin, Dept Biol & Chem Engn, Madison, WI 53706 USA. [Horkay, Ferenc] NICHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. [Douglas, Jack F.] US Natl Inst Stand & Technol, Div Polymers, Gaithersburg, MD 20899 USA. RP de Pablo, JJ (reprint author), Univ Wisconsin, Dept Biol & Chem Engn, Madison, WI 53706 USA. EM depablo@engr.wisc.edu OI Yin, De-Wei/0000-0002-0032-8108 FU U. S. National Science Foundation through the University of Wisconsin-Madison Materials Research Science and Engineering Center (UWMRSEC); Grainger Wisconsin Foundation; Natural Sciences and Engineering Research Council of Canada [PGSB-242497-2001]; NICHD; NIH FX The authors are grateful for funding support by the U. S. National Science Foundation through the University of Wisconsin-Madison Materials Research Science and Engineering Center (UWMRSEC). D. W. Y. thanks the Grainger Wisconsin Foundation and the Natural Sciences and Engineering Research Council of Canada (PGSB-242497-2001) during the course of his studies. F. H. acknowledges the support of the Intramural Research Program of the NICHD, NIH. The authors also wish to thank T. A. Darden of the U. S. National Institute of Environmental Health Sciences for the SPME (Ref.42) computer code that was used to calculate the electrostatic interactions. The simulations were performed on computers of the Grid Laboratory of Wisconsin at the University of Wisconsin-Madison. NR 57 TC 31 Z9 31 U1 1 U2 27 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 21 PY 2008 VL 129 IS 15 AR 154902 DI 10.1063/1.2991179 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 363QA UT WOS:000260280600055 PM 19045224 ER PT J AU Brin, YS Golenser, J Mizrahi, B Maoz, G Domb, AJ Peddada, S Tuvia, S Nyska, A Nyska, M AF Brin, Yaron S. Golenser, Jacob Mizrahi, Boaz Maoz, Guy Domb, Abraham J. Peddada, Shyamal Tuvia, Shmuel Nyska, Abraham Nyska, Meir TI Treatment of osteomyelitis in rats by injection of degradable polymer releasing gentamicin SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Delivery vehicle; Injectable degradable polymer; Poly(sebacic-co-ricinoleic-ester-anhydride); Gentamicin; Osteomyelitis; S. aureus ID IMPLANT-RELATED OSTEOMYELITIS; ACID) BIODEGRADABLE CARRIER; IN-VITRO RELEASE; STAPHYLOCOCCUS-AUREUS; PMMA BEADS; BONE; VIVO; INFECTION; MODEL; POLYANHYDRIDES AB We evaluated the potential of an injectable degradable polymer-poly(sebacic-co-ricinoleic-ester-anhydride) containing gentamicin for the treatment of osteomyelitis. Osteomyelitis of both tibiae was induced in 13 female Fischer rats by injecting a suspension containing approximately 105 (CFU)/ml of S. aureus into the tibial medullar canal. Three weeks later both tibiae were X-rayed, drilled down the medullar canal, washed with 50 mu l gentamicin solution (80 mg/2 ml) and then injected with 50 mu l P(SA-RA)+gentamycin 20% w/v to the right tibia and 50 mu l P(SA-RA) without gentamicin to the left tibia. After an additional 3 weeks, the rats were sacrificed, and radiographs of the tibiae were taken. Histopathological evaluation of the tibiae was done in a blinded manner. X-ray radiographs showed that all tibiae developed changes compatible with osteomyelitis in 3 weeks. Histological evaluation revealed significant differences between right and left tibiae in 10 rats. In the left tibia moderate intramedullary abscess formation occurred. In most treated tibiae typical changes included the absence (or minimal grade only) of abscesses. The treated group developed significantly less intramedullary abscesses; the p value was 0.028. Locally injected degradable polymer releasing gentamicin proved to be efficient histologically in the treatment of osteomyelitis. (C) 2008 Elsevier B.V. All rights reserved. C1 [Brin, Yaron S.; Maoz, Guy; Nyska, Meir] Meir Med Ctr, Dept Orthoped Surg, IL-44281 Kefar Sava, Israel. [Brin, Yaron S.; Maoz, Guy; Nyska, Abraham; Nyska, Meir] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Golenser, Jacob] Hebrew Univ Jerusalem, Kuvin Ctr Study Infect & Trop Dis, Dept Parasitol, IL-91120 Jerusalem, Israel. [Mizrahi, Boaz; Domb, Abraham J.] Hebrew Univ Jerusalem, Sch Pharm, Dept Med Chem & Nat Prod, IL-91120 Jerusalem, Israel. [Peddada, Shyamal] Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Tuvia, Shmuel] BioLineRx Ltd, IL-91450 Jerusalem, Israel. RP Brin, YS (reprint author), Meir Med Ctr, Dept Orthoped Surg, 48 Tchernichovsky Str, IL-44281 Kefar Sava, Israel. EM yaronbrin@gmail.com RI Peddada, Shyamal/D-1278-2012 FU BioLineRx, Ltd., Israel FX This work was supported in part by BioLineRx, Ltd. 19 Hartum Street, P.O. Box 45158 Jerusalem 91450, Israel. Committee of the Hebrew University of Jerusalem (Reg. No. 10581-4) approved the study protocol. NR 51 TC 26 Z9 26 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD OCT 21 PY 2008 VL 131 IS 2 BP 121 EP 127 DI 10.1016/j.jconrel.2008.07.022 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 372ED UT WOS:000260883700007 PM 18692531 ER PT J AU Gorshkova, II Svitel, J Razjouyan, F Schuck, P AF Gorshkova, Inna I. Svitel, Juraj Razjouyan, Fazeh Schuck, Peter TI Bayesian Analysis of Heterogeneity in the Distribution of Binding Properties of Immobilized Surface Sites SO LANGMUIR LA English DT Article ID ATOMIC-FORCE MICROSCOPE; PLASMON RESONANCE; MONOCLONAL-ANTIBODIES; PROTECTIVE ANTIGEN; VACCINIA VIRUS; MASS-TRANSPORT; ANTHRAX TOXIN; PROTEIN; KINETICS; ADSORPTION AB Once a homogeneous ensemble of a protein ligand is taken from solution and immobilized to a surface, for many reasons the resulting ensemble of surface binding sites to soluble analytes may be heterogeneous. For example, this can be due to the intrinsic surface roughness causing variations in the local microenvironment, nonuniform density distribution of polymeric linkers, or nonuniform chemical attachment producing different protein orientations and conformations. We previously described a computational method for determining the distribution of affinity and rate constants of surface sites from analysis of experimental surface binding data. It fully exploits the high signal/noise ratio and reproducibility provided by optical biosensor technology, such as surface plasmon resonance. Since the computational analysis is ill conditioned, the previous approach used a regularization strategy assuming a priori all binding parameters to be equally likely, resulting in the broadest possible parameter distribution consistent with the experimental data. We now extended this method in a Bayesian approach to incorporate the opposite assumption, i.e., that the surface sites a priori are expected to be uniform (as one would expect in free solution). This results in a distribution of binding parameters as close to monodispersity as possible given the experimental data. Using several model protein systems immobilized on a carboxymethyl dextran surface and probed with surface plasmon resonance, we show microheterogeneity of the surface sites in addition to broad populations of significantly altered affinity. The distributions obtained are highly reproducible. Immobilization conditions and the total surface density of immobilized sites can have a substantial impact on the functional distribution of the binding sites. C1 [Gorshkova, Inna I.; Svitel, Juraj; Razjouyan, Fazeh; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. EM pschuck@helix.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering, NIH FX We thank Drs. Zhaochun Chen and Robert Purcell for providing the antibodies used in this study. This research was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, NIH. NR 42 TC 14 Z9 14 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD OCT 21 PY 2008 VL 24 IS 20 BP 11577 EP 11586 DI 10.1021/la801186w PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 360HT UT WOS:000260049300035 PM 18816013 ER PT J AU van der Knaap, MS Arts, WFM Garbern, JY Hedlund, G Winkler, F Barbosa, C King, MD Bjornstad, A Hussain, N Beyer, MK Gomez, C Patterson, MC Grattan-Smith, P Timmons, M van der Valk, P AF van der Knaap, M. S. Arts, W. F. M. Garbern, J. Y. Hedlund, G. Winkler, F. Barbosa, C. King, M. D. Bjornstad, A. Hussain, N. Beyer, M. K. Gomez, C. Patterson, M. C. Grattan-Smith, P. Timmons, M. van der Valk, P. TI Cerebellar leukoencephalopathy Most likely histiocytosis-related SO NEUROLOGY LA English DT Article ID LANGERHANS CELL HISTIOCYTOSIS; CENTRAL-NERVOUS-SYSTEM; ERDHEIM-CHESTER-DISEASE; PROGRESSIVE SPINOCEREBELLAR DEGENERATION; SPINAL-CORD INVOLVEMENT; WHITE-MATTER DISEASE; OF-THE-LITERATURE; ENDOCRINE DISORDERS; MEMBRANE-PROTEIN; BRAIN-STEM AB Background: Histiocytosis, both Langerhans and non-Langerhans cell type, can be associated with cerebellar white matter abnormalities, thought to be paraneoplastic. The associated clinical picture consists of ataxia, spasticity, and cognitive decline. Hormonal dysfunction is frequent. MRI shows cerebellar white matter abnormalities, as well as brainstem and basal ganglia abnormalities. This so-called "neurodegenerative syndrome" may occur years before or during manifest histiocytosis and also years after cure. We discovered similar MRI abnormalities in 13 patients and wondered whether they could have the same syndrome. Methods: We reviewed the clinical and laboratory information of these 13 patients and evaluated their brain MRIs. Seven patients underwent spinal cord MRI. Results: All patients were isolated cases; 10 were male. They had signs of cerebellar and pyramidal dysfunction, behavioral problems, and cognitive decline. MRI showed abnormalities of the cerebellar white matter, brainstem, basal ganglia, and, to a lesser extent, cerebral white matter. Three patients had spinal cord lesions. Three patients had laboratory evidence of hormonal dysfunction. No evidence was found of an underlying metabolic defect. In two patients biopsy of nodular brain lesions revealed histiocytic infiltrates. Conclusions: Considering the striking clinical and MRI similarities between our patients and the patients with this neurodegenerative syndrome in the context of proven histiocytosis, it is likely that they share the same paraneoplastic syndrome, although we cannot exclude a genetic disorder with certainty. The fact that we found histiocytic lesions in two patients substantiates our conclusion. Patients with cerebellar white matter abnormalities should be monitored for histiocytosis. Neurology (R) 2008; 71: 1361-1367 C1 [van der Knaap, M. S.] Vrije Univ Amsterdam, Med Ctr, Dept Child Neurol, NL-1081 HV Amsterdam, Netherlands. [van der Valk, P.] Vrije Univ Amsterdam, Med Ctr, Dept Neuropathol, NL-1081 HV Amsterdam, Netherlands. [Arts, W. F. M.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Neurol, Rotterdam, Netherlands. [Garbern, J. Y.] Wayne State Univ, Dept Neurol, Detroit, MI USA. [Garbern, J. Y.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Hedlund, G.] Primary Childrens Med Ctr, Pediat Med Imaging Dept, Salt Lake City, UT 84103 USA. [Winkler, F.] Univ Munich, Dept Neurol, D-8000 Munich, Germany. [Barbosa, C.] Hosp Pedro Hispano, Neuropediat Unit, Dept Pediat, Matosinhos, Portugal. [King, M. D.] Childrens Univ Hosp, Dept Neurol, Temple St Dublin, Ireland. [Bjornstad, A.] Univ Hosp, Rikshosp, Div Paediat, Oslo, Norway. [Hussain, N.] Queens Med Ctr, Nottingham Univ Hosp NHS Trust, Dept Paediat Neurol, Nottingham NG7 2UH, England. [Beyer, M. K.] Stavanger Univ Hosp, Dept Radiol, Stavanger, Norway. [Gomez, C.] Univ Chicago, Med Ctr, Dept Neurol, Chicago, IL 60637 USA. [Patterson, M. C.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Patterson, M. C.] Mayo Clin, Dept Pediat & Adolescent Med, Rochester, MN USA. [Patterson, M. C.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Grattan-Smith, P.] Sydney Childrens Hosp, Dept Neurol, Randwick, NSW, Australia. [Timmons, M.] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. RP van der Knaap, MS (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Child Neurol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM ms.vanderknaap@vumc.nl OI Patterson, Marc/0000-0002-1116-126X FU Dutch Organization for Scientific Research [9120.6002]; National Multiple Sclerosis Society [RG3204] FX M.S.v.d.K. is supported by the Dutch Organization for Scientific Research (ZonMw, TOP grant 9120.6002) and the Optimix Foundation for Scientific Research. J.G. is supported by the National Multiple Sclerosis Society (RG3204). NR 40 TC 6 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 21 PY 2008 VL 71 IS 17 BP 1361 EP 1367 DI 10.1212/01.wnl.0000327680.74910.93 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 362IJ UT WOS:000260191100011 PM 18936429 ER PT J AU Ghosh, AK Gennna, S Takayama, J Baldridge, A Leshchenko-Yashchuk, S Miller, HB Wang, YF Kovalevsky, AY Koh, Y Weber, IT Mitsuya, H AF Ghosh, Arun K. Gennna, Sandra Takayama, Jun Baldridge, Abigail Leshchenko-Yashchuk, Sofiya Miller, Heather B. Wang, Yuan-Fang Kovalevsky, Andrey Y. Koh, Yashiro Weber, Irene T. Mitsuya, Hiroaki TI Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RESOLUTION CRYSTAL-STRUCTURES; DRUG-RESISTANT MUTANTS; ANTIVIRAL ACTIVITY; TYPE-1 PROTEASE; HYDROGEN-BONDS; INTERFACE; SELECTION; THERAPY; ANALOGS AB Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor 1 with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the 1-bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor 2 (K(i) = 0.11 nM; IC(50) = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor 3 showed comparable enzyme inhibitory activity (K(i) = 0.18 nM) its antiviral activity (IC(50) = 170 nM) was significantly weaker than inhibitor 2. Inhibitor 2 maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of 3-bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor 2 based upon this X-ray structure. C1 [Ghosh, Arun K.; Gennna, Sandra; Takayama, Jun; Baldridge, Abigail; Leshchenko-Yashchuk, Sofiya; Miller, Heather B.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Gennna, Sandra; Takayama, Jun; Baldridge, Abigail; Leshchenko-Yashchuk, Sofiya; Miller, Heather B.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Wang, Yuan-Fang; Kovalevsky, Andrey Y.; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Koh, Yashiro; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Gemma, Sandra/D-3568-2009; OI Gemma, Sandra/0000-0002-8313-2417; Kovalevsky, Andrey/0000-0003-4459-9142 FU National Institutes of Health [GM53386, GM62920]; Intramural Research Program of the Center for Cancer Research; National Cancer Institute; Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho); Ministry of Health, Welfare, and Labor of Japan [H15-AIDS-001] FX The research was supported by grants from the National Institutes of Health (GM53386, AKG, and GM62920, IW). This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health and in part by a Grant-in-aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan (Kosei Rohdosho: H15-AIDS-001), and a Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Re-emerging Infectious Diseases (Renkei Jigyo: No. 78, Kumamoto University) of Monbu-Kagakusho. NR 34 TC 11 Z9 11 U1 0 U2 2 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PD OCT 21 PY 2008 VL 6 IS 20 BP 3703 EP 3713 DI 10.1039/b809178a PG 11 WC Chemistry, Organic SC Chemistry GA 365SW UT WOS:000260429100010 PM 18843400 ER PT J AU Leary, RJ Lin, JC Cummins, J Boca, S Wood, LD Parsons, DW Jones, S Sjoblom, T Park, BH Parsons, R Willis, J Dawson, D Willson, JKV Nikolskaya, T Nikolsky, Y Kopelovich, L Papadopoulos, N Pennacchio, LA Wang, TL Markowitz, SD Parmigiani, G Kinzler, KW Vogelstein, B Velculescu, VE AF Leary, Rebecca J. Lin, Jimmy C. Cummins, Jordan Boca, Simina Wood, Laura D. Parsons, D. Williams Jones, Sian Sjoeblom, Tobias Park, Ben-Ho Parsons, Ramon Willis, Joseph Dawson, Dawn Willson, James K. V. Nikolskaya, Tatiana Nikolsky, Yuri Kopelovich, Levy Papadopoulos, Nick Pennacchio, Len A. Wang, Tian-Li Markowitz, Sanford D. Parmigiani, Giovanni Kinzler, Kenneth W. Vogelstein, Bert Velculescu, Victor E. TI Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amplification; copy number changes; Digital Karyotyping; high-density SNP arrays; homozygous deletion ID CANDIDATE TUMOR-SUPPRESSOR; NUCLEOTIDE POLYMORPHISM ARRAYS; COPY NUMBER ANALYSIS; GENETIC ALTERATIONS; HUMAN GENOME; RESOLUTION; LEUKEMIA; THERAPY; SITES AB we have performed a genome-wide analysis of copy number changes in breast and colorectal tumors using approaches that can reliably detect homozygous deletions and amplifications. We found that the number of genes altered by major copy number changes, deletion of all copies or amplification to at least 12 copies per cell, averaged 17 per tumor. We have integrated these data with previous mutation analyses of the Reference Sequence genes in these same tumor types and have identified genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations included those controlling cell adhesion, intracellular signaling, DNA topological change, and cell cycle control. These analyses provide an integrated view of copy number and sequencing alterations on a genome-wide scale and identify genes and pathways that could prove useful for cancer diagnosis and therapy. C1 [Leary, Rebecca J.; Lin, Jimmy C.; Cummins, Jordan; Boca, Simina; Wood, Laura D.; Parsons, D. Williams; Jones, Sian; Sjoeblom, Tobias; Papadopoulos, Nick; Wang, Tian-Li; Parmigiani, Giovanni; Kinzler, Kenneth W.; Vogelstein, Bert; Velculescu, Victor E.] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. [Leary, Rebecca J.; Lin, Jimmy C.; Cummins, Jordan; Boca, Simina; Wood, Laura D.; Parsons, D. Williams; Jones, Sian; Sjoeblom, Tobias; Papadopoulos, Nick; Wang, Tian-Li; Parmigiani, Giovanni; Kinzler, Kenneth W.; Vogelstein, Bert; Velculescu, Victor E.] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD 21231 USA. [Boca, Simina; Parmigiani, Giovanni] Johns Hopkins Kimmel Canc Ctr, Dept Bioinformat, Baltimore, MD 21231 USA. [Boca, Simina; Parmigiani, Giovanni] Johns Hopkins Kimmel Canc Ctr, Dept Pathol, Baltimore, MD 21231 USA. [Park, Ben-Ho] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21231 USA. [Parsons, Ramon] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA. [Willis, Joseph; Dawson, Dawn; Markowitz, Sanford D.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Willis, Joseph; Dawson, Dawn; Markowitz, Sanford D.] Case Western Reserve Univ, Ireland Canc Ctr, Cleveland, OH 44106 USA. [Willis, Joseph; Dawson, Dawn; Markowitz, Sanford D.] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Willis, Joseph; Dawson, Dawn; Markowitz, Sanford D.] Howard Hughes Med Inst, Cleveland, OH 44106 USA. [Willson, James K. V.] Univ Texas SW Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. [Nikolskaya, Tatiana] NI Vavilov Gen Genet Res Inst, Moscow 117809, Russia. [Nikolskaya, Tatiana; Nikolsky, Yuri] GeneGo Inc, St Joseph, MI 49085 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Pennacchio, Len A.] Joint Genome Inst, Dept Energy, Walnut Creek, CA 94598 USA. RP Vogelstein, B (reprint author), Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. EM velculescu@jhmi.edu RI Jones, Sian/A-5050-2012; Papadopoulos, Nickolas/K-7272-2012; Nikolskaya, Tatiana/M-5008-2013 FU Virginia and D. K. Ludwig Fund for Cancer Research; National Institutes of Health [CA121113, CA 57345, CA 43460, CA 109274]; National Cancer Institute Division of Cancer Prevention [HHSN261200433002C]; Pew Charitable Trusts; Avon Foundation FX We thank R. Ashworth and A. Scott for assistance with Illumina analyses, S. Bentivegna for assistance with DK, D. H. Nguyen for the artwork in Fig. 2, and M. Newton for sharing software for non-id Bernoulli calculations. This work was supported by the Virginia and D. K. Ludwig Fund for Cancer Research; National Institutes of Health Grants CA121113, CA 57345, CA 43460, and CA 109274; National Cancer Institute Division of Cancer Prevention Contract HHSN261200433002C; the Pew Charitable Trusts, and the Avon Foundation. NR 41 TC 170 Z9 173 U1 3 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 21 PY 2008 VL 105 IS 42 BP 16224 EP 16229 DI 10.1073/pnas.0808041105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 368BX UT WOS:000260597400030 PM 18852474 ER PT J AU Zhu, Q Egelston, C Vivekanandhan, A Uematsu, S Akira, S Klinman, DM Belyakov, IM Berzofsky, JA AF Zhu, Qing Egelston, Colt Vivekanandhan, Aravindhan Uematsu, Satoshi Akira, Shizuo Klinman, Dennis M. Belyakov, Igor M. Berzofsky, Jay A. TI Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV; innate immunity; adjuvants; MyD88; TRIF ID DOUBLE-STRANDED-RNA; ACTIVATED PROTEIN-KINASE; INDUCED INTERLEUKIN-12P70 SECRETION; NF-KAPPA-B; SIGNALING PATHWAY; IMMUNE-RESPONSE; MAP KINASE; IN-VIVO; C-FOS; RIG-I AB Toll-like receptors (TLRs) may need to cooperate with each other to be effective in detecting imminent infection and trigger immune responses. understanding is still limited about the intracellular mechanism of this cooperation. We found that when certain TLRs are involved, dendritic cells (DCs) establish unidirectional intracellular cross-talk, in which the MyD88-independent TRIF-dependent pathway amplifies the MyD88-dependent DC function through a JNK-dependent mechanism. The amplified MyD88-dependent DC function determines the induction of the T cell response to a given vaccine in vivo. Therefore, our study revealed an underlying TLR mechanism governing the functional, nonrandom interplay among TLRs for recognition of combinatorial ligands that may be dangerous to the host, providing important guidance for design of novel synergistic molecular vaccine adjuvants. C1 [Zhu, Qing; Egelston, Colt; Belyakov, Igor M.; Berzofsky, Jay A.] NCI, NIH, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Vivekanandhan, Aravindhan; Klinman, Dennis M.] NCI, NIH, Expt Immunol Lab, Bethesda, MD 20892 USA. [Uematsu, Satoshi; Akira, Shizuo] Osaka Univ, Microbial Dis Res Inst, Dept Host Def, Osaka 5600043, Japan. RP Berzofsky, JA (reprint author), NCI, NIH, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM zhuq@mail.nih.gov; berzofsk@helix.nih.gov RI Akira, Shizuo/C-3134-2009; OI Aravindhan, Vivekanandhan/0000-0002-5639-4948 FU National Institutes of Health (NIH; National Cancer Institute; Center for Cancer Research FX We thank Eisai Corp. for E6020; Liang Cao and Yunkai Yu for their assistance in cytokine multiplex assays; Giogio Trinchieri for critical reading of the manuscript; and Susan Gagnon and Yongjun Sui for helpful discussion. We also thank Lisa Smith for her secretarial assistance. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and the NIH Intramural AIDS Targeted Antiviral Program. NR 48 TC 99 Z9 100 U1 2 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 21 PY 2008 VL 105 IS 42 BP 16260 EP 16265 DI 10.1073/pnas.0805325105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 368BX UT WOS:000260597400036 PM 18845682 ER PT J AU Jakacki, RI Hamilton, M Gilbertson, RJ Blaney, SM Tersak, J Krailo, MD Ingle, AM Voss, SD Dancey, JE Adamson, PC AF Jakacki, Regina I. Hamilton, Marta Gilbertson, Richard J. Blaney, Susan M. Tersak, Jean Krailo, Mark D. Ingle, Ashish M. Voss, Stephan D. Dancey, Janet E. Adamson, Peter C. TI Pediatric Phase I and Pharmacokinetic Study of Erlotinib Followed by the Combination of Erlotinib and Temozolomide: A Children's Oncology Group Phase I Consortium Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; CELL LUNG-CANCER; ADVANCED PANCREATIC-CANCER; TUMOR XENOGRAFT MODELS; SOLID TUMORS; III TRIAL; CHEMOTHERAPY; OSI-774; NEUROBLASTOMA AB Purpose We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors. Patients and Methods Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed. Results Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m(2)/d. At 110 mg/m(2)/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m(2)/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m(2) and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response. Conclusion The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m(2)/d, either alone or in combination with temozolomide. C1 [Jakacki, Regina I.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. OSI Pharmaceut, Boulder, CO USA. St Jude Childrens Hosp, Memphis, TN 38105 USA. Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. Childrens Hosp, Boston, MA 02115 USA. Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. Childrens Oncol Grp, Arcadia, CA USA. RP Jakacki, RI (reprint author), Childrens Hosp Pittsburgh, 3705 5th Ave, Pittsburgh, PA 15213 USA. EM regina.jakacki@chp.edu FU NCATS NIH HHS [UL1 TR000005]; NCI NIH HHS [CA97452, P30 CA021765] NR 30 TC 56 Z9 59 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2008 VL 26 IS 30 BP 4921 EP 4927 DI 10.1200/JCO.2007.15.2306 PG 7 WC Oncology SC Oncology GA 361FT UT WOS:000260113600014 PM 18794549 ER PT J AU Anderson, LA Pfeiffer, RM Rapkin, JS Gridley, G Mellemkjaer, L Hemminki, K Bjorkholm, M Caporaso, NE Landgren, O AF Anderson, Lesley A. Pfeiffer, Ruth M. Rapkin, Joshua S. Gridley, Gloria Mellemkjaer, Lene Hemminki, Kari Bjorkholm, Magnus Caporaso, Neil E. Landgren, Ola TI Survival Patterns Among Lymphoma Patients With a Family History of Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; CANCER DATABASE; GENETIC POLYMORPHISMS; LYMPHOPROLIFERATIVE MALIGNANCIES; 1ST-DEGREE RELATIVES; RISK; DISEASE; SUSCEPTIBILITY AB Purpose Genetic factors are important in the etiology and pathogenesis of chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). Only a few small studies have assessed clinical characteristics and prognosis for familial patients, with inconsistent findings. Methods Using population-based registries from Sweden and Denmark, 7,749 patients with CLL, 7,476 patients with HL, and 25,801 patients with NHL with linkable first-degree relatives were identified. Kaplan-Meier curves were constructed to compare survival in patients with lymphoma with and without a family history of lymphoma. The risk of dying was assessed using adjusted Cox proportional hazard models. Results We found 85 patients with CLL (1.10%), 95 patients with HL (1.28%), and 206 patients with NHL (0.80%) with a family history of any lymphoma. Five-year mortality was similar for patients with CLL (hazard ratio [HR], 1.28; 95% CI, 0.95 to 1.72), HL (HR, 0.78; 95% CI, 0.49 to 1.25), and NHL (HR, 0.91; 95% CI, 0.74 to 1.12) versus without a family history of any lymphoma. Mortality was also similar for patients with versus without a family history of the same lymphoma. T-cell/anaplastic lymphoma patients with a family history of NHL had poorer outcome 5-years after diagnosis (HR, 5.38; 95% CI, 1.65 to 17.52). Results were similar for 10 years of follow-up. Conclusion With the exception of T-cell/anaplastic lymphoma, survival patterns for patients with CLL, HL, and NHL with a family history of lymphoma were similar to those for sporadic patients, suggesting that most familial lymphomas do not have an altered clinical course. Our findings provide no evidence to modify therapeutic strategies for patients with CLL, HL, or NHL based solely on family history. C1 [Anderson, Lesley A.] NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Div Canc Prevent,NIH, Bethesda, MD 20892 USA. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany. Karolinska Inst, Ctr Family & Community Med, Huddinge, Sweden. Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden. RP Anderson, LA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Room 7068,6120 Execut Blvd, Bethesda, MD 20892 USA. EM l.anderson@qub.ac.uk RI Pfeiffer, Ruth /F-4748-2011; OI Anderson, Lesley/0000-0002-1000-3649 FU National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics, Bethesda; Cancer Prevention Fellowship Program FX Supported by the intramural program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD. The Research and Development Office, Northern Ireland sponsored L. A. A. to participate in the Cancer Prevention Fellowship Program, Office of Preventative Oncology, Division of Cancer Prevention, National Cancer Institute through the Ireland-Northern Ireland-USA Consortium. NR 58 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2008 VL 26 IS 30 BP 4958 EP 4965 DI 10.1200/JCO.2007.14.6571 PG 8 WC Oncology SC Oncology GA 361FT UT WOS:000260113600020 PM 18606984 ER PT J AU Kammula, US Serrano, OK AF Kammula, Udai S. Serrano, Oscar K. TI Use of high throughput qPCR screening to rapidly clone low frequency tumour specific T-cells from peripheral blood for adoptive immunotherapy SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID VIVO ANTITUMOR EFFICACY; MELANOMA ANTIGEN GP100; METASTATIC MELANOMA; IN-VITRO; MONONUCLEAR-CELLS; TRANSFER THERAPY; REACTIVE CTL; PHASE-I; LYMPHOCYTES; CHEMOTHERAPY AB Background: The adoptive transfer of autologous tumor reactive lymphocytes can mediate significant tumor regression in some patients with refractory metastatic cancer. However, a significant obstacle for this promising therapy has been the availability of highly efficient methods to rapidly isolate and expand a variety of potentially rare tumor reactive lymphocytes from the natural repertoire of cancer patients. Methods: We developed a novel in vitro T cell cloning methodology using high throughput quantitative RT-PCR (qPCR assay) as a rapid functional screen to detect and facilitate the limiting dilution cloning of a variety of low frequency T cells from bulk PBMC. In preclinical studies, this strategy was applied to the isolation and expansion of gp100 specific CD8+ T cell clones from the peripheral blood of melanoma patients. Results: In optimization studies, the qPCR assay could detect the reactivity of 1 antigen specific T cell in 100,000 background cells. When applied to short term sensitized PBMC microcultures, this assay could detect T cell reactivity against a variety of known melanoma tumor epitopes. This screening was combined with early limiting dilution cloning to rapidly isolate gp100(154-162) reactive CD8+ T cell clones. These clones were highly avid against peptide pulsed targets and melanoma tumor lines. They had an effector memory phenotype and showed significant proliferative capacity to reach cell numbers appropriate for adoptive transfer trials (similar to 10(10) cells). Conclusion: This report describes a novel high efficiency strategy to clone tumor reactive T cells from peripheral blood for use in adoptive immunotherapy. C1 [Kammula, Udai S.; Serrano, Oscar K.] NCI, Surg Branch, Bethesda, MD 20892 USA. RP Kammula, US (reprint author), NCI, Surg Branch, Bldg 10, Bethesda, MD 20892 USA. EM udai_kammula@nih.gov; oks@jhmi.edu NR 22 TC 6 Z9 7 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 20 PY 2008 VL 6 AR 60 DI 10.1186/1479-5876-6-60 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 371ZC UT WOS:000260870200001 PM 18937837 ER PT J AU Burbelo, PD Meoli, E Leahy, HP Graham, J Yao, K Oh, U Janik, JE Mahieux, R Kashanchi, F Iadarola, MJ Jacobson, S AF Burbelo, Peter D. Meoli, Elise Leahy, Hannah P. Graham, Jhanelle Yao, Karen Oh, Unsong Janik, John E. Mahieux, Renaud Kashanchi, Fatah Iadarola, Michael J. Jacobson, Steven TI Anti-HTLV antibody profiling reveals an antibody signature for HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) SO RETROVIROLOGY LA English DT Article ID VIRUS TYPE-I; T-CELL LEUKEMIA; PERIPHERAL-BLOOD; PROVIRAL LOAD; NEUROLOGICAL DISEASES; ASYMPTOMATIC CARRIERS; MOLECULAR MIMICRY; LYMPHOCYTES; TAX; INFECTION AB Background: HTLV-I is the causal agent of adult T cell leukemia (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Biomarkers are needed to diagnose and/or predict patients who are at risk for HAM/TSP or ATLL. Therefore, we investigated using luciferase immunoprecipitation technology (LIPS) antibody responses to seven HTLV-I proteins in noninfected controls, asymptomatic HTLV-I-carriers, ATLL and HAM/TSP sera samples. Antibody profiles were correlated with viral load and examined in longitudinal samples. Results: Anti-GAG antibody titers detected by LIPS differentiated HTLV-infected subjects from uninfected controls with 100% sensitivity and 100% specificity, but did not differ between HTLV-I infected subgroups. However, anti-Env antibody titers were over 4-fold higher in HAM/TSP compared to both asymptomatic HTLV-I (P < 0.0001) and ATLL patients (P < 0.0005). Anti-Env antibody titers above 100,000 LU had 75% positive predictive value and 79% negative predictive value for identifying the HAM/TSP sub-type. Anti-Tax antibody titers were also higher (P < 0.0005) in the HAM/TSP compared to the asymptomatic HTLV-I carriers. Proviral load correlated with anti-Env antibodies in asymptomatic carriers (R = 0.76), but not in HAM/TSP. Conclusion: These studies indicate that anti-HTLV-I antibody responses detected by LIPS are useful for diagnosis and suggest that elevated anti-Env antibodies are a common feature found in HAM/TSP patients. C1 [Meoli, Elise; Graham, Jhanelle; Yao, Karen; Oh, Unsong; Jacobson, Steven] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA. [Burbelo, Peter D.; Leahy, Hannah P.; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Lab Sensory Biol, Neurobiol & Pain Therapeut Sect, Bethesda, MD 20892 USA. [Janik, John E.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Mahieux, Renaud] Inst Pasteur, CNRS, Dept Virol, Unite Epidemiol & Physiopathol Virus Oncogenes,UR, F-75015 Paris, France. [Mahieux, Renaud; Kashanchi, Fatah] George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. RP Jacobson, S (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov; meolie@od.nih.gov; hleahy@mail.une.edu; grahamjh@ninds.nih.gov; YaoK@ninds.nih.gov; OhU@ninds.nih.gov; janikj@mail.nih.gov; renaud.mahieux@pasteur.fr; bcmfxk@gwumc.edu; miadarola@dir.nidcr.nih.gov; JacobsonS@ninds.nih.gov FU Division of Intramural Research; National Institute of Dental and Craniofacial Research; National Institute of Neurological Disorders and Stroke; National Institutes of Health; INSERM FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research and National Institute of Neurological Disorders and Stroke, National Institutes of Health and, in part, by a Bench to Bedside award from the NIH Clinical Research Center. R. M. was supported by INSERM. NR 37 TC 29 Z9 29 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD OCT 20 PY 2008 VL 5 AR 96 DI 10.1186/1742-4690-5-96 PG 11 WC Virology SC Virology GA 372DN UT WOS:000260882000001 PM 18937847 ER PT J AU Fontana, G Savona, G Rodriguez, B Dersch, CM Rothman, RB Prisinzano, TE AF Fontana, Gianfranco Savona, Giuseppe Rodriguez, Benjamin Dersch, Christina M. Rothman, Richard B. Prisinzano, Thomas E. TI Synthetic studies of neoclerodane diterpenoids from Salvia splendens and evaluation of opioid receptor affinity SO TETRAHEDRON LA English DT Article DE Salvia splendens; Opioid receptors; Neoclerodane diterpenes; Semisynthetic derivatives ID SALVINORIN-A ANALOGS; CLERODANE DITERPENOIDS; ASSIGNMENTS; SALVIFARIN; FARINACEA; AGONISTS; C(2); H-1 AB Salvinorin A (1), a neoclerodane diterpene from the hallucinogenic mint Salvia divinorum, is the only known non-nitrogenous and specific x-opioid agonist. Several structural congeners of 1 isolated from Salvia splendens (2-8) together with a series of semisynthetic derivatives (9-24), some of which possess a pyrazoline structural moiety (9, 19-22), have been tested for affinity at human mu, delta, and kappa opioid receptors. None of these compounds showed high affinity binding to these receptors. However, 10 showed modest affinity for kappa receptors suggesting that other natural neoclerodanes from different Salvia species may possess opioid affinity. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Fontana, Gianfranco; Savona, Giuseppe] Univ Palermo, Dipartimento Chim Organ E paterno, I-90128 Palermo, Italy. [Rodriguez, Benjamin] CSIC, Inst Quim Organ, E-28006 Madrid, Spain. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA. RP Savona, G (reprint author), Univ Palermo, Dipartimento Chim Organ E paterno, Parco Orleans 2, I-90128 Palermo, Italy. EM giussav@unipa.it; iqor107@iqog.csic.es RI Prisinzano, Thomas/B-7877-2010 FU Spanish 'Comision Interministerial de Ciencia y Tecnologia' (CICYT) [CTQ2006-15279-C02-02]; Italian 'Universita degli Studi di Palermo' [Ex 60%-2005]; National Institute on Drug Abuse [R01DA018151] FX This work was supported in part by funds from the Spanish 'Comision Interministerial de Ciencia y Tecnologia' (CICYT), grant No. CTQ2006-15279-C02-02, Italian 'Universita degli Studi di Palermo', grant 'Ex 60%-2005', and R01DA018151 (to T.E.R) from the National Institute on Drug Abuse. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. NR 23 TC 26 Z9 27 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD OCT 20 PY 2008 VL 64 IS 43 BP 10041 EP 10048 DI 10.1016/j.tet.2008.08.043 PG 8 WC Chemistry, Organic SC Chemistry GA 360UA UT WOS:000260082200002 PM 20027203 ER PT J AU Nayak, B Kumar, S Collins, PL Samal, SK AF Nayak, Baibaswata Kumar, Sachin Collins, Peter L. Samal, Siba K. TI Molecular characterization and complete genome sequence of avian paramyxovirus type 4 prototype strain duck/Hong Kong/D3/75 SO VIROLOGY JOURNAL LA English DT Article ID NEWCASTLE-DISEASE VIRUS; SENDAI-VIRUS; SEROLOGICAL SURVEY; HONG-KONG; RNA; REPLICATION; PROTEIN; RULE; GENE; IDENTIFICATION AB Background: Avian paramyxoviruses (APMVs) are frequently isolated from domestic and wild birds throughout the world. All APMVs, except avian metapneumovirus, are classified in the genus Avulavirus of the family Paramyxoviridae. At present, the APMVs of genus Avulavirus are divided into nine serological types (APMV 1-9). Newcastle disease virus represents APMV-1 and is the most characterized among all APMV types. Very little is known about the molecular characteristics and pathogenicity of APMV 2-9. Results: As a first step towards understanding the molecular genetics and pathogenicity of APMV-4, we have sequenced the complete genome of APMV-4 strain duck/Hong Kong/D3/75 and determined its pathogenicity in embryonated chicken eggs. The genome of APMV-4 is 15,054 nucleotides (nt) in length, which is consistent with the "rule of six". The genome contains six non-overlapping genes in the order 3'-N-P/V-M-F-HN-L-5'. The genes are flanked on either side by highly conserved transcription start and stop signals and have intergenic sequences varying in length from 9 to 42 nt. The genome contains a 55 nt leader region at 3' end. The 5' trailer region is 17 nt, which is the shortest in the family Paramyxoviridae. Analysis of mRNAs transcribed from the P gene showed that 35% of the transcripts were edited by insertion of one non-templated G residue at an editing site leading to production of V mRNAs. No message was detected that contained insertion of two non-templated G residues, indicating that the W mRNAs are inefficiently produced in APMV-4 infected cells. The cleavage site of the F protein (DIPQR down arrow F) does not conform to the preferred cleavage site of the ubiquitous intracellular protease furin. However, exogenous proteases were not required for the growth of APMV-4 in cell culture, indicating that the cleavage does not depend on a furin site. Conclusion: Phylogenic analysis of the nucleotide sequences of viruses of all five genera of the family Paramyxoviridae showed that APMV- 4 is more closely related to the APMVs than to other paramyxoviruses, reinforcing the classification of all APMVs in the genus Avulavirus of the family Paramyxoviridae. C1 [Nayak, Baibaswata; Kumar, Sachin; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM bnayak@umd.edu; sachin22@umd.edu; pcollins@niaid.nih.gov; ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU NIAID [N01A060009] FX We thank Daniel Rockemann and all our laboratory members for their excellent technical assistance and help. We also thank Hamp Edwards for performing electron microscopy and Ireen Dryburgh-Barry for proofreading the manuscript. "This research was supported by NIAID contract no. N01A060009 (85% support) and NIAID, NIH Intramural Research Program (15% support). The views expressed here in neither necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U. S. Government." NR 39 TC 30 Z9 30 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD OCT 20 PY 2008 VL 5 AR 124 DI 10.1186/1743-422X-5-124 PG 11 WC Virology SC Virology GA 372DS UT WOS:000260882500004 PM 18937854 ER PT J AU Vitiello, B AF Vitiello, Benedetto TI Truly independent research? Treatment for Adolescents with Depression Study (TADS) SO BRITISH MEDICAL JOURNAL LA English DT Letter C1 [Vitiello, Benedetto] NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20817 USA. RP Vitiello, B (reprint author), NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20817 USA. EM bvitiell@mail.nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD OCT 18 PY 2008 VL 337 IS 7675 AR a2070 DI 10.1136/bmj.a2070 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 360YE UT WOS:000260093900009 PM 18852171 ER PT J AU Tischkowatz, MD Yilmaz, A Chen, LQ Karyadi, DM Novak, D Kirchhoff, T Hamel, N Tavtigian, SV Kolb, S Bismar, TA Aloyz, R Nelson, PS Hood, L Narod, SA White, KA Ostrander, EA Isaacs, WB Offit, K Cooney, KA Stanford, JL Foulkes, WD AF Tischkowatz, Marc D. Yilmaz, Ahmet Chen, Long Q. Karyadi, Danielle M. Novak, David Kirchhoff, Tomas Hamel, Nancy Tavtigian, Sean V. Kolb, Suzanne Bismar, Tarek A. Aloyz, Raquel Nelson, Peter S. Hood, Lee Narod, Steven A. White, Kirsten A. Ostrander, Elaine A. Isaacs, William B. Offit, Kenneth Cooney, Kathleen A. Stanford, Janet L. Foulkes, William D. TI Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer SO CANCER LETTERS LA English DT Article DE checkpoint kinase 2; prostate cancer; CHEK2; single-nucleotide polymorphism; Ashkenazi Jewish; budding yeast ID DNA-DAMAGE CHECKPOINT; LI-FRAUMENI-SYNDROME; GENOME-WIDE SCAN; SUSCEPTIBILITY GENES; BREAST-CANCER; FAMILIES; RISK; MUTATIONS; BRCA1; CHK2 AB Checkpoint kinase 2 (CHEK2) is a protein involved in arresting cell cycle in response to DNA damage. To investigate whether it plays an important role in the development of prostate cancer (PRCA) in the Ashkenazi Jewish (AJ) population, we sequenced CHEK2 in 75 AJ individuals with prostate, breast, or no cancer (n = 25 each). We identified seven coding SNPs (five are novel) that changed the amino-acid sequence, resulting in R3W, E394F, Y424H, S428F, D438Y, P509S, and P509L. We determined the frequency of each variant in 76 AJ families collected by members of the International Consortium for Prostate Cancer Genetics (ICPCG) where >= 2 men were affected by PRCA. Only one variant, Y424H in exon 11, was identified in more than two families. Exon 11 was then screened in nine additional AJ ICPCG families (a total of 85 families). The Y424H variant occurred in nine affected cases from four different families; however, it did not completely segregate with the disease. We performed bioinformatics analysis, which showed that Y424H is a non-conservative missense substitution that falls at a position that is invariant in vertebrate CHEK2 orthologs. Both SIFT and Align-GVGD predict that Y424H is a loss of function mutation. However, the frequency of Y424H was not significantly different between unselected AJ cases from Montreal/Memorial Sloan Kettering Cancer Centre (MSKCC) and AJ controls from Israel/MSKCC (OR 1.18, 95%CI: 0.34-4.61, p=.99). Moreover, functional assays using Saccharomyces cerevisiae revealed that the Y424H substitution did not alter function of CHEK2 protein. Although we cannot rule out a subtle influence of the CHEK2 variants on PRCA risk, these results suggest that germline CHEK2 mutations have a minor role in, if any, PRCA susceptibility in AJ men. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Tischkowatz, Marc D.; Yilmaz, Ahmet; Novak, David; Bismar, Tarek A.; Aloyz, Raquel; Foulkes, William D.] McGill Univ, Sir Mortimer B Davis Jewish Hosp, Dept Oncol, Canc Prevent Ctr, Montreal, PQ, Canada. [Tischkowatz, Marc D.; Yilmaz, Ahmet; Novak, David; Bismar, Tarek A.; Aloyz, Raquel; Foulkes, William D.] McGill Univ, Sir Mortimer B Davis Jewish Hosp, Dept Med Genet, Canc Prevent Ctr, Montreal, PQ, Canada. [Tischkowatz, Marc D.; Yilmaz, Ahmet; Chen, Long Q.; Novak, David; Hamel, Nancy; Foulkes, William D.] McGill Univ, Dept Med Genet, Montreal, PQ, Canada. [Tischkowatz, Marc D.; Yilmaz, Ahmet; Chen, Long Q.; Novak, David; Hamel, Nancy; Foulkes, William D.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Karyadi, Danielle M.; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98104 USA. [Kirchhoff, Tomas; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Tavtigian, Sean V.] Int Agcy Res Canc, F-69372 Lyon, France. [Kolb, Suzanne; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Bismar, Tarek A.] McGill Univ, Sir Mortimer B Davis Jewish Hosp, Dept Pathol, Montreal, PQ, Canada. [Aloyz, Raquel] McGill Univ, Div Expt Med, Montreal, PQ, Canada. [Hood, Lee] Inst Syst Biol, Seattle, WA USA. [Narod, Steven A.] Univ Toronto, Toronto, ON, Canada. [White, Kirsten A.; Cooney, Kathleen A.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [White, Kirsten A.; Cooney, Kathleen A.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Karyadi, Danielle M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Isaacs, William B.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Foulkes, WD (reprint author), McGill Univ, Sir Mortimer B Davis Jewish Hosp, Dept Oncol, Canc Prevent Ctr, E740, Montreal, PQ, Canada. EM william.foulkes@mcgill.ca OI foulkes, william/0000-0001-7427-4651; Kirchhoff, Tomas/0000-0002-9055-2364; Ostrander, Elaine/0000-0001-6075-9738 FU National Institutes of Health [U01CA89600, CA79596, CA78836]; Koodish Fellowship and the Evan Frankel Foundation; National Human Genome Research Institute; US National Cancer Institute [CA080122]; Prostate Cancer Foundation; Fred Hutchinson Cancer Research Center; Department of Defense [W81XWH-04-1-0083]; Canadian Genetic Disease Network [DAMD17-00-1-0033]; Montreal Center for Experimental Therapeutics in Cancer FX We acknowledge support from the National Institutes of Health, on behalf of ICPCG, (grant recipient and grant number in parentheses) (W.B.I., U01CA89600; K.A.C., CA79596; and P.S.N., CA78836), the Koodish Fellowship and the Evan Frankel Foundation (T.K.), the National Human Genome Research Institute and National Institutes of Health (E.A.O.), the US National Cancer Institute (J.L.S., CA080122), the Prostate Cancer Foundation and the Fred Hutchinson Cancer Research Center (J.L.S.), the Department of Defense (D.M.K., W81XWH-04-1-0083), the Canadian Genetic Disease Network (W.D.F., DAMD17-00-1-0033), the Montreal Center for Experimental Therapeutics in Cancer (A.Y.), and the Intramural Program of the National Human Genome Research Institute. We are also grateful for the financial contribution of the Fonds de Recherche en Sante du Quebec via their continuing support to the Research Institute of the McGill University Health Center. The authors gratefully acknowledge technical support from Drs. A. Al-Moustafa, S. Elledge, R. Rothstein, B. Bhullar, B. Andreson, and U. Stohaj in performing yeast functional assays. NR 46 TC 6 Z9 7 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD OCT 18 PY 2008 VL 270 IS 1 BP 173 EP 180 DI 10.1016/j.canlet.2008.05.006 PG 8 WC Oncology SC Oncology GA 357LL UT WOS:000259847200017 PM 18571837 ER PT J AU Peterson, ME Long, EO AF Peterson, Mary E. Long, Eric O. TI Inhibitory Receptor Signaling via Tyrosine Phosphorylation of the Adaptor Crk SO IMMUNITY LA English DT Article ID NATURAL-KILLER-CELLS; CLASS-I MOLECULES; MHC CLASS-I; C-CBL; UBIQUITIN LIGASES; SELF-TOLERANCE; IMMUNE SYNAPSE; NK CELLS; ACTIVATION; COMPLEX AB Many cellular responses, such as autoimmunity and cytotoxicity, are controlled by receptors with cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). Here, we showed that binding of inhibitory natural killer (NK) cell receptors to human leukocyte antigen (HLA) class I on target cells induced tyrosine phosphorylation of the adaptor Crk, concomitant with dephosphorylation of the guanine exchange factor Vav1. Furthermore, Crk dissociated from the guanine exchange factor C3G and bound to the tyrosine kinase c-Abl during inhibition. Membrane targeting of a tyrosine-mutated form of Crk could overcome inhibition of NK cell cytotoxicity, providing functional evidence that Crk phosphorylation contributes to inhibition. The specific phosphorylation of Crk and its dissociation from a signaling complex, observed here with two types of inhibitory receptors, expands the signaling potential of the large ITIM-receptor family and reveals an unsuspected component of the inhibitory mechanism. C1 [Peterson, Mary E.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM elong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank M. March and A. Shaw for useful discussions; G. Cohen, D. Geraghty, J. Gumperz, P. Parham, and M. Robertson for cell lines; and R. Klemke for a CrkII cDNA. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 48 TC 61 Z9 63 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 17 PY 2008 VL 29 IS 4 BP 578 EP 588 DI 10.1016/j.immuni.2008.07.014 PG 11 WC Immunology SC Immunology GA 364DP UT WOS:000260316700011 PM 18835194 ER PT J AU Hall, JA Bouladoux, N Sun, CM Wohlfert, EA Blank, RB Zhu, Q Grigg, ME Berzofsky, JA Belkaid, Y AF Hall, Jason A. Bouladoux, Nicolas Sun, Cheng Ming Wohlfert, Elizabeth A. Blank, Rebecca B. Zhu, Qing Grigg, Michael E. Berzofsky, Jay A. Belkaid, Yasmine TI Commensal DNA Limits Regulatory T Cell Conversion and Is a Natural Adjuvant of Intestinal Immune Responses SO IMMUNITY LA English DT Article ID TOLL-LIKE RECEPTORS; ENCEPHALITOZOON-CUNICULI INFECTION; INFLAMMATORY-BOWEL-DISEASE; DENDRITIC CELLS; CROHNS-DISEASE; ESCHERICHIA-COLI; RETINOIC-ACID; EPITHELIAL-CELLS; TOXOPLASMA-GONDII; ORAL INFECTION AB The intestinal tract is in intimate contact with the commensal microflora. Nevertheless, how commensals communicate with cells to ensure immune homeostasis is still unclear. In this study, we found that gut flora DNA (gfDNA) plays a major role in intestinal homeostasis through Toll-like receptor 9 (TLR9) engagement. Tlr9(-/-) mice displayed increased frequencies of CD4(+)Foxp3(+) regulatory T (Treg) cells within intestinal effector sites and reduced Constitutive IL-17-and IFN-gamma-producing effector T (Teff) cells. Complementing this, gfDNA limited lamina propria dendritic cell-induced Treg cell conversion in vitro. Further, Treg/Teff cell disequilibrium in Tlr9(-/-) mice led to impaired immune responses to oral infection and to oral vaccination. Impaired intestinal immune responses were recapitulated in mice treated with antibiotics and were reversible after reconstitution with gfDNA. Together, these data point to gfDNA as a natural adjuvant for priming intestinal responses via modulation of Treg/Teff cell equilibrium. C1 [Hall, Jason A.; Bouladoux, Nicolas; Sun, Cheng Ming; Wohlfert, Elizabeth A.; Blank, Rebecca B.; Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Hall, Jason A.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Zhu, Qing; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grigg, Michael E.] NIAID, Mol Parasitol Unit, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank the MAID sorting facility and K. Beacht for technical assistance. We would like to thank A. Sher and D. Chou for critical reading of the manuscript. NR 71 TC 265 Z9 269 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 17 PY 2008 VL 29 IS 4 BP 637 EP 649 DI 10.1016/j.immuni.2008.08.009 PG 13 WC Immunology SC Immunology GA 364DP UT WOS:000260316700016 PM 18835196 ER PT J AU Schieke, SM Ma, MC Cao, L Mccoy, JP Liu, CY Hensel, NF Barrett, AJ Boehm, M Finkel, T AF Schieke, Stefan M. Ma, Mingchao Cao, Liu Mccoy, J. Philip, Jr. Liu, Chengyu Hensel, Nancy F. Barrett, A. John Boehm, Manfred Finkel, Toren TI Mitochondrial metabolism modulates differentiation and teratoma formation capacity in mouse embryonic stem cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BONE-MARROW; HYPOXIA; OXYGEN; MESODERM; MTOR; PROLIFERATION; PRECURSORS; PATHWAY; GROWTH AB Relatively little is known regarding the role of mitochondrial metabolism in stem cell biology. Here we demonstrate that mouse embryonic stem cells sorted for low and high resting mitochondrial membrane potential ( Delta Psi L-m and Delta Psi H-m) are indistinguishable morphologically and by the expression of pluripotency markers, whereas markedly differing in metabolic rates. Interestingly, Delta Psi L-m cells are highly efficient at in vitro mesodermal differentiation yet fail to efficiently form teratomas in vivo, whereas Delta Psi H-m cells behave in the opposite fashion. We further demonstrate that Delta Psi(m) reflects the degree of overall mammalian target of rapamycin ( mTOR) activation and that the (mTOR) inhibitor rapamycin reduces metabolic rate, augments differentiation, and inhibits tumor formation of the mouse embryonic stem cells with a high metabolic rate. Taken together, our results suggest a coupling between intrinsic metabolic parameters and stem cell fate that might form a basis for novel enrichment strategies and therapeutic options. C1 [Schieke, Stefan M.; Ma, Mingchao; Cao, Liu; Boehm, Manfred; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Hensel, Nancy F.; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Boehm, M (reprint author), Bldg 10-CRC 5-3132,10 Ctr Dr Bethesda, Bethesda, MD 20892 USA. EM Manfred.Boehm@nih.gov; finkelt@nih.gov NR 25 TC 83 Z9 85 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 17 PY 2008 VL 283 IS 42 BP 28506 EP 28512 DI 10.1074/jbc.M802763200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 359EN UT WOS:000259969300053 PM 18713735 ER PT J AU Yamashita, T Suzuki, R Backlund, PS Yamashita, Y Yergey, AL Rivera, J AF Yamashita, Toshiyuki Suzuki, Ryo Backlund, Peter S. Yamashita, Yumi Yergey, Alfred L. Rivera, Juan TI Differential dephosphorylation of the FcR gamma immunoreceptor tyrosine-based activation motif tyrosines with dissimilar potential for activating Syk SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AFFINITY IGE RECEPTOR; LEUKEMIA RBL-2H3 CELLS; EPSILON-RI; MAST-CELLS; IMMUNOGLOBULIN-E; KINASE SYK; MEDIATED DEGRANULATION; PHOSPHATASES SHP-1; BETA-SUBUNIT; PHOSPHORYLATION AB The cell surface-expressed gamma chain of the high affinity receptor for IgE (Fc epsilon RI) can be phosphorylated on two tyrosine residues of the immunoreceptor tyrosine-based activation motif (ITAM), leading to recruitment and activation of spleen tyrosine kinase (Syk), a kinase that is essential for mast cell signaling and allergic responses. However, it is not known whether preferential phosphorylation or dephosphorylation of the two individual FcR gamma tyrosines (the N-terminal Tyr(47) and C-terminal Tyr(58)) could regulate Syk activation. Herein we report that phosphorylation of only Tyr(58) was able to elicit Syk phosphorylation and a weak rise in intracellular calcium, suggesting that Tyr(58) phosphorylation may be distinctively important for Syk activation. In vitro and in vivo studies revealed that both Tyr(47) and Tyr(58) could be similarly phosphorylated. However, mass spectrometric analysis of the phosphorylated Fc epsilon R gamma from bone marrow-derived mast cells showed that phosphorylation at Tyr(47) was at least 2-fold greater than at Tyr(58). This suggested that, once phosphorylated, Tyr(58) is preferentially dephosphorylated. In vitro studies demonstrated more efficient dephosphorylation of Tyr(58) (by the receptor-associated phosphatases SHP-1 and SHP-2) than of Tyr(47). Analysis of Syk binding to wild type and mutant phosphorylated Fc epsilon RI revealed that mutation at Tyr(58) almost completely ablated Syk binding, whereas mutation at Tyr(47) moderately reduced Syk binding. The findings argue for a novel regulatory mechanism, where dephosphorylation of phospho-Tyr(58) is likely to promote the down-regulation of Syk activation and suppression of mast cell responses. C1 [Yamashita, Toshiyuki; Suzuki, Ryo; Yamashita, Yumi; Rivera, Juan] NIAMS, Lab Immune Cell Signaling, Bethesda, MD 20892 USA. [Backlund, Peter S.; Yergey, Alfred L.] NICHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMS, NIH, Bldg 10,Rm 13C103, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov NR 38 TC 16 Z9 16 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 17 PY 2008 VL 283 IS 42 BP 28584 EP 28594 DI 10.1074/jbc.M802679200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 359EN UT WOS:000259969300061 PM 18715866 ER PT J AU Lewis, DEA Komissarova, N Le, P Kashlev, M Adhya, S AF Lewis, Dale E. A. Komissarova, Natalia Le, Phuoc Kashlev, Mikhail Adhya, Sankar TI DNA sequences in gal operon override transcription elongation blocks SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Ga1R; backtracking; roadblock; pausing; transcription ID COLI RNA-POLYMERASE; CAMP RECEPTOR PROTEIN; CLEAVAGE FACTORS GREA; ESCHERICHIA-COLI; GALACTOSE OPERON; IN-VIVO; PROMOTERS; REPRESSOR; COMPLEX; HYBRID AB The DNA loop that represses transcription from galactose (gal) promoters is infrequently formed in stationary-phase cells because the concentration of the loop architectural protein HU is significantly low at that state, resulting in expression of the operon in the absence of the gal inducer D-galactose. Unexpectedly, transcription from the gal promoters under these conditions overrides physical block because of the presence of the Gal repressor bound to an internal operator (O-I) located downstream of the promoters. We have shown,here that although a stretch of pyrimidine residues (UUCU) in the RNA:DNA hybrid located immediately upstream of O-I weakens the RNA: DNA hybrid and favors RNA polymerase (RNAP) pausing and backtracking, a stretch of purines (GAGAG) in the RNA present immediately upstream of the pause sequence in the hybrid acts as an antipause element by stabilizing the RNA:DNA duplex and preventing backtracking. This facilitates forward translocation of RNAP, including overriding of the DNA-bound Gal repressor barrier at O-I. When the GAGAG sequence is separated from the pyrimidine sequence by a 5-by DNA insertion, RNAP backtracking is favored from a weak hybrid to a more stable hybrid. RNAP backtracking is sensitive to Gre factors, D-galactose, and antisense oligonucleotides. The ability of a native DNA sequence to override transcription elongation blocks in the gal operon uncovers a previously unknown way of regulating gal metabolism in Escherichia coli. It also explains the synthesis of gal enzymes in the absence of inducer for biosynthetic reactions. Published by Elsevier Ltd. C1 [Lewis, Dale E. A.; Le, Phuoc; Adhya, Sankar] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Komissarova, Natalia] NICHHD, Sect Microbial Genet, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Kashlev, Mikhail] NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Lewis, DEA (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM aed@helix.nih.gov FU Intramural Research Program; National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. We thank S. Borukhov, M. Liu, M. Soukhodolets, and T. Soares for the gift of purified proteins, and V Zhurkin for critical discussions. NR 52 TC 12 Z9 12 U1 1 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 17 PY 2008 VL 382 IS 4 BP 843 EP 858 DI 10.1016/j.jmb.2008.07.060 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 359YP UT WOS:000260024500003 PM 18691599 ER PT J AU Melman, A Zhong, M Marquez, VE Jacobson, KA AF Melman, Artem Zhong, Minghong Marquez, Victor E. Jacobson, Kenneth A. TI Synthesis of enantiomerically pure (S)-methanocarbaribo uracil nucleoside derivatives for use as antiviral agents and P2Y receptor ligands SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ADENOSINE; CONFORMATION; TEMPLATE; AGONISTS; POTENCY AB We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]-hexane system. D-Ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5'-hydroxymethyl group. An ester group appended to a tertiary carbon (Cl) was transformed to an amino group as a nucleobase precursor. C1 [Zhong, Minghong; Marquez, Victor E.] NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. [Melman, Artem] Clarkson Univ, Dept Chem & Biomol Sci, Potsdam, NY 13699 USA. [Melman, Artem; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. RI Jacobson, Kenneth/A-1530-2009; yu, yan/C-2322-2012 OI Jacobson, Kenneth/0000-0001-8104-1493; FU National Institutes of Health; NIDDK; Center for Cancer Research FX We thank Dr. Dina M. Sigano for optical rotation measurements and Drs. James A. Kelley, Christopher Lai, and Dilip Tosh for high-resolution mass spectral measurements. This research was supported in part by the Intramural Research Programs of the National Institutes of Health, NIDDK and the Center for Cancer Research, National Cancer Institute at Frederick. NR 15 TC 6 Z9 6 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD OCT 17 PY 2008 VL 73 IS 20 BP 8085 EP 8088 DI 10.1021/jo801224j PG 4 WC Chemistry, Organic SC Chemistry GA 359GH UT WOS:000259973900035 PM 18811198 ER PT J AU Nanda, S Havert, MB Calderon, GM Thomson, M Jacobson, C Kastner, D Liang, TJ AF Nanda, Santosh Havert, Michael B. Calderon, Gloria M. Thomson, Michael Jacobson, Christian Kastner, Daniel Liang, T. Jake TI Hepatic Transcriptome Analysis of Hepatitis C Virus Infection in Chimpanzees Defines Unique Gene Expression Patterns Associated with Viral Clearance SO PLOS ONE LA English DT Article AB Hepatitis C virus infection leads to a high rate of chronicity. Mechanisms of viral clearance and persistence are still poorly understood. In this study, hepatic gene expression analysis was performed to identify any molecular signature associated with the outcome of hepatitis C virus (HCV) infection in chimpanzees. Acutely HCV-infected chimpanzees with self-limited infection or progression to chronicity were studied. Interferon stimulated genes were induced irrespective of the outcome of infection. Early induction of a set of genes associated with cell proliferation and immune activation was associated with subsequent viral clearance. Specifically, two of the genes: interleukin binding factor 3 (ILF3) and cytotoxic granule-associated RNA binding protein (TIA1), associated with robust T-cell response, were highly induced early in chimpanzees with self-limited infection. Up-regulation of genes associated with CD8+ T cell response was evident only during the clearance phase of the acute self-limited infection. The induction of these genes may represent an initial response of cellular injury and proliferation that successfully translates to a "danger signal'' leading to induction of adaptive immunity to control viral infection. This primary difference in hepatic gene expression between self-limited and chronic infections supports the concept that successful activation of HCV-specific T-cell response is critical in clearance of acute HCV infection. C1 [Nanda, Santosh; Havert, Michael B.; Calderon, Gloria M.; Thomson, Michael; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Jacobson, Christian; Kastner, Daniel] NIAMS, Genet & Genom Branch, NIH, Bethesda, MD USA. [Nanda, Santosh; Havert, Michael B.] FDA, CBER, Bethesda, MD USA. [Thomson, Michael] GlaxoSmithKline Inc, Virol Dept, Res Triangle Pk, NC USA. [Jacobson, Christian] Univ Waterloo, Dept Biol & Mech & Mechatron Engn, Waterloo, ON N2L 3G1, Canada. RP Nanda, S (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM JakeL@intra.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 38 TC 15 Z9 15 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2008 VL 3 IS 10 AR e3442 DI 10.1371/journal.pone.0003442 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432GV UT WOS:000265122400012 PM 18927617 ER PT J AU Okubadejo, N Britton, A Crews, C Akinyemi, R Hardy, J Singleton, A Bras, J AF Okubadejo, Njideka Britton, Angela Crews, Cynthia Akinyemi, Rufus Hardy, John Singleton, Andrew Bras, Jose TI Analysis of Nigerians with Apparently Sporadic Parkinson Disease for Mutations in LRRK2, PRKN and ATXN3 SO PLOS ONE LA English DT Article AB Several genetic variations have been associated with Parkinson disease in different populations over the past few years. Although a considerable number of worldwide populations have been screened for these variants, results from Sub-Saharan populations are very scarce in the literature. In the present report we have screened a cohort of Parkinson disease patients (n = 57) and healthy controls (n = 51) from Nigeria for mutations in the genes PRKN, LRRK2 and ATXN3. No pathogenic mutations were found in any of the genes. Hence, common pathogenic mutations in these genes, observed in several different populations, are not a frequent cause of Parkinson disease in Nigeria. C1 [Okubadejo, Njideka] Univ Lagos, Coll Med, Dept Med, Neurol Unit, Lagos, Nigeria. [Britton, Angela; Crews, Cynthia; Singleton, Andrew; Bras, Jose] NIA, Lab Neurogenet, NIH, Bethesda, MD USA. [Akinyemi, Rufus] Fed Med Ctr, Dept Med, Neurol Unit, Abeokuta, Nigeria. [Hardy, John] Reta Lila Weston Inst, Inst Neurol, Dept Mol Neurosci & Neurodegenerat Dis, London, England. [Bras, Jose] Univ Coimbra, Ctr Neurosci & Cell Biol, P-3000 Coimbra, Portugal. RP Okubadejo, N (reprint author), Univ Lagos, Coll Med, Dept Med, Neurol Unit, Lagos, Nigeria. EM brasj@mail.nih.gov RI Bras, Jose/A-1428-2011; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01-AG000957-05]; Portuguese FCT [SFRH/BD/29647/2006] FX This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; Annual Report number Z01-AG000957-05 and Portuguese FCT grant #SFRH/BD/29647/2006. NR 26 TC 23 Z9 24 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2008 VL 3 IS 10 AR e3421 DI 10.1371/journal.pone.0003421 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432GV UT WOS:000265122400002 PM 18927607 ER PT J AU Roguev, A Bandyopadhyay, S Zofall, M Zhang, K Fischer, T Collins, SR Qu, HJ Shales, M Park, HO Hayles, J Hoe, KL Kim, DU Ideker, T Grewal, SI Weissman, JS Krogan, NJ AF Roguev, Assen Bandyopadhyay, Sourav Zofall, Martin Zhang, Ke Fischer, Tamas Collins, Sean R. Qu, Hongjing Shales, Michael Park, Han-Oh Hayles, Jacqueline Hoe, Kwang-Lae Kim, Dong-Uk Ideker, Trey Grewal, Shiv I. Weissman, Jonathan S. Krogan, Nevan J. TI Conservation and rewiring of functional modules revealed by an epistasis map in fission yeast SO SCIENCE LA English DT Article ID POLYMERASE-II HOLOENZYME; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; HISTONE-3 LYSINE-4; PROTEIN COMPLEXES; GENE-EXPRESSION; DNA-DAMAGE; CHECKPOINT; TRANSCRIPTION; ORGANIZATION AB An epistasis map (E-MAP) was constructed in the fission yeast, Schizosaccharomyces pombe, by systematically measuring the phenotypes associated with pairs of mutations. This high-density, quantitative genetic interaction map focused on various aspects of chromosome function, including transcription regulation and DNA repair/replication. The E-MAP uncovered a previously unidentified component of the RNA interference (RNAi) machinery (rsh1) and linked the RNAi pathway to several other biological processes. Comparison of the S. pombe E-MAP to an analogous genetic map from the budding yeast revealed that, whereas negative interactions were conserved between genes involved in similar biological processes, positive interactions and overall genetic profiles between pairs of genes coding for physically associated proteins were even more conserved. Hence, conservation occurs at the level of the functional module (protein complex), but the genetic cross talk between modules can differ substantially. C1 [Bandyopadhyay, Sourav; Ideker, Trey] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Bandyopadhyay, Sourav; Ideker, Trey] Univ Calif San Diego, Program Bioinformat, La Jolla, CA 92093 USA. [Zofall, Martin; Zhang, Ke; Fischer, Tamas; Grewal, Shiv I.] NCI, Biochem & Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Collins, Sean R.; Weissman, Jonathan S.] Howard Hughes Med Inst, San Francisco, CA 94158 USA. [Park, Han-Oh] Bioneer Corp, Taejon, South Korea. [Hayles, Jacqueline] London Res Inst, Canc Res UK, Cell Cycle Lab, London WC2A 3PX, England. [Hoe, Kwang-Lae; Kim, Dong-Uk] Korea Res Inst Biosci & Biotechnol, Genom Res Ctr, Taejon, South Korea. [Roguev, Assen; Collins, Sean R.; Qu, Hongjing; Shales, Michael; Weissman, Jonathan S.; Krogan, Nevan J.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Roguev, Assen; Collins, Sean R.; Qu, Hongjing; Shales, Michael; Weissman, Jonathan S.; Krogan, Nevan J.] Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA 94158 USA. RP Ideker, T (reprint author), Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. EM trey@bioeng.ucsd.edu; grewals@mail.nih.gov; weissman@cmp.ucsf.edu; krogan@cmpmail.ucsf.edu RI Fischer, Tamas/A-7729-2016; OI Fischer, Tamas/0000-0002-7996-4042; Collins, Sean/0000-0002-4276-5840 FU NIH [GM084279]; Sandler Family Foundation; Howard Hughes Medical Institute; National Cancer Institute; Center for Cancer Research; California Institute of Quantitative Biology FX We thank P. Beltrao and G. Cagney for critical reading of the manuscript; M. Wiren and S. Forsburg for discussion; P. Kemmeren for setting up the web database; S. Wang, C. Wen, and D. Avdic for technical help; and F. Stewart for sharing unpublished data. This work was supported by NIH [National Institute of General Medical Sciences grant GM084279 (T.I. and N.J.K.)], the Sandler Family Foundation (N. J. K), the Howard Hughes Medical Institute (J.S.W.), National Cancer Institute (S.I.G.), Center for Cancer Research (S.I.G.), and the California Institute of Quantitative Biology (N.J.K.). NR 39 TC 204 Z9 205 U1 0 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 17 PY 2008 VL 322 IS 5900 BP 405 EP 410 DI 10.1126/science.1162609 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 360YK UT WOS:000260094500037 PM 18818364 ER PT J AU Parry, CS AF Parry, Christian S. TI Flanking p10 contribution and sequence bias in matrix based epitope prediction: revisiting the assumption of independent binding pockets SO BMC STRUCTURAL BIOLOGY LA English DT Article ID COMPLEX-CLASS-II; T-CELL EPITOPE; HLA-DR; DEPENDENT INTERACTIONS; CUTTING EDGE; SIDE-CHAINS; PEPTIDE; MHC; ANTIGEN; IDENTIFICATION AB Background: Eluted natural peptides from major histocompatibility molecules show patterns of conserved residues. Crystallographic structures show that the bound peptide in class II major histocompatibility complex adopts a near uniform polyproline II-like conformation. This way allele-specific favoured residues are able to anchor into pockets in the binding groove leaving other peptide side chains exposed for recognition by T cells. The anchor residues form a motif. This sequence pattern can be used to screen large sequences for potential epitopes. Quantitative matrices extend the motif idea to include the contribution of non-anchor peptide residues. This report examines two new matrices that extend the binding register to incorporate the polymorphic p10 pocket of human leukocyte antigen DRI. Their performance is quantified against experimental binding measurements and against the canonical nine-residue register matrix. Results: One new matrix shows significant improvement over the base matrix; the other does not. The new matrices differ in the sequence of the peptide library. Conclusion: One of the extended quantitative matrices showed significant improvement in prediction over the original nine residue matrix and over the other extended matrix. Proline in the sequence of the peptide library of the better performing matrix presumably stabilizes the peptide conformation through neighbour interactions. Such interactions may influence epitope prediction in this test of quantitative matrices. This calls into question the assumption of the independent contribution of individual binding pockets. C1 NHLBI, NIH, Lab Computat Biol, Computat Biophys Sect, Bethesda, MD 20892 USA. RP Parry, CS (reprint author), NHLBI, NIH, Lab Computat Biol, Computat Biophys Sect, Bldg 10, Bethesda, MD 20892 USA. EM csparry@helix.nih.gov FU Intramural Research Program of the National Heart, Lung and Blood Institute; National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Heart, Lung and Blood Institute, National Institutes of Health. I am grateful to Dr. Bernard R. Brooks for his help and support. NR 42 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2237 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD OCT 16 PY 2008 VL 8 AR 44 DI 10.1186/1472-6807-8-44 PG 11 WC Biophysics SC Biophysics GA 384OC UT WOS:000261753100001 PM 18925947 ER PT J AU Ballano, G Zanuy, D Jimenez, AI Cativiela, C Nussinov, R Aleman, C AF Ballano, Gema Zanuy, David Jimenez, Ana I. Cativiela, Carlos Nussinov, Ruth Aleman, Carlos TI Structural Analysis of a beta-Helical Protein Motif Stabilized by Targeted Replacements with Conformationally Constrained Amino Acids SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID X-RAY-DIFFRACTION; BUILDING-BLOCKS; 1-AMINOCYCLOPENTANE-1-CARBOXYLIC ACID; C-ALPHA,ALPHA-DIALKYLATED GLYCINES; MOLECULAR-DYNAMICS; LINEAR OLIGOPEPTIDES; NANOSTRUCTURE DESIGN; SOLID-STATE; SIDE-CHAIN; CRYSTALLOGRAPHIC CHARACTERIZATION AB Here we study conformational stabilization induced in a beta-helical nanostructure by position-specific mutations. The nanostructure is constructed through the self-assembly of the beta-helical building block excised from E. coli galactoside acetyltransferase (PDB code 1krr, chain A; residues 131-165). The mutations involve substitutions by cyclic, conformationally constrained amino acids. Specifically, a complete structural analysis of the Pro-Xaa-Val sequence [with Xaa being Gly, Ac(3)c (1-aminocyclopropane-l-carboxylic acid) and Ac(5)c (1-aminocyclopentane-1-carboxylic acid)], corresponding to the 148-150 loop region in the wild-type (Gly) and mutated (Ac3c and Ac(5)c 1krr, has been performed using Molecular Dynamics simulations and X-ray crystallography. Simulations have been performed for the wild-type and mutants of three different systems, namely the building block, the nanoconstruct and the isolated Pro-Xaa-Val tripeptide. Furthermore, the crystalline structures of five peptides of Pro-Xaa-Val or Xaa-Val sequences have been solved by X-ray diffraction analysis and compared with theoretical predictions. Both the theoretical and crystallographic studies indicate that the Pro-Ac(n)c-Val sequences exhibit a high propensity to adopt turn-like conformations, and this propensity is little affected by the chemical environment. Overall, the results indicate that replacement of Gly149 by Ac(3)c or Ac(5)c significantly reduce the conformational flexibility of the target site enhancing the structural specificity of the building block and the nanoconstruct derived from the 1 krr beta-helical motif. C1 [Ballano, Gema; Jimenez, Ana I.; Cativiela, Carlos] Univ Zaragoza, Inst Ciencia Mat Aragon, Dept Quim Organ, CSIC, E-50009 Zaragoza, Spain. [Zanuy, David; Aleman, Carlos] Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, E-08028 Barcelona, Spain. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sch Med, Dept Human Genet Sackler, IL-69978 Tel Aviv, Israel. RP Jimenez, AI (reprint author), Univ Zaragoza, Inst Ciencia Mat Aragon, Dept Quim Organ, CSIC, E-50009 Zaragoza, Spain. EM anisjim@unizar.es; carlos.aleman@upc.edu RI Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 FU Gobierno de Aragon [E40]; Ministerio de Educacion y Ciencia-FEDER [CTQ2007-62245]; National Cancer Institute, National Institutes of Health [NOI-CO-12400] FX Gratitude is expressed to the Centre de Supercomputacio de Catalunya (CESCA) and to the Barcelona Supercomputing Center (BSC) for computational facilities. Financial support from the Gobierno de Aragon (research group E40) and Ministerio de Educacion y Ciencia-FEDER (Project CTQ2007-62245) is gratefully acknowledged. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number NOI-CO-12400. The content of this publication does not necessarily reflect the view of the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization 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 73 TC 14 Z9 14 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 16 PY 2008 VL 112 IS 41 BP 13101 EP 13115 DI 10.1021/jp8032116 PG 15 WC Chemistry, Physical SC Chemistry GA 358UO UT WOS:000259943200030 PM 18811190 ER PT J AU Itsko, M Zaritsky, A Rabinovitch, A AF Itsko, Mark Zaritsky, Arieh Rabinovitch, Avinoam TI Thermodynamics of Unstable DNA Structures from the Kinetics of the Microgene PCR SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID REPEAT EXPANSION; POLYMERIZATION; PROTEINS; SEQUENCE AB The microgene polymerization reaction (MPR) generates head-to-tail tandem repeats from homoduplexes (HDs). In MPR initiation, one HD putatively aligns two others in the proximity required to form a nucleation complex, thus allowing the DNA polymerase to skip the intertemplate gap and generate an initial doublet (ID) prone to repeat propagation. The current investigation refines this stage by additional thermodynamic considerations and elucidates the fundamental mechanism underlying propagation. Four different HD types were designed to extend the range of melting temperatures and to simultaneously modify the stabilities of their secondary structures. Following the propagation kinetics with these, using real-time PCR at different temperatures revealed a new stage in the MPR, amplification of an ID by an original HD, and enabled us to decipher the biphasic kinetics of the process. This amplification merges with the propagation stage if the lifetime of the staggered conformation of the ID is sufficiently long for DNA polymerase to fill in the overhangs. The observed increase with temperature of thermodynamically unfavorable conformations of singlet and doublet HDs that underlies, respectively, MPR initiation and propagation is well correlated with simulations by UNAFold. C1 [Itsko, Mark; Zaritsky, Arieh] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel. [Rabinovitch, Avinoam] Ben Gurion Univ Negev, Dept Phys, IL-84105 Beer Sheva, Israel. RP Itsko, M (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM ariehz@bgu.ac.il RI Zaritsky, Arieh/K-2578-2012 OI Zaritsky, Arieh/0000-0001-9333-6854 FU Ministry of Science, Jerusalem, Israel; United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel [2001-042, 2007037]; UNAFold simulations; RT-PCR; DNA Software Inc FX This investigation was partially supported by Eshkol Fellowship, Ministry of Science, Jerusalem, Israel, (to M.I.) and the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel (Grants # 2001-042 and 2007037 to A.Z.). Thanks are due to Michael Zuker and Idan Gabdank for assistance in UNAFold simulations, to Eitan BenDov for help in performing RT-PCR, and to DNA Software Inc. for providing a free 7 day trial license to Visual OMP, version 6.3. NR 15 TC 3 Z9 3 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 16 PY 2008 VL 112 IS 41 BP 13149 EP 13156 DI 10.1021/jp8045142 PG 8 WC Chemistry, Physical SC Chemistry GA 358UO UT WOS:000259943200035 PM 18795769 ER PT J AU McLellan, JS Zheng, XY Hauk, G Ghirlando, R Beachy, PA Leahy, DJ AF McLellan, Jason S. Zheng, Xiaoyan Hauk, Glenn Ghirlando, Rodolfo Beachy, Philip A. Leahy, Daniel J. TI The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla SO NATURE LA English DT Article ID SONIC HEDGEHOG; CANDIDATE GENE; PROTEIN; CDO; EXPRESSION; GAS1; ULTRACENTRIFUGATION; MUTATIONS; PATHWAY; COMPLEX AB Hedgehog ( Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration- dependent cellular differentiation or proliferation responses(1,2). Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer(3-7). Hh signalling is mediated by its amino- terminal domain ( HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle(8-10). Reception of the HhN signal is modulated by several cell- surface proteins on responding cells, including Patched ( Ptc), Smoothened ( Smo), Ihog ( known as CDO or CDON in mammals) and the vertebrate- specific proteins Hip ( also known as Hhip) and Gas1 ( ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III ( FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner(12,13). Surprisingly, pull- down experiments suggest that a mammalian Sonic hedgehog N- terminal domain ( ShhN) binds a non- orthologous FNIII repeat of CDO(12,14). Here we report biochemical, biophysical and X- ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN - CDO interaction is completely unlike the HhN - Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners. C1 [McLellan, Jason S.; Hauk, Glenn; Leahy, Daniel J.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Zheng, Xiaoyan; Beachy, Philip A.] Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA. [Beachy, Philip A.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Leahy, DJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. EM dleahy@jhmi.edu RI Ghirlando, Rodolfo/A-8880-2009; McLellan, Jason/A-6874-2010 FU Intramural Research Program of the NIH; National Institute of Diabetes and Digestive and Kidney Diseases; National Science Foundation Graduate Research Fellowship; Damon Runyon Cancer Research Foundation [DRG-1915-06]; [R01 HD055545] FX We thank R. Abramowitz and J. Schwanof of beamline X4C at the National Synchroton Light Source for assistance with X- ray data collection, C. W. Vander Kooi for suggesting ions may promote Shh - CDO interactions, W. Yang, J. Nathans, W.I. Weis, K.C. Garcia, P.A. Cole and L. M. Amzel for comments on the manuscript, and D. Chan and K. Cheah for communicating results before publication. We thank A. P. McMahon and C. M. Fan for the mouse Hip1 and mouse Gas1 - Fc complementary DNAs, respectively. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (R.G.). D.J.L. is supported by R01 HD055545 and P.A.B. is an HHMI investigator. J.S.M. is supported by a National Science Foundation Graduate Research Fellowship. X.Z. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-1915-06). NR 38 TC 78 Z9 80 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 16 PY 2008 VL 455 IS 7215 BP 979 EP U62 DI 10.1038/nature07358 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 360DW UT WOS:000260038300053 PM 18794898 ER PT J AU Burioni, R Mancini, N De Marco, D Clementi, N Perotti, M Nitti, G Sassi, M Canducci, F Shvela, K Bagnarelli, P Mascola, JR Clementi, M AF Burioni, Roberto Mancini, Nicasio De Marco, Donata Clementi, Nicola Perotti, Mario Nitti, Giovanni Sassi, Monica Canducci, Filippo Shvela, Krisha Bagnarelli, Patrizia Mascola, John R. Clementi, Massimo TI Anti-HIV-1 Response Elicited in Rabbits by Anti-Idiotype Monoclonal Antibodies Mimicking the CD4-Binding Site SO PLOS ONE LA English DT Article AB Antibodies against conserved epitopes on HIV-1 envelope glycoproteins (Env), such as the gp120 CD4-binding site (CD4bs), could contribute to protection against HIV-1. Env-based immunogens inducing such a response could be a major component of future anti-HIV-1 strategies. In this proof-of-concept study we describe the generation of two anti-idiotype (AI) murine antibodies mimicking the CD4bs epitope. Sera were collected from long-term non-progressor patients to obtain CD4bs-directed IgG, through sequential purification steps. The purified IgG were then used as Fab fragments to immunize mice for hybridoma generation. Two hybridomas (P1 and P2), reacting only against the CD4bs-directed IgG, were identified and characterized. The P1 and P2 antibodies were shown to recognize the idiotype of the broadly neutralizing anti-CD4bs human mAb b12. Both P1 and P2 Fabs were able to induce a strong anti-gp120 response in rabbits. Moreover, the rabbits' sera were shown to neutralize two sensitive tier 1 strains of HIV-1 in an Env-pseudotype neutralization assay. In particular, 3/5 rabbits in the P1 group and 1/5 in the P2 group showed greater than 80% neutralizing activity against the HXB2 pseudovirus. Two rabbits also neutralized the pseudovirus HIV-MN. Overall, these data describe the first anti-idiotypic vaccine approach performed to generate antibodies to the CD4bs of the HIV-1 gp120. Although future studies will be necessary to improve strength and breadth of the elicited neutralizing response, this proof-of-concept study documents that immunogens designed on the idiotype of broadly neutralizing Abs are feasible and could help in the design of future anti-HIV strategies. C1 [Burioni, Roberto; Mancini, Nicasio; De Marco, Donata; Clementi, Nicola; Perotti, Mario; Nitti, Giovanni; Sassi, Monica; Canducci, Filippo; Clementi, Massimo] Univ Vita Salute San Raffaele, Ist Sci San Raffaele Diagnost & Ric San Raf, Lab Microbiol & Virol, Milan, Italy. [Shvela, Krisha; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD USA. [Bagnarelli, Patrizia] Univ Politecn Marche, Lab Viro, Ancona, Italy. RP Burioni, R (reprint author), Univ Vita Salute San Raffaele, Ist Sci San Raffaele Diagnost & Ric San Raf, Lab Microbiol & Virol, Milan, Italy. EM burioni.roberto@hsr.it RI Burioni, Roberto /F-2396-2012; Clementi, Massimo/F-6646-2013; Clementi, Nicola/G-8545-2014; OI Clementi, Nicola/0000-0002-1822-9861; Clementi, Massimo/0000-0002-7461-5898; MANCINI, Nicasio/0000-0003-0637-0910; Canducci, Filippo/0000-0002-5637-6205 FU Intramural Research Program of the Vaccine Research Center, NIAID, NI FX This research was supported, in part, by the Intramural Research Program of the Vaccine Research Center, NIAID, NI to J.R.M.. NR 41 TC 16 Z9 16 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 16 PY 2008 VL 3 IS 10 AR e3423 DI 10.1371/journal.pone.0003423 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432GT UT WOS:000265122200004 PM 18923648 ER PT J AU Isik, N Hereld, D Jin, T AF Isik, Nilgun Hereld, Dale Jin, Tian TI Fluorescence Resonance Energy Transfer Imaging Reveals that Chemokine-Binding Modulates Heterodimers of CXCR4 and CCR5 Receptors SO PLOS ONE LA English DT Article AB Background: Dimerization has emerged as an important feature of chemokine G-protein-coupled receptors. CXCR4 and CCR5 regulate leukocyte chemotaxis and also serve as a co-receptor for HIV entry. Both receptors are recruited to the immunological synapse during T-cell activation. However, it is not clear whether they form heterodimers and whether ligand binding modulates the dimer formation. Methodology/Principal Findings: Using a sensitive Fluorescence Resonance Energy Transfer (FRET) imaging method, we investigated the formation of CCR5 and CXCR4 heterodimers on the plasma membrane of live cells. We found that CCR5 and CXCR4 exist as constitutive heterodimers and ligands of CCR5 and CXCR4 promote different conformational changes within these preexisting heterodimers. Ligands of CCR5, in contrast to a ligand of CXCR4, induced a clear increase in FRET efficiency, indicating that selective ligands promote and stabilize a distinct conformation of the heterodimers. We also found that mutations at C-terminus of CCR5 reduced its ability to form heterodimers with CXCR4. In addition, ligands induce different conformational transitions of heterodimers of CXCR4 and CCR5 or CCR5(STA) and CCR5(Delta 4). Conclusions/Significance: Taken together, our data suggest a model in which CXCR4 and CCR5 spontaneously form heterodimers and ligand-binding to CXCR4 or CCR5 causes different conformational changes affecting heterodimerization, indicating the complexity of regulation of dimerization/function of these chemokine receptors by ligand binding. C1 [Isik, Nilgun; Hereld, Dale; Jin, Tian] NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil 2, Rockville, MD USA. RP Isik, N (reprint author), NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil 2, Rockville, MD USA. EM tjin@niaid.nih.gov FU IATAP program from NIH FX The study was supported by IATAP program from NIH. NR 27 TC 32 Z9 33 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 16 PY 2008 VL 3 IS 10 AR e3424 DI 10.1371/journal.pone.0003424 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432GT UT WOS:000265122200005 PM 18923649 ER PT J AU Domanski, M Tian, X Fleg, J Coady, S Gosen, C Kirby, R Sachdev, V Knatterud, G Braunwald, E AF Domanski, Michael Tian, Xin Fleg, Jerome Coady, Sean Gosen, Christine Kirby, Ruth Sachdev, Vandana Knatterud, Genell Braunwald, Eugene TI Pleiotropic Effect of Lovastatin, With and Without Cholestyramine, in the Post Coronary Artery Bypass Graft (Post CABG) Trial SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID IMPROVES ENDOTHELIAL FUNCTION; RANDOMIZED CONTROLLED-TRIAL; LOW-DENSITY-LIPOPROTEIN; STATIN THERAPY; HYPERCHOLESTEROLEMIC PATIENTS; MYOCARDIAL-INFARCTION; CHOLESTEROL LEVELS; HEART-FAILURE; SERUM-LEVELS; PRAVASTATIN AB This study evaluated patients in the Post Coronary Artery Bypass Graft (Post CABG) trial for evidence of statin pleiotropic effects in preventing atherosclerotic progression in saphenous vein grafts (SVGs). We studied 1,116 of the 1,351 patients in the Post CABG trial who were randomized to aggressive (low-density lipoprotein [LDL] cholesterol target <85 mg/dl) or moderate (target LDL cholesterol < 140 mg/dl) lovastatin treatment and who had sufficient data available. The generalized estimating equation models, adjusting for important covariates, were applied to estimate the odds ratios (ORs) and probability of substantial atherosclerotic SVG progression (decrease in lumen diameter >= 0.6 mm) and the difference in minimum lumen diameter change between treatment groups. Aggressive lovastatin treatment compared with moderate treatment was associated with a significant decrease in risk of significant SVG atherosclerotic progression after adjustment for baseline cholesterol level, LDL cholesterol on treatment, high-density. lipoprotein cholesterol, and triglyceride changes on treatment and other independent predictors (OR 0.68, 95% confidence interval 0.49 to 0.94, p = 0.019). Results were similar when the change or percent change from baseline of LDL cholesterol level on treatment was adjusted for rather than on-treatment LDL cholesterol and in the subset achieving a year-1 LDL cholesterol level from 90 to 135 mg/dl (OR 0.64, 95% confidence interval 0.42 to 0.98, p = 0.042). Mean decrease in minimum lumen diameter was also significantly smaller in the aggressive than the moderate treatment arm (-0.256 vs -0.343 mm, p = 0.042). In conclusion, aggressive versus moderate lovastatin treatment appeared therapeutic in slowing the atherosclerotic process in SVGs from Post CABG patients, independent of its greater LDL cholesterol-lowering effect. (C) 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:1023-1027) C1 [Domanski, Michael; Fleg, Jerome; Gosen, Christine; Kirby, Ruth] NHLBI, Atherothrombosis & Coronary Artery Dis Branch, Bethesda, MD 20892 USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Coady, Sean] NHLBI, Program Epidemiol, Bethesda, MD 20892 USA. [Sachdev, Vandana] NHLBI, Cardiovasc Dis Branch, Bethesda, MD 20892 USA. [Knatterud, Genell] Maryland Med Res Inst, Baltimore, MD USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. RP Domanski, M (reprint author), NHLBI, Atherothrombosis & Coronary Artery Dis Branch, Bldg 10, Bethesda, MD 20892 USA. EM domanskm@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, Bethesda, Maryland; Merck & Company, West Point, Pennsylvania FX The Post Coronary Artery Bypass Graft Trial (Post CABG) was supported by research contracts with the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and Merck & Company, West Point, Pennsylvania. NR 30 TC 13 Z9 15 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD OCT 15 PY 2008 VL 102 IS 8 BP 1023 EP 1027 DI 10.1016/j.amjcard.2008.05.053 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 360YN UT WOS:000260094800011 PM 18929703 ER PT J AU Zhang, J Sundaram, R Sun, WY Troendle, J AF Zhang, Jun Sundaram, Rajeshwari Sun, Wenyu Troendle, James TI Fetal Growth and Timing of Parturition in Humans SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE fetal development; labor; obstetric; parturition; pregnancy ID PRETERM DELIVERY; RESTRICTION; ENDOCRINOLOGY; INFANTS; WEIGHT AB Animal studies indicate that either the fetus or the intrauterine environment, both of which set the pattern for fetal growth, may affect the timing of parturition. The authors examined the association between fetal growth and timing of spontaneous onset of labor in humans among low-risk white US women with singleton pregnancies (1987-1991). They restricted the data to pregnancies which had a reliable date of the last menstrual period, normal fetal growth in the first half of pregnancy, and no history of or current pregnancy complications that might have impaired fetal growth (n = 3,360). Subjects received ultrasound examinations at 15-22 and 31-35 weeks' gestation. Fetal growth was adjusted for parity, fetal sex, and maternal prepregnancy weight and height. Results showed that slower or faster fetal growth in the second half of pregnancy resulted in substantially lower or higher birth weight, respectively. However, fetal growth in the second half of pregnancy, even at extremes (2 standard deviations below or above the mean), did not have a meaningful impact on the timing of parturition; neither did fetal growth acceleration or deceleration in late pregnancy. Thus, in low-risk pregnancies where fetal growth is normal in early gestation, fetal growth in the second half of pregnancy does not affect the timing of normal parturition. C1 [Zhang, Jun; Sundaram, Rajeshwari; Sun, Wenyu; Troendle, James] NIH, Div Epidemiol Stat & Prevent Res, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Zhang, J (reprint author), NICHHD, Epidemiol Branch, NIH Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. EM zhangj@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was supported by the Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 20 TC 7 Z9 7 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2008 VL 168 IS 8 BP 946 EP 951 DI 10.1093/aje/kwn203 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 359DF UT WOS:000259965800013 PM 18775925 ER PT J AU Hjuler, T Poulsen, G Wohlfahrt, J Kaltoft, M Biggar, RJ Melbye, M AF Hjuler, Thomas Poulsen, Gry Wohlfahrt, Jan Kaltoft, Margit Biggar, Robert J. Melbye, Mads TI RE: "AGE AT RETIREMENT AND MORTALITY IN A GENERAL POPULATION SAMPLE: THE GREEK EPIC STUDY" REPLY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID INVASIVE-PNEUMOCOCCAL-DISEASE; INFECTION; CHILDREN; SUSCEPTIBILITY; ALLELES; RISK C1 [Hjuler, Thomas; Poulsen, Gry; Wohlfahrt, Jan; Biggar, Robert J.; Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. [Kaltoft, Margit] Statens Serum Inst, Dept Bacteriol Mycol & Parasitol, DK-2300 Copenhagen, Denmark. [Biggar, Robert J.] NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Hjuler, T (reprint author), Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark. EM tta@ssi.dk NR 9 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2008 VL 168 IS 8 BP 976 EP 976 DI 10.1093/aje/kwn226 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 359DF UT WOS:000259965800019 ER PT J AU Pangilinan, F Geiler, K Dolle, J Troendle, J Swanson, DA Molloy, AM Sutton, M Conley, M Kirke, PN Scott, JM Mills, JL Brody, LC AF Pangilinan, Faith Geiler, Kerry Dolle, Jessica Troendle, James Swanson, Deborah A. Molloy, Anne M. Sutton, Marie Conley, Mary Kirke, Peadar N. Scott, John M. Mills, James L. Brody, Lawrence C. TI Construction of a High Resolution Linkage ZIP Disequilibrium Map to Evaluate Common Genetic Variation in TP53 and Neural Tube Defect Risk in an Irish Population SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE neural tube defects; spina bifida; p53; TP53; MDM2; linkage disequilibrium ID TUMOR-SUPPRESSOR GENE; BREAST-CANCER; P53 POLYMORPHISMS; LUNG-CANCER; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; HAPLOTYPE RECONSTRUCTION; COLORECTAL-CANCER; OVARIAN-CANCER; BIRTH-DEFECTS; OBESE WOMEN AB Genetic and environmental factors contribute to the etiology Of neural tube defects (NTDs). While periconceptional folic acid supplementation is known to significantly reduce the risk of NTDs, folate metabolic pathway related factors do not account for all NTDs. Evidence from mouse models indicates that the tumor protein p53 (TP53) is involved in implantation and normal neural tube development. To determine whether genetic variation in TP53 might contribute to NTD risk in humans, We Constructed a high resolution linkage disequilibrium (LID) map of the TP53 genomic region based on genotyping 21 markers in an Irish population. We found that nine of these variants can be Used to capture the majority of common variation in the TP53 genomic region. In contrast, the 3-marker haplotype commonly reported in the TP53 literature offers limited coverage of the variation in the gene. We used the expanded set of polymorphisms to measure the influence of TP53 on NTDs using both case-control and family based tests of association. We also assayed a functional variant in the p53 regulator MDM2 (rs2279744). Alleles of three noncoding TP53 markers were associated with NTD risk. A case effect was seen with the GG genotype of rs1625895 in intron 6 (OR=1.37 [1.04-1.791, P=0.02). A maternal effect was seen with the 135/135 genotype of the intron 1 VNTR (OR = 1.86 [1.16-2.961, P = 0.01) and the TT genotype of rs1614984 (RR=0.58 [0-37-0-911, P=0.02). As Multiple comparisons were made, these cannot be considered definitive positive findings and additional investigation is required. published 2008 Wiley-Liss, Inc.(dagger) C1 [Pangilinan, Faith; Geiler, Kerry; Dolle, Jessica; Swanson, Deborah A.; Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. [Troendle, James; Conley, Mary; Mills, James L.] NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Molloy, Anne M.] Univ Dublin Trinity Coll, Dept Clin Med, Dublin 2, Ireland. [Sutton, Marie; Kirke, Peadar N.] Hlth Res Board, Child Hlth Epidemiol Unit, Dublin, Ireland. [Scott, John M.] Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. RP Brody, LC (reprint author), NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bldg 50,Room 5306,50 S Dr,MSC 8004, Bethesda, MD 20892 USA. EM lbrody@helix.nih.gov FU National Human Genome Research Institute; National Institute of Child Health and Human Development; Health Research Board, Ireland; National Institute of General Medical Sciences; National Institutes of Health FX These Studies Would not be possible Without the participation of the affected families, and their recruitment by the Irish Association of Spina Bifida and Hydrocephalus and the Irish Public Health Nurses. The authors acknowledge research Support from the intramural research programs of the National Human Genome Research Institute, the National Institute of Child Health and Human Development and the Health Research Board, Ireland. FP was supported by a Pharmacology Research Associate Fellowship from the National Institute of General Medical Sciences, National Institutes of Health. NR 54 TC 12 Z9 13 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 15 PY 2008 VL 146A IS 20 BP 2617 EP 2625 DI 10.1002/ajmg.a.32504 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 361IZ UT WOS:000260122600006 PM 18798306 ER PT J AU Gucev, ZS Tasic, V Jancevska, A Konstantinova, MK Pop-Jordanova, N Trajkovski, Z Biesecker, LG AF Gucev, Zoran S. Tasic, Velibor Jancevska, Aleksandra Konstantinova, Marina Krstevska Pop-Jordanova, Nada Trajkovski, Zoran Biesecker, Leslie G. TI Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi (CLOVE) Syndrome: CNS Malformations and Seizures may be a Component of This Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article ID PROTEUS-SYNDROME; ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS; DIAGNOSTIC-CRITERIA; MANIFESTATIONS AB A newborn girl was found to have a massive lymphatic truncal vascular malformation with overlying cutaneous venous anomaly associated with overgrown feet and splayed toes. These manifestations comprise the recently described CLOVE syndrome. She also had cranial asymmetry and developed generalized seizures, which were treated with anticonvulsants. Granial CT showed encephalomalacia, widening of the ventricles and the sulci, hemimegalencephaly (predominantly white matter) and partial agenesis of corpus callosum. Review of the literature identified several other patients with CLOVE syndrome, some of whom were misdiagnosed as having Proteus syndrome, with strikingly similar manifestations. We conclude that CNS manifestations including hemimegalencephaly, dysgenesis of the corpus callosum, neuronal migration defects, and the consequent seizures, may be an rarely recognized manifestation of CLOVE syndrome. (C) 2008 Wiley-Liss, Inc. C1 [Gucev, Zoran S.; Tasic, Velibor; Jancevska, Aleksandra; Konstantinova, Marina Krstevska; Pop-Jordanova, Nada; Trajkovski, Zoran] Univ Skopje, Skopje 1000, Macedonia. [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Gucev, ZS (reprint author), Univ Skopje, 50 Divizija BB, Skopje 1000, Macedonia. EM gucevz@gmail.com FU Intramural NIH HHS [Z01 HG200328-04] NR 11 TC 27 Z9 27 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 15 PY 2008 VL 146A IS 20 BP 2688 EP 2690 DI 10.1002/ajmg.a.32515 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 361IZ UT WOS:000260122600016 PM 18816642 ER PT J AU Liu, X Palma, J Kinders, R Shi, Y Donawho, C Ellis, PA Rodriguez, LE Colon-Lopez, M Saltarelli, M LeBlond, D Lin, CT Frost, DJ Luo, Y Giranda, VL AF Liu, Xuesong Palma, Joann Kinders, Robert Shi, Yan Donawho, Cherrie Ellis, Paul A. Rodriguez, Luis E. Colon-Lopez, Milagros Saltarelli, Mary LeBlond, David Lin, C. Thomas Frost, David J. Luo, Yan Giranda, Vincent L. TI An enzyme-linked immunosorbent poly(ADP-ribose) polymerase biomarker assay for clinical trials of PARP inhibitors SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE PAR; ELISA; ABT-888 ID SYNTHESIZED IN-VITRO; DNA-REPAIR; BLOT METHOD; CANCER; CELLS; ANGIOGENESIS; VIVO; GLYCOHYDROLASE; RIBOSYLATION; ACTIVATION AB Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. The DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA damage and has Critical roles in DNA repair. Inhibition of PARP potentiates the activity of DNA-damaging agents such as temozolomide, topoisomerase inhibitors and radiation in both in vitro and in vivo preclinical models. Recently, several PARP inhibitors have entered Clinical trials either as single agents or in combination with DNA-damaging chemotherapy. Because PARP inhibitors are not cytotoxic, a biomarker assay is useful to guide the selection of an optimal biological dose. We set out to develop an assay that enables LIS to detect 50% PAR reduction in human tumors with 80% power in a single-plate assay while assuring no more than a 10% false-positive rate. We have developed and optimized an enzyme-linked immunosorbent assay (ELISA) to measure PARP activity that meets the above-mentioned criterion. This robust assay is able to detect PAR levels of 30-2000 pg/ml in both tumor and peripheral blood monocyte samples. In a B16F10 mouse syngeneic tumor model, PARP inhibitor ABT-888 potentiates the effect of temozolomide in suppressing tumor growth, and PARP activity is greatly reduced by ABT-888 at efficacious doses. In summary, the ELISA assay described here is suitable for biomarker studies in clinical trials of PARP inhibitors. (C) 2008 Elsevier Inc. All rights reserved. C1 [Liu, Xuesong; Palma, Joann; Shi, Yan; Donawho, Cherrie; Ellis, Paul A.; Rodriguez, Luis E.; Colon-Lopez, Milagros; Saltarelli, Mary; LeBlond, David; Lin, C. Thomas; Frost, David J.; Luo, Yan; Giranda, Vincent L.] Abbott Labs, GPRD, Abbott Pk, IL 60064 USA. [Kinders, Robert] NCI Frederick, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Liu, X (reprint author), Abbott Labs, GPRD, 100 Abbott Pk Rd, Abbott Pk, IL 60064 USA. EM xuesong.liu@abbott.com; Vincent.giranda@abbott.com NR 29 TC 23 Z9 23 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 15 PY 2008 VL 381 IS 2 BP 240 EP 247 DI 10.1016/j.ab.2008.07.007 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 346VT UT WOS:000259098400009 PM 18674509 ER PT J AU Fernandez, C Minton, AP AF Fernandez, Cristina Minton, Allen P. TI Automated measurement of the static light scattering of macromolecular solutions over a broad range of concentrations SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Rayleigh scattering; nonideal solutions; concentrated protein solutions; bovine serum albumin; ovalbumin; ovomucoid ID HARD PARTICLE MODEL; SELF-ASSOCIATING PROTEINS; BOVINE SERUM-ALBUMIN; QUANTITATIVE CHARACTERIZATION; OSMOTIC-PRESSURE; CONSEQUENCES; CHALLENGES; BEHAVIOR AB A method and apparatus for automated measurement of the concentration dependence of static light scattering Of Protein solutions over a broad range of concentrations is described. The gradient of protein concentrations is created by successive dilutions of an initially concentrated solution contained within the scattering measurement cell, which is maintained at constant total volume. The method is validated by measurement of the concentration dependence of light scattering of bovine serum albumin, ovalbumin, and ovomucoid at concentrations up to 130 g/L. The experimentally obtained concentration dependence of scattering obtained from all three proteins is quantitatively consistent with the assumption that no significant self-association occurs over the measured range of concentrations. Published by Elsevier Inc. C1 [Fernandez, Cristina; Minton, Allen P.] NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bldg 8,Room 226, Bethesda, MD 20892 USA. EM minton@helix.nih.gov RI Fernandez, Cristina/G-2269-2015; OI Fernandez, Cristina/0000-0003-3792-4015; Minton, Allen/0000-0001-8459-1247 FU National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Peter McPhie (National Institutes of Health) for helpful comments on a draft. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 24 TC 19 Z9 20 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 15 PY 2008 VL 381 IS 2 BP 254 EP 257 DI 10.1016/j.ab.2008.06.032 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 346VT UT WOS:000259098400011 PM 18627764 ER PT J AU Rosales, T Royer, CA AF Rosales, Tilman Royer, Catherine A. TI A graphical user interface for BIOEQS: A program for simulating and analyzing complex biomolecular interactions SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material AB BIOEQS is a global analysis and simulation program for complex biomolecular interaction data developed during the 1990s. Its continued usefulness derives from the fact that it is based on a numerical solver for complex Coupled biological equilibria rather than on closed-form analytical equations for the binding isotherms. Therefore, it is quite versatile, allowing easy testing of multiple binding models and analysis of systems too complex for closed-form solutions. However, a major drawback to a generalized use of this program has been the lack of a graphical user interface (GUI) for setting up the binding models and experimental conditions as well as for visualizing the results. We present here a new GUI for BIOEQS that should be useful in both research and teaching applications. (C) 2008 Elsevier Inc. All rights reserved. C1 [Royer, Catherine A.] Univ Montpellier 1, CNRS UMR5048, U554, INSERM, F-34090 Montpellier, France. [Rosales, Tilman] NHLBI, Lab Mol Biophys, Opt Spect Sect, NIH, Bethesda, MD 20892 USA. RP Royer, CA (reprint author), Univ Montpellier 1, CNRS UMR5048, U554, INSERM, F-34090 Montpellier, France. EM catherine.royer@cbs.cnrs.fr RI Royer, Catherine/E-5266-2016 OI Royer, Catherine/0000-0002-2670-3391 FU Intramural NIH HHS [Z99 HL999999] NR 2 TC 6 Z9 6 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 15 PY 2008 VL 381 IS 2 BP 270 EP 272 DI 10.1016/j.ab.2008.05.056 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 346VT UT WOS:000259098400014 PM 18644343 ER PT J AU Needham, PG Masison, DC AF Needham, Patrick G. Masison, Daniel C. TI Prion-impairing mutations in Hsp70 chaperone Ssa1: Effects on ATPase and chaperone activities SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Hsp70; prion; yeast; chaperone; [PSI+] ID NUCLEOTIDE EXCHANGE FACTOR; EUKARYOTIC DNAJ HOMOLOG; SACCHAROMYCES-CEREVISIAE; MOLECULAR CHAPERONES; SUBSTRATE-BINDING; INTERDOMAIN COMMUNICATION; STRUCTURAL-ANALYSIS; YEAST PRIONS; PSI+ PRION; HSP40 SIS1 AB We previously described many Hsp70 Ssa1p mutants that impair [PSI+] prion propagation in yeast without affecting cell growth. To determine how the mutations alter Hsp70 we analyzed biochemically the substrate-binding domain (SBD) mutant L483W and the nucleotide-binding domain (NBD) mutants A17V and R34K. SSa1(L483W) ATPase activity was elevated 10-fold and was least stimulated by substrates or Hsp40 co-chaperones. Ssa1(A17V) and Ssa1(R34K) ATPase activities were nearly wild type but both showed increased stimulation by substrates. Peptide binding and reactivation of denatured luciferase were enhanced in Ssa1(A17V) and Ssa1(R34K) but compromised in SSa1(L483W). The nucleotide exchange factor Fes1 influenced ATPase of wild type Ssa1 and each mutant differently. Partial protease digestion uncovered similar and distinct conformational changes of the substrate-binding domain among the three mutants. Our data suggest that prion-impairing Mutations of Ssa1 can increase or decrease substrate interactions, alter the Hsp70 reaction cycle at different points and impair normal NBD-SBD cooperation. Published by Elsevier Inc. C1 [Needham, Patrick G.; Masison, Daniel C.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 407, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov FU NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 70 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD OCT 15 PY 2008 VL 478 IS 2 BP 167 EP 174 DI 10.1016/j.abb.2008.07.023 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 359WK UT WOS:000260018700007 PM 18706386 ER PT J AU Aletaha, D Landewe, R Karonitsch, T Bathon, J Boers, M Bombardier, C Bombardieri, S Choi, H Combe, B Dougados, M Emery, P Gomez-Reino, J Keystone, E Koch, G Kvien, TK Martin-Mola, E Matucci-Cerinic, M Michaud, K O'Dell, J Paulus, H Pincus, T Richards, P Simon, L Siegel, J Smolen, JS Sokka, T Strand, V Tugwell, P van der Heijde, D van Riel, P Vlad, S van Vollenhoven, R Ward, M Weinblatt, M Wells, G White, B Wolfe, F Zhang, B Zink, A Felson, D AF Aletaha, D. Landewe, R. Karonitsch, T. Bathon, J. Boers, M. Bombardier, C. Bombardieri, S. Choi, H. Combe, B. Dougados, M. Emery, P. Gomez-Reino, J. Keystone, E. Koch, G. Kvien, T. K. Martin-Mola, E. Matucci-Cerinic, M. Michaud, K. O'Dell, J. Paulus, H. Pincus, T. Richards, P. Simon, L. Siegel, J. Smolen, J. S. Sokka, T. Strand, V. Tugwell, P. van der Heijde, D. van Riel, P. Vlad, S. van Vollenhoven, R. Ward, M. Weinblatt, M. Wells, G. White, B. Wolfe, F. Zhang, B. Zink, A. Felson, D. TI Reporting Disease Activity in Clinical Trials of Patients With Rheumatoid Arthritis: EULAR/ACR Collaborative Recommendations SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID ACTIVITY SCORE; FUNCTIONAL-CAPACITY; IMPROVEMENT AB Objective. To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods. The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). Results. Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. Conclusion. These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses. C1 [Aletaha, D.] Med Univ Vienna, Div Rheumatol, A-1090 Vienna, Austria. [Landewe, R.] Univ Hosp Maastricht, Maastricht, Netherlands. [Bathon, J.] Johns Hopkins Univ, Baltimore, MD USA. [Boers, M.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Bombardier, C.] Inst Work & Hlth, Toronto, ON, Canada. [Bombardieri, S.] Univ Pisa, Pisa, Italy. [Choi, H.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Combe, B.] CHU Montpellier, Montpellier, France. [Dougados, M.] Paris Descartes Univ, Paris, France. [Emery, P.] Univ Leeds, Leeds, W Yorkshire, England. [Gomez-Reino, J.] Univ Santiago de Compostela, Sch Med, Santiago, Spain. [Keystone, E.] Univ Toronto, Toronto, ON, Canada. [Koch, G.] Univ N Carolina, Chapel Hill, NC USA. [Kvien, T. K.] Diakonhjemmet Hosp, Oslo, Norway. [Martin-Mola, E.] Hosp Univ La Paz, Madrid, Spain. [Matucci-Cerinic, M.] Univ Florence, Florence, Italy. [Michaud, K.; O'Dell, J.] Univ Nebraska, Omaha, NE 68182 USA. [Paulus, H.] Univ Calif Los Angeles, Los Angeles, CA USA. [Pincus, T.] NYU, Hosp Joint Dis, New York, NY USA. [Richards, P.] Univ Bristol, Bristol, Avon, England. [Simon, L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Siegel, J.] US FDA, Rockville, MD 20857 USA. [Smolen, J. S.] Med Univ Vienna, Vienna, Austria. [Smolen, J. S.] Hietzing Hosp, Vienna, Austria. [Sokka, T.] Jyvaskyla Cent Hosp, Jyvaskyla, Finland. [Strand, V.] Stanford Univ, Portola Valley, CA USA. [Tugwell, P.] Inst Populat Hlth, Ottawa, ON, Canada. [van der Heijde, D.] Leiden Univ, Med Ctr, Leiden, Netherlands. [van Riel, P.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Vlad, S.; Zhang, B.; Felson, D.] Boston Univ, Sch Med, Boston, MA 02118 USA. [van Vollenhoven, R.] Karolinska Univ Hosp, Stockholm, Sweden. [Ward, M.] NIH, Bethesda, MD 20892 USA. [Weinblatt, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wells, G.] Univ Ottawa, Ottawa, ON, Canada. [White, B.] Medimmune Inc, Gaithersburg, MD 20878 USA. [Wolfe, F.] Natl Data Bank Rheumat Dis, Wichita, KS USA. [Zink, A.] Charite Univ Med Berlin, Berlin, Germany. RP Aletaha, D (reprint author), Med Univ Vienna, Div Rheumatol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM daniel.aletaha@meduniwien.ac.at RI Riel, P.L.C.M./H-8082-2014; OI Felson, David/0000-0002-2668-2447; Tugwell, Peter/0000-0001-5062-0556 FU Arthritis Research UK [18475] NR 19 TC 90 Z9 95 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD OCT 15 PY 2008 VL 59 IS 10 BP 1371 EP 1377 DI 10.1002/art.24123 PG 7 WC Rheumatology SC Rheumatology GA 362RN UT WOS:000260214900002 PM 18821648 ER PT J AU Scofield, L Reinlib, L Alarcon, GS Cooper, GS AF Scofield, Lacie Reinlib, Leslie Alarcon, Graciela S. Cooper, Glinda S. TI Employment and Disability Issues in Systemic Lupus Erythematosus: A Review SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID SOCIAL-SECURITY DISABILITY; WORK DISABILITY; INDIRECT COSTS; RELIABILITY; DISEASE AB Objective. To summarize research pertaining to work disability in lupus patients, discuss challenges patients face applying for federal disability assistance in the US, and make recommendations for clinical and health policy research. Methods. We searched Medline for articles on work or disability in lupus patients and gathered information from the Social Security Administration and the National Organization of Social Security Claimants' Representatives. Results. We found 12 publications with employment-related data; 6 included analysis of predictors of work status. The prevalence of inability to work or cessation of work was 15-51% in these studies (3-15 years after diagnosis); 20-32% of patients received disability benefits. Lower education level, higher disease activity, higher disease damage, older age, and higher physical job strain were independent predictors of work disability or work cessation in at least 2 studies. Lupus patients may be less successful than patients with other diseases when applying for federal disability assistance, possibly because medical records may not accurately reflect functional limitations. In addition, symptoms contributing to work disability (e.g., fatigue, pain, neurocognitive dysfunction) may be difficult to assess and quantify. Conclusion. Work disability in lupus patients is common. Additional research on risk factors for work disability in lupus patients and on strategies for reducing the impact of these factors on work-related activities is needed. The development of better measures and rating scales for the symptoms responsible for work disability in lupus patients and studies of factors influencing the success of obtaining federal disability benefits would also be useful. C1 [Scofield, Lacie; Reinlib, Leslie; Cooper, Glinda S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Scofield, Lacie] US Dept HHS, Off Womens Hlth, Washington, DC 20201 USA. [Alarcon, Graciela S.] Univ Alabama, Birmingham, AL USA. [Cooper, Glinda S.] US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. RP Cooper, GS (reprint author), US EPA, Natl Ctr Environm Assessment 8601P, 1200 Penn Ave NW, Washington, DC 20460 USA. EM cooper.glinda@epa.gov NR 26 TC 24 Z9 24 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD OCT 15 PY 2008 VL 59 IS 10 BP 1475 EP 1479 DI 10.1002/art.24113 PG 5 WC Rheumatology SC Rheumatology GA 362RN UT WOS:000260214900016 PM 18821664 ER PT J AU Roh, EJ Keller, JM Olah, Z Iadarola, MJ Jacobson, KA AF Roh, Eun Joo Keller, Jason M. Olah, Zoltan Iadarola, Michael J. Jacobson, Kenneth A. TI Structure-activity relationships of 1,4-dihydropyridines that act as enhancers of the vanilloid receptor 1 (TRPV1) SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE ion channel; pain; receptor; capsaicin; dorsal root ganglion ID ADENOSINE RECEPTOR ANTAGONISTS; ROOT GANGLION NEURONS; VANILLOID RECEPTOR; DIRECT PHOSPHORYLATION; 3,5-DIACYL-2,4-DIALKYLPYRIDINE DERIVATIVES; PLASMA-MEMBRANE; SENSORY NEURONS; CAPSAICIN; PAIN; HYPERALGESIA AB Vanilloid agonists such as capsaicin activate ion flux through the TRPV1 channel, a heat- and ligand-gated cation channel that transduces painful chemical or thermal stimuli applied to peripheral nerve endings in skin or deep tissues. We have probed the SAR of a variety of 1,4-dihydropyridine (DHP) derivatives as novel 'enhancers' of TRPV1 activity by examining changes in capsaicin-induced elevations in (45)Ca(2+)-uptake in either cells ectopically expressing TRPV1 or in cultured dorsal root ganglion (DRG) neurons. The enhancers increased the maximal capsaicin effect on (45)Ca(2+)-uptake by typically 2- to 3-fold without producing an action when used alone. The DHP enhancers contained 6-aryl substitution and small alkyl groups at the 1 and 4 positions, and a 3-phenylalkylthioester was tolerated. Levels of free intracellular Ca(2+), as measured by calcium imaging, were also increased in DRG neurons when exposed to the combination of capsaicin and the most efficacious enhancer 23 compared to capsaicin alone. Thus, DHPs can modulate TRPV1 channels in a positive fashion. Published by Elsevier Ltd. C1 [Keller, Jason M.; Olah, Zoltan; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, NIH, Bethesda, MD 20892 USA. [Roh, Eun Joo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Iadarola, MJ (reprint author), Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, NIH, Bethesda, MD 20892 USA. EM miadarola@dir.nidcr.nih.gov; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK and NIDCR; National Institutes of Health FX This research was supported in part by the Intramural Research Programs of the NIDDK and NIDCR, National Institutes of Health. We thank Dr. William Trenkle for advice on the chemical synthesis of compound 23 and Dr. Herman Yeh for the assistance with the NMR characterization. NR 52 TC 20 Z9 21 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 15 PY 2008 VL 16 IS 20 BP 9349 EP 9358 DI 10.1016/j.bmc.2008.08.048 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 359GA UT WOS:000259973200032 PM 18809334 ER PT J AU Kumar, V Malhotra, SV AF Kumar, Vineet Malhotra, Sanjay V. TI Synthesis of nucleoside-based antiviral drugs in ionic liquids SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE nucleoside; antiviral drugs; ionic liquid; HIV; HSV ID SELECTIVE BENZOYLATION; BETA-ELIMINATION; EFFICIENT METHOD; CHEMISTRY; D4T AB Nucleoside-based antiviral drugs have been synthesized using imidazolium-based ionic liquids as reaction medium. The ionic liquids were proved to be better solvents for all the nucleoside in terms of solubility and reaction medium as compared to conventional molecular solvents. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Kumar, Vineet; Malhotra, Sanjay V.] NCI, SAIC Frederick Inc, Lab Synthet Chem, Frederick, MD 21702 USA. RP Malhotra, SV (reprint author), NCI, SAIC Frederick Inc, Lab Synthet Chem, 1050 Boyles St, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov FU NCI [N01-CO-12400] FX This project was funded by NCI Contract N01-CO-12400. NR 30 TC 17 Z9 20 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 15 PY 2008 VL 18 IS 20 BP 5640 EP 5642 DI 10.1016/j.bmcl.2008.08.090 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 359FW UT WOS:000259972800068 PM 18796352 ER PT J AU Shafrir, Y Durell, SR Guy, HR AF Shafrir, Yinon Durell, Stewart R. Guy, H. Robert TI Models of the structure and gating mechanisms of the pore domain of the NaChBac ion channel SO BIOPHYSICAL JOURNAL LA English DT Article ID GATED CA2+ CHANNEL; DEPENDENT K+ CHANNEL; SODIUM-CHANNEL; CYSTEINE MUTAGENESIS; CRYSTAL-STRUCTURE; CALCIUM-CHANNELS; LINING SEGMENTS; INNER PORE; VOLTAGE; ARCHITECTURE AB The NaChBac prokaryotic sodium channel appears to be a descendent of an evolutionary link between voltage-gated K(V) and Ca(V) channels. Like K(V) channels, four identical six-transmembrane subunits comprise the NaChBac channel, but its selectivity. filter possesses a signature sequence of eukaryotic Ca(V) channels. We developed structural models of the NaChBac channel in closed and open conformations, using K(+)-channel crystal structures as initial templates. Our models were also consistent with numerous experimental results and modeling criteria. This study concerns the pore domain. The major differences between our models and K(+) crystal structures involve the latter portion of the selectivity filter and the bend region in S6 of the open conformation. These NaChBac models may serve as a stepping stone between K(+) channels of known structure and Na(V), Ca(V), and TRP channels of unknown structure. C1 [Shafrir, Yinon; Durell, Stewart R.; Guy, H. Robert] NCI, Cell Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Guy, HR (reprint author), NCI, Cell Biol Lab, CCR, NIH, 12 South Dr, Bethesda, MD 20892 USA. EM bg4y@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 36 TC 21 Z9 21 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT 15 PY 2008 VL 95 IS 8 BP 3650 EP 3662 DI 10.1529/biophysj.108.135327 PG 13 WC Biophysics SC Biophysics GA 352NM UT WOS:000259503900013 PM 18641075 ER PT J AU Shafrir, Y Durell, SR Guy, HR AF Shafrir, Yinon Durell, Stewart R. Guy, H. Robert TI Models of voltage-dependent conformational changes in NaChBac channels SO BIOPHYSICAL JOURNAL LA English DT Article ID SHAKER K+ CHANNEL; GATED ION CHANNELS; SODIUM-CHANNEL; GATING-CHARGE; TRANSMEMBRANE MOVEMENT; POTASSIUM CHANNELS; CRYSTAL-STRUCTURE; MEMBRANE; RESIDUES; SENSOR AB Models of the transmembrane region of the NaChBac channel were developed in two open/inactivated and several closed conformations. Homology models of NaChBac were developed using crystal structures of Kv1.2 and a Kv1.2/2.1 chimera as templates for open conformations, and MlotiK and KcsA channels as templates for closed conformations. Multiple molecular-dynamic simulations were performed to refine and evaluate these models. A striking difference between the S4 structures of the Kv1.2-like open models and MlotiK-like closed models is the secondary structure. In the open model, the first part of S4 forms an alpha-helix, and the last part forms a 3(10) helix, whereas in the closed model, the first part of S4 forms a 3(10) helix, and the last part forms an alpha-helix. A conformational change that involves this type of transition in secondary structure should be voltage-dependent. However, this transition alone is not sufficient to account for the large gating charge movement reported for NaChBac channels and for experimental results in other voltage-gated channels. To increase the magnitude of the motion of S4, we developed another model of an open/inactivated conformation, in which S4 is displaced farther outward, and a number of closed models in which S4 is displaced farther inward. A helical screw motion for the alpha-helical part of S4 and a simple axial translation for the 3(10) portion were used to develop models of these additional conformations. In our models, four positively charged residues of S4 moved outwardly during activation, across a transition barrier formed by highly conserved hydrophobic residues on S1, S2, and S3. The S4 movement was coupled to an opening of the activation gate formed by S6 through interactions with the segment linking S4 to S5. Consistencies of our models with experimental studies of NaChBac and K(v) channels are discussed. C1 [Shafrir, Yinon; Durell, Stewart R.; Guy, H. Robert] NCI, Cell Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Guy, HR (reprint author), NCI, Cell Biol Lab, CCR, NIH, 12 South Dr, Bethesda, MD 20892 USA. EM bg4y@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 30 TC 27 Z9 27 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT 15 PY 2008 VL 95 IS 8 BP 3663 EP 3676 DI 10.1529/biophysj.108.135335 PG 14 WC Biophysics SC Biophysics GA 352NM UT WOS:000259503900014 PM 18641074 ER PT J AU Krishnamoorthy, S Iliadis, AA Bei, T Chrousos, GP AF Krishnamoorthy, Soumya Iliadis, Agis A. Bei, Thaleia Chrousos, George P. TI An interleukin-6 ZnO/SiO2/Si surface acoustic wave biosensor SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE interleukin-6; ZnO; SAW biosensor; protein immobilization; SiO2/Si ID ESCHERICHIA-COLI O157-H7; IMMUNOSENSOR; SENSORS; IL-6; NANOPARTICLES; CYTOKINES; BINDING; OBESITY; STRESS; LIQUID AB A novel high sensitivity ZnO/SiO2/Si Love mode surface acoustic wave (SAW) biosensor for the detection of interleukin-6 (IL-6), is reported. The biosensors operating at 747.7 MHz and 1.586 GHz were functionalized by immobilizing the monoclonal IL-6 antibody onto the ZnO biosensor surface both through direct surface adsorption and through covalent binding on gluteraldehyde. The morphology of the IL-6 antibody-protein complex was studied using scanning electron microscopy (SEM), and the mass of the IL-6 protein immobilized on the surface was measured from the frequency shift of the SAW resonator biosensor. The biosensor was shown to have extended linearity, which was observed to improve with higher sensor frequency and for IL-6 immobilization through the monoclonal antibody. Preliminary results of biosensor measurements of low levels of IL-6 in normal human serum are reported. The biosensor can be fully integrated with CMOS Si chips and developed as a portable real time detection system for the interleukin family of proteins in human serum. (C) 2008 Elsevier B.V. All rights reserved. C1 [Krishnamoorthy, Soumya; Iliadis, Agis A.] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. [Iliadis, Agis A.] Univ Aegean, Dept Informat & Commun Syst Engn, Aegean, Greece. [Bei, Thaleia] NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Chrousos, George P.] NIH, Sect Pediat Endocrinol, Reprod & Mol Biol Branch, Bethesda, MD 20892 USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Iliadis, AA (reprint author), Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. EM agis@eng.umd.edu FU National Science Foundation [ECS0302494] FX The support of National Science Foundation through grant # ECS0302494 is gratefully acknowledged. NR 23 TC 36 Z9 38 U1 2 U2 34 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD OCT 15 PY 2008 VL 24 IS 2 BP 313 EP 318 DI 10.1016/j.bios.2008.04.011 PG 6 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA 355MB UT WOS:000259711900023 PM 18502114 ER PT J AU Kristinsson, SY Bjorkholm, M Goldin, LR McMaster, ML Turesson, I Landgren, O AF Kristinsson, Sigurdur Y. Bjorkholm, Magnus Goldin, Lynn R. McMaster, Mary L. Turesson, Ingemar Landgren, Ola TI Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; FAMILIAL WALDENSTROMS MACROGLOBULINEMIA; GENE; AGGREGATION; EXPRESSION; POLYMORPHISMS; AUTOIMMUNE; PATTERNS; DISEASES AB A role for genetic factors in the etiology of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) is implicated based on prior findings from multiply affected families and small case-control and cohort studies. We identified 2144 LPL/WM patients (1539 WM [72%] and 605 LPL [28%]) diagnosed in Sweden, 8279 population-based matched controls, and linkable first-degree relatives of patients (n = 6177) and controls (n = 24 609). Using a marginal survival model, we calculated relative risks and 95% confidence intervals as measures of familial aggregation. We found first-degree relatives of LPL/WM patients to have 20-fold (4.1-98.4), 3.0-fold (2.0-4.4), 3.4-fold (1.7-6.6), and 5.0-fold (1.3-18.9) increased risks of developing LPL/WM, non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and monoclonal gammopathy of undetermined significance (MGUS), respectively. However, there was no evidence of an increased risk of developing multiple myeloma or Hodgkin lymphoma. In analyses stratified by type of first-degree relative (parent, sibling, offspring), age at diagnosis of the probands (greater or less than 70 years), and sex of the first-degree relative, we did not observe the risk estimates to be significantly different compared with the overall analyses. Our findings of highly increased risks of developing LPL/WM, NHL, CLL, and MGUS support the operation of shared susceptibility genes that predispose to LPL/WM and other lymphoproliferative disorders. C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Univ, Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Inst, Stockholm, Sweden. [Goldin, Lynn R.; McMaster, Mary L.; Landgren, Ola] NCI, NIH, Bethesda, MD 20892 USA. [Turesson, Ingemar] Malmo Univ Hosp, Sect Hematol, Dept Med, Malmo, Sweden. RP Kristinsson, SY (reprint author), Karolinska Univ, Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@karolinska.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; National Institutes of Health; National Cancer Institute FX This research was supported by grants from the Swedish Cancer Society, Stockholm County Council, the Karolinska Institutet Foundations, and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 41 TC 67 Z9 71 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2008 VL 112 IS 8 BP 3052 EP 3056 DI 10.1182/blood-2008-06-162768 PG 5 WC Hematology SC Hematology GA 357SH UT WOS:000259866100016 PM 18703425 ER PT J AU Young, KH Leroy, K Moller, MB Colleoni, GWB Sanchez-Beato, M Kerbauy, FR Haioun, C Eickhoff, JC Young, AH Gaulard, P Piris, MA Oberley, TD Rehrauer, WM Kahl, BS Malter, JS Campo, E Delabie, J Gascoyne, RD Rosenwald, A Rimsza, L Huang, J Braziel, RM Jaffe, ES Wilson, WH Staudt, LM Vose, JM Chan, WC Weisenburger, DD Greiner, TC AF Young, Ken H. Leroy, Karen Moller, Michael B. Colleoni, Gisele W. B. Sanchez-Beato, Margarita Kerbauy, Fabio R. Haioun, Corinne Eickhoff, Jens C. Young, Allen H. Gaulard, Philippe Piris, Miguel A. Oberley, Terry D. Rehrauer, William M. Kahl, Brad S. Malter, James S. Campo, Elias Delabie, Jan Gascoyne, Randy D. Rosenwald, Andreas Rimsza, Lisa Huang, James Braziel, Rita M. Jaffe, Elaine S. Wilson, Wyndham H. Staudt, Louis M. Vose, Julie M. Chan, Wing C. Weisenburger, Dennis D. Greiner, Timothy C. TI Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study SO BLOOD LA English DT Article ID TUMOR-SUPPRESSOR GENE; NON-HODGKINS-LYMPHOMA; LI-FRAUMENI-SYNDROME; MUTANT P53 GAIN; POOR SURVIVAL; BREAST-CANCER; COLORECTAL-CANCER; BINDING DOMAINS; EXPRESSION; GROWTH AB The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell-like DLBCL, but not nongerminal center B cell-like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL. C1 [Young, Ken H.; Eickhoff, Jens C.; Young, Allen H.; Oberley, Terry D.; Rehrauer, William M.; Kahl, Brad S.; Malter, James S.] Univ Wisconsin, Sch Med & Publ Hlth, Paul P Carbone Comprehens Canc Ctr, Dept Pathol & Lab Med, Madison, WI 53792 USA. [Young, Ken H.; Eickhoff, Jens C.; Young, Allen H.; Oberley, Terry D.; Rehrauer, William M.; Kahl, Brad S.; Malter, James S.] Univ Wisconsin, Sch Med & Publ Hlth, Paul P Carbone Comprehens Canc Ctr, Dept Biostat & Med Informat, Madison, WI 53792 USA. [Young, Ken H.; Eickhoff, Jens C.; Young, Allen H.; Oberley, Terry D.; Rehrauer, William M.; Kahl, Brad S.; Malter, James S.] Univ Wisconsin, Sch Med & Publ Hlth, Paul P Carbone Comprehens Canc Ctr, Dept Hematol & Oncol, Madison, WI 53792 USA. [Leroy, Karen; Haioun, Corinne; Gaulard, Philippe] Univ Paris 12, Hop Henri Mondor, F-94010 Creteil, France. [Moller, Michael B.] Odense Univ Hosp, DK-5000 Odense, Denmark. [Colleoni, Gisele W. B.; Kerbauy, Fabio R.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Sanchez-Beato, Margarita; Piris, Miguel A.] Spanish Natl Canc Ctr CNIO, Madrid, Spain. [Campo, Elias] Univ Barcelona, Barcelona, Spain. [Delabie, Jan] Norwegian Radium Hosp, Oslo, Norway. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Rosenwald, Andreas] Univ Wurzburg, Wurzburg, Germany. [Rimsza, Lisa] Univ Arizona, Tucson, AZ USA. [Huang, James; Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Jaffe, Elaine S.; Wilson, Wyndham H.; Staudt, Louis M.] NCI, Bethesda, MD 20892 USA. [Vose, Julie M.; Chan, Wing C.; Weisenburger, Dennis D.; Greiner, Timothy C.] Univ Nebraska Med Ctr, Omaha, NE USA. RP Young, KH (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Paul P Carbone Comprehens Canc Ctr, Dept Pathol & Lab Med, Madison, WI 53792 USA. EM khyoung@wisc.edu RI Leroy, Karen/E-9235-2011; Colleoni, Gisele/F-9185-2014; Moller, Michael/G-8340-2016; OI Campo, elias/0000-0001-9850-9793; Moller, Michael/0000-0003-2041-3630; Delabie, Jan/0000-0001-5023-0689; Piris, Miguel A/0000-0001-5839-3634 FU US Public Health Service [CA36727, CA84967]; National Cancer Institute; Department of Health and Human Services; Gundersen Medical Foundation; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; Lymphoma Research Foundation FX This work was supported by grants from the US Public Health Service (grants CA36727 and CA84967) awarded by the National Cancer Institute, Department of Health and Human Services and by awards from the Gundersen Medical Foundation and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center. T. C. G. is a Lymphoma Research Foundation Mantle Cell Lymphoma Program Research Grantee. NR 82 TC 84 Z9 98 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2008 VL 112 IS 8 BP 3088 EP 3098 DI 10.1182/blood-2008-01-129783 PG 11 WC Hematology SC Hematology GA 357SH UT WOS:000259866100021 PM 18559976 ER PT J AU O'Shea, D O'Riain, C Taylor, C Waters, R Carlotti, E MacDougall, F Gribben, J Rosenwald, A Ott, G Rimsza, LM Smeland, EB Johnson, N Campo, E Greiner, TC Chan, WC Gascoyne, RD Wright, G Staudt, LM Lister, TA Fitzgibbon, J AF O'Shea, Derville O'Riain, Ciaran Taylor, Claire Waters, Rachel Carlotti, Emanuela MacDougall, Finlay Gribben, John Rosenwald, Andreas Ott, German Rimsza, Lisa M. Smeland, Erlend B. Johnson, Nathalie Campo, Elias Greiner, Timothy C. Chan, Wing C. Gascoyne, Randy D. Wright, George Staudt, Louis M. Lister, T. Andrew Fitzgibbon, Jude TI The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival SO BLOOD LA English DT Article ID INTERNATIONAL PROGNOSTIC INDEX; NON-HODGKINS-LYMPHOMAS; FRONT-LINE; P53; TRANSFORMATION; EXPRESSION; RITUXIMAB; FEATURES; DATABASE; THERAPY AB The International Prognostic Index and the Follicular Lymphoma International Prognostic Index are widely used for the risk assessment of follicular lymphoma (FL). Although molecular studies have provided insight into the biology of FL, no molecular marker has impacted on treatment stratification. Because TP53 mutations are associated with poor prognosis in hematologic malignancies, we investigated the prognostic value of TP53 mutation at diagnosis in FL. Heterozygous TP53 mutation was detected in 12 of 185 (6%) analyzed cases. Mutation was associated with older age (P = .02) and higher International Prognostic Index score (P = .04). On multivariate analysis, TP53 mutation correlated with shorter progression-free survival (P < .001) and overall survival (P = .009). TP53 mutation was associated with low expression of the immune-response 1 gene expression signature (P = .016) and with an unfavorable gene expression-based survival predictor score (P < .001), demonstrating for the first time that molecular features of the malignant cell may correlate with the nature of the immune response in FL. C1 [O'Shea, Derville; O'Riain, Ciaran; Carlotti, Emanuela; MacDougall, Finlay; Gribben, John; Lister, T. Andrew; Fitzgibbon, Jude] Barts & London Queen Marys Sch Med & Dent, Ctr Med Oncol, London EC1M 6BQ, England. [Taylor, Claire] St James Univ Hosp, Mutat Detect Facil, Leeds, W Yorkshire, England. [Waters, Rachel] Univ Oxford, Ctr Stat Med, Oxford, England. [Rosenwald, Andreas; Ott, German] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Rimsza, Lisa M.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Smeland, Erlend B.] Univ Hosp, Rikshosp, Inst Canc Res, Dept Immunol, Oslo, Norway. [Smeland, Erlend B.] Univ Oslo, Norwegian Radium Hosp, Fac Div, Ctr Canc Biomed, Oslo, Norway. [Johnson, Nathalie; Gascoyne, Randy D.] British Columbia Canc Agcy, Div Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Johnson, Nathalie; Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Univ Barcelona, Dept Pathol, Inst Invest Biomed August Pi & Sunyer, Hematopathol Sect, Barcelona, Spain. [Greiner, Timothy C.; Chan, Wing C.] Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Wright, George] Natl Canc Inst, Biometr Res Branch, Ctr Canc Res, NIH, Bethesda, MD USA. [Staudt, Louis M.] Natl Canc Inst, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD USA. RP O'Shea, D (reprint author), Barts & London Queen Marys Sch Med & Dent, Ctr Med Oncol, Charterhouse Sq, London EC1M 6BQ, England. EM derville.oshea@cancer.org.uk OI Campo, elias/0000-0001-9850-9793 FU Cancer Research UK, the Medical Research Council; NIH SPEC [5U01CA114778]; Medical Research Council Clinical Research Fellow grant FX The work was supported by grants from Cancer Research UK, the Medical Research Council, and NIH SPEC grant 5U01CA114778. D.O. is supported by a Medical Research Council Clinical Research Fellow grant. C.O. is a Cancer Research UK Barts-Cambridge Molecular Pathology Clinical Research Fellow. NR 25 TC 47 Z9 47 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2008 VL 112 IS 8 BP 3126 EP 3129 DI 10.1182/blood-2008-05-154013 PG 4 WC Hematology SC Hematology GA 357SH UT WOS:000259866100026 PM 18628487 ER PT J AU Williams, KM Lucas, PJ Bare, CV Wang, J Chu, YW Tayler, E Kapoor, V Gress, RE AF Williams, Kirsten M. Lucas, Philip J. Bare, Catherine V. Wang, Jiun Chu, Yu-Waye Tayler, Ezekiel Kapoor, Veena Gress, Ronald E. TI CCL25 increases thymopoiesis after androgen withdrawal SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; THYMIC EPITHELIAL-CELLS; ACCELERATE THYMOCYTE APOPTOSIS; BONE-MARROW-TRANSPLANTATION; GROWTH-FACTOR-I; EARLY T-CELL; IMMUNE RECONSTITUTION; LYMPHOCYTE DEVELOPMENT; MICE; PROLIFERATION AB Although studies have demonstrated that androgen withdrawal increases thymic size, molecular mechanisms underlying this expansion remain largely unknown. We show that decreased androgen signaling leads to enhanced immigration of bone marrow T-cell precursors, as manifested by both an early increase of early thymic progenitors (ETP) and improved uptake of adoptively transferred quantified precursors into congenic castrated hosts. We provide evidence that the ETP niche is enhanced after androgen withdrawal by proliferation of UEA(+) thymic epithelial cells (TEC) and increased TEC production of CCL25, a ligand critical for ETP entry. Moreover, the greatest increase in CCL25 production is by UEA(+) TEC, linking function of this subset with the increase in ETP immigration. Furthermore, blockade of CCL25 abrogated the effects of castration by impairing ETP entry, retarding immature thymocyte development, limiting increase of thymic size, and impairing increase of thymopoiesis. Taken together, these findings describe a cohesive mechanism underlying increased thymic productivity after androgen withdrawal. C1 [Williams, Kirsten M.; Lucas, Philip J.; Bare, Catherine V.; Wang, Jiun; Chu, Yu-Waye; Tayler, Ezekiel; Kapoor, Veena; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Williams, KM (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bldg 10 CRC,Room 3-3288,10 Ctr Dr, Bethesda, MD 20892 USA. EM williaki@mail.nih.gov NR 50 TC 27 Z9 28 U1 0 U2 2 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 OCT 15 PY 2008 VL 112 IS 8 BP 3255 EP 3263 DI 10.1182/blood-2008-04-153627 PG 9 WC Hematology SC Hematology GA 357SH UT WOS:000259866100041 PM 18694999 ER PT J AU Mazzucchelli, R Hixon, JA Spolski, R Chen, X Li, WQ Hall, VL Willette-Brown, J Hurwitz, AA Leonard, WJ Durum, SK AF Mazzucchelli, Renata Hixon, Julie A. Spolski, Rosanne Chen, Xin Li, Wen Qing Hall, Veronica L. Willette-Brown, Jami Hurwitz, Arthur A. Leonard, Warren J. Durum, Scott K. TI Development of regulatory T cells requires IL-7R alpha stimulation by IL-7 or TSLP SO BLOOD LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; IMMUNOLOGICAL SELF-TOLERANCE; RECEPTOR-DEFICIENT MICE; GROWTH-FACTOR-BETA; INTERLEUKIN-7 RECEPTOR; AUTOIMMUNE-DISEASE; CUTTING EDGE; IN-VITRO; INTESTINAL INFLAMMATION; SUPPRESSOR FUNCTION AB Interleukin-7 (IL-7), a cytokine produced by stromal cells, is required for thymic development and peripheral homeostasis of most major subsets of T cells. We examined whether regulatory T (Treg) cells also required the IL-7 pathway by analyzing IL-7R alpha(-/-) mice. We observed a striking reduction in cells with the Treg surface phenotype (CD4, CD25, GITR (glucocorticoid-induced tumor necrosis factor [TNF]-like receptor), CD45RB, CD62L, CD103) or intracellular markers (cytotoxic T-lymphocyte associated antigen-4, CTLA-4, and forkhead box transcription factor 3, Foxp3). Foxp3 transcripts were virtually absent in IL-7R alpha(-/-) lymphoid tissues, and no Treg cell suppressive activity could be detected. There are 2 known ligands for IL-7R alpha: IL-7 itself and thymic stromal lymphopoietin (TSLP). Surprisingly, mice deficient in IL-7 or the other chain of the TSLP receptor (TSLPR) developed relatively normal numbers of Treg cells. Combined deletion of IL-7 and TSLP receptor greatly reduced Treg cell development in the thymus but was not required for survival of mature peripheral Treg cells. We conclude that Treg cells, like other T cells, require signals from the IL-7 receptor, but unlike other T cells, do not require IL-7 itself because of at least partially overlapping actions of IL-7 and TSLP for development of Treg cells. C1 [Durum, Scott K.] NCI, FCRDC, Mol Immunoregulat Lab, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Chen, Xin] NCI Frederick, Basic Res Program, SAIC Frederick, Frederick, MD USA. [Hall, Veronica L.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Durum, SK (reprint author), NCI, FCRDC, Mol Immunoregulat Lab, Canc & Inflammat Program,Ctr Canc Res,NIH, Bldg 560,Room 31-71, Frederick, MD 21702 USA. EM durums@ncifcrf.gov RI Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU Intramural Research Program of the NIH, NCI,; NCI, NIH [N01-CO-12400] FX We thank C. Willis (Amgen) for providing anti-IL-7 antibody; M. Guimond and C. L. Mackall for providing a verifying source of IL-7R alpha-/- mice; R. Wyles and S. Stull for animal technical assistance; K. Noer, R. Matthai, S. Bauchiero, and M. Anderson for flow cytometry assistance; and J. J. Oppenheim for comments on the manuscript.; This work was supported by the Intramural Research Program of the NIH, NCI, and with federal funds from the NCI, NIH, under contract N01-CO-12400.; 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 United States government. NR 94 TC 69 Z9 71 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2008 VL 112 IS 8 BP 3283 EP 3292 DI 10.1182/blood-2008-02-137414 PG 10 WC Hematology SC Hematology GA 357SH UT WOS:000259866100044 PM 18664628 ER PT J AU Zhou, L Nguyen, AN Sohal, D Ma, JY Pahanish, P Gundabolu, K Hayman, J Chubak, A Mo, YK Bhagat, TD Das, B Kapoun, AM Navas, TA Parmar, S Kambhampati, S Pellagatti, A Braunchweig, I Zhang, Y Wickrema, A Medicherla, S Boultwood, J Platanias, LC Higgins, LS List, AF Bitzer, M Verma, A AF Zhou, Li Nguyen, Aaron N. Sohal, Davendra Ma, Jing Ying Pahanish, Perry Gundabolu, Krishna Hayman, Josh Chubak, Adam Mo, Yongkai Bhagat, Tushar D. Das, Bhaskar Kapoun, Ann M. Navas, Tony A. Parmar, Simrit Kambhampati, Suman Pellagatti, Andrea Braunchweig, Ira Zhang, Ying Wickrema, Amittha Medicherla, Satyanarayana Boultwood, Jacqueline Platanias, Leonidas C. Higgins, Linda S. List, Alan F. Bitzer, Markus Verma, Amit TI Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS SO BLOOD LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; GENE-EXPRESSION PROFILES; MYELODYSPLASTIC SYNDROMES; MICROARRAY PLATFORMS; MYELOFIBROSIS; CELLS; APOPTOSIS; CANCER; CYTOKINES; PATHWAY AB MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor-beta (TGF-beta) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34(+) cells, providing direct evidence of overactivation of TGF-beta pathway in this disease. Suppression of the TGF-beta signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-beta-mediated gene activation in BM stromal cells, and reverses TGF-beta-mediated cell-cycle arrest in BM CD34(+) cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-beta 1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-beta signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS. C1 [Zhou, Li; Sohal, Davendra; Pahanish, Perry; Gundabolu, Krishna; Hayman, Josh; Chubak, Adam; Mo, Yongkai; Bhagat, Tushar D.; Das, Bhaskar; Braunchweig, Ira; Bitzer, Markus; Verma, Amit] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Pahanish, Perry; Parmar, Simrit; Verma, Amit] Univ Texas SW Med Sch, Dallas, TX USA. [Pahanish, Perry; Parmar, Simrit; Verma, Amit] Dallas Vet Affairs Med Ctr, Dallas, TX USA. [Kambhampati, Suman] VAMC, Kansas City, MO USA. [Pellagatti, Andrea; Boultwood, Jacqueline] John Radcliffe Hosp, Oxford OX3 9DU, England. [Zhang, Ying] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Wickrema, Amittha] Univ Chicago, Chicago, IL 60637 USA. [Platanias, Leonidas C.] Northwestern Univ, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [List, Alan F.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. RP Verma, A (reprint author), Albert Einstein Canc Ctr, Chanin 302B,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM averma@aecom.yu.edu OI Pellagatti, Andrea/0000-0002-6122-0221; Boultwood, Jacqueline/0000-0002-4330-2928 FU National Institutes of Health (NIH, Bethesda, MD) [1R01HL082946-01, RO1 AG029138]; Community Foundation of Southeastern Michigan (Detroit); J. P. McCarthy fund award; Immunooncology Training Program [T32 CA009173] FX This work was supported by National Institutes of Health (NIH, Bethesda, MD) 1R01HL082946-01 and Community Foundation of Southeastern Michigan (Detroit) J. P. McCarthy fund award (A.V.); by NIH RO1 AG029138 (L.C.P.); and by Immunooncology Training Program T32 CA009173 (L.Z.). NR 59 TC 61 Z9 63 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2008 VL 112 IS 8 BP 3434 EP 3443 DI 10.1182/blood-2008-02-139824 PG 10 WC Hematology SC Hematology GA 357SH UT WOS:000259866100060 PM 18474728 ER PT J AU Wells, KJ Battaglia, TA Dudley, DJ Garcia, R Greene, A Calhoun, E Mandelblatt, JS Paskett, ED Raich, PC AF Wells, Kristen J. Battaglia, Tracy A. Dudley, Donald J. Garcia, Roland Greene, Amanda Calhoun, Elizabeth Mandelblatt, Jeanne S. Paskett, Electra D. Raich, Peter C. CA Patient Navigation Res Program TI Patient Navigation: State of the Art or Is it Science? SO CANCER LA English DT Review DE neoplasms; healthcare disparities; quality of healthcare; delivery of healthcare ID BREAST-CANCER; FOLLOW-UP; ABNORMAL MAMMOGRAM; UNDERSERVED WOMEN; HEALTH-INSURANCE; CLINICAL-TRIALS; RISK PERCEPTION; LOW-INCOME; CARE; COMMUNITY AB First implemented in 1990, patient navigation interventions are emerging today as an approach to reduce cancer disparities. However, there is lack of consensus about how patient navigation is defined, what patient navigators do, and what their qualifications should be. Little is known about the efficacy and cost-effectiveness of patient navigation. For this review, the authors conducted a qualitative synthesis of published literature on cancer patient navigation. By using the keywords 'navigator' or 'navigation' and 'cancer,' 45 articles were identified in the PubMed database and from reference searches that were published or in press through October 2007. Sixteen studies provided data on the efficacy of navigation in improving timeliness and receipt of cancer screening, diagnostic follow-up care, and treatment. Patient navigation services were defined and differentiated from other outreach services. Overall, there was evidence of some degree of efficacy for patient navigation in increasing participation in cancer screening and adherence to diagnostic follow-up care after the detection of an abnormality. The reported increases in screening ranged from 10.8% to 17.1%, and increases in adherence to diagnostic follow-up care ranged from 21% to 29.2% compared with control patients. There was less evidence regarding the efficacy of patient navigation in reducing either late-stage cancer diagnosis or delays in the initiation of cancer treatment or improving outcomes during cancer survivorship. There were methodological limitations in most studies, such as a lack of control groups, small sample sizes, and contamination with other interventions. Although cancer-related patient navigation interventions are being adopted increasingly across the United States and Canada, further research will be necessary to evaluate their efficacy and cost-effectiveness in improving cancer care. Cancer 2008;113:1999-2010. (C) 2008 American Cancer Society. C1 [Wells, Kristen J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control,Dept Hlth Outcomes & B, Tampa, FL 33612 USA. [Battaglia, Tracy A.] Boston Univ, Sch Med, Gen Internal Med Sect, Womens Hlth Unit, Boston, MA 02118 USA. [Dudley, Donald J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, Div Maternal Fetal Med, San Antonio, TX 78229 USA. [Garcia, Roland] NCI, Ctr Reduce Canc Hlth Dispar, Bethesda, MD 20892 USA. [Greene, Amanda] NOVA Res Co, Bethesda, MD USA. [Calhoun, Elizabeth] Univ Illinois, Sch Publ Hlth, Div Hlth Policy & Adm, Chicago, IL USA. [Mandelblatt, Jeanne S.] Georgetown Univ, Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Mandelblatt, Jeanne S.] Georgetown Univ, Med Ctr, Dept Med, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Paskett, Electra D.] Ohio State Univ, Ctr Comprehens Canc, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Raich, Peter C.] Denver Hlth & Hosp Author, Dept Med, Div Hematol Oncol, Denver, CO USA. RP Wells, KJ (reprint author), H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr,FOW EDU, Tampa, FL 33612 USA. EM kristen.wells@moffitt.org RI Wells, Kristen/J-1838-2012; OI Battaglia, Tracy/0000-0001-8475-1212 FU National Cancer Institute (NCI) [U01 CA 117281-01]; American Cancer Society (ACS) [SIRSG-05-253-01] FX This study was funded by the National Cancer Institute (NCI) through its Center to Reduce Cancer Health Disparities, National Institutes of Health, Department of Health and Human Services (U01 CA 117281-01) and by the American Cancer Society (ACS) (SIRSG-05-253-01). NR 77 TC 209 Z9 210 U1 4 U2 20 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 15 PY 2008 VL 113 IS 8 BP 1999 EP 2010 DI 10.1002/cncr.23815 PG 12 WC Oncology SC Oncology GA 362LA UT WOS:000260198000002 PM 18780320 ER PT J AU Huang, H Abraham, J Hung, E Averbuch, S Merino, M Steinberg, SM Pacak, K Fojo, T AF Huang, Hui Abraham, Jame Hung, Elizabeth Averbuch, Steven Merino, Maria Steinberg, Seth M. Pacak, Karel Fojo, Tito TI Treatment of Malignant Pheochromocytoma/Paraganglioma With Cyclophosphamide, Vincristine, and Dacarbazine Recommendation From a 22-Year Follow-up of 18 Patients SO CANCER LA English DT Article DE pheochromocytoma; paraganglioma; cyclophosphamide; vincristine; dacarbazine ID FUNCTIONAL PARAGANGLIOMA; NEUROENDOCRINE TUMORS; CLINICAL-EXPERIENCE; MANAGEMENT; MUTATIONS; SDHB; TEMOZOLOMIDE; COMBINATION; DIAGNOSIS; SUBUNIT AB BACKGROUND. A long-term follow-up was conducted of 18 patients with a diagnosis of pheochromocytoma/paraganglioma treated with a combination of cyclophosphamide, vincristine, and dacarbazine (CVD). METHODS. The study design was a nonrandomized, single-arm trial conducted at a government medical referral center. Eighteen patients with metastatic malignant pheochromocytoma/paraganglioma were studied. After controlling symptoms of catecholamine excess, patients were treated with cyclophosphamide at 750 mg/m(2), vincristine at 1.4 mg/m(2), and dacarbazine at 600 mg/m(2) on Day 1 and dacarbazine at 600 mg/m(2) on Day 2, every 21 to 28 days. RESULTS. Combination chemotherapy with CVD produced a complete response rate of 11% and a partial response rate of 44%. Median survival from a landmark was 3.8 years for patients whose tumors responded to therapy and 1.8 years for patients whose tumors did not respond (P = .65). All patients with tumors scored as responding reported improvement in their symptoms related to excessive catecholamine release and had objective improvements in blood pressure. CVD was well tolerated with only grade I/II toxicities. CONCLUSIONS. Combination chemotherapy with CVD produced objective tumor responses in patients with advanced malignant pheochromocytoma/paraganglioma. In this 22-year follow-up there was no difference in overall survival between patients whose tumors objectively shrank and those with stable or progressive disease. However, patients reported improvement in symptoms, had objective improvements in blood pressure, and had tumor shrinkage that made surgical resection possible. The authors conclude that CVD therapy is not indicated in every patient with metastatic pheochromocytoma/paraganglioma, but should be considered in the management of patients with symptoms and where tumor shrinkage might be beneficial. Cancer 2008;113:2020-8. (C) 2008 American Cancer Society. C1 [Huang, Hui; Hung, Elizabeth; Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Abraham, Jame] W Virginia Univ, Mary Babb Canc Ctr, Morgantown, WV 26506 USA. [Averbuch, Steven] Bristol Myers Squibb Co, Hillside, NJ USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pacak, Karel] Natl Inst Child Hlth, Reprod Biol & Adult Endocrinol Program, NIH, Bethesda, MD USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, NIH, NIH Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fojot@mail.nih.gov NR 53 TC 80 Z9 84 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 15 PY 2008 VL 113 IS 8 BP 2020 EP 2028 DI 10.1002/cncr.23812 PG 9 WC Oncology SC Oncology GA 362LA UT WOS:000260198000004 PM 18780317 ER PT J AU Lacey, JV Mutter, GL Nucci, MR Ronnett, BM Ioffe, OB Rush, BB Glass, AG Richesson, DA Chatterjee, N Langholz, B Sherman, ME AF Lacey, James V., Jr. Mutter, George L. Nucci, Marisa R. Ronnett, Brigitte M. Ioffe, Olga B. Rush, Brenda B. Glass, Andrew G. Richesson, Douglas A. Chatterjee, Nilanjan Langholz, Bryan Sherman, Mark E. TI Risk of Subsequent Endometrial Carcinoma Associated With Endometrial Intraepithelial Neoplasia Classification of Endometrial Biopsies SO CANCER LA English DT Article DE endometrial hyperplasia; atypical hyperplasia; uterine cancer; cancer precursor; volume percentage stroma ID HYPERPLASIA; DIAGNOSIS; REPRODUCIBILITY; WOMEN; EIN AB BACKGROUND. Histopathologic diagnosis of endometrial biopsies is used to estimate the risk of progression to carcinoma and guide clinical management. Problems with the widely used World Health Organization (WHO) system for classifying endometrial hyperplasia (EH) have prompted the development of all alternative system based on endometrial intraepithelial neoplasia (EIN). The authors estimated progression risk associated with EIN among endometrial biopsies in a nested case-control study of EH progression. METHODS. index biopsies with original community pathology diagnoses of disordered proliferative endometrium (DPEM) or EH that were independently confirmed by a panel of pathologists were independently reviewed and assigned EIN classifications (inadequate, benign, EIN, or cancer) by a second panel of pathologists. Cases (N = 138) progressed to carcinoma at least 1 year (median, 6 years) after their index biopsy. Controls (N = 241) also had EH, did not progress to carcinoma, and were individually matched to cases based on age at EH, date of EH, and length of follow-up. By using conditional logistic regression, the authors estimated relative risks (RRs) with 95% confidence intervals (95% CIs) for progression to carcinoma for EIN versus benign. RESULTS. in the EIN system, 71 (52.6%) cases and 159 (66.8%) controls were classified as benign and 42 (31.1%) cases and 65 (27.3%) controls were classified as EIN. The RR for EIN versus benign was 7.76 (95% CI, 3.36-17.91). In the WHO system, the RR for atypical hyperplasia (AH) versus DPEM, simple hyperplasia, or complex hyperplasia was 9.19 (95% CI, 3.87-21.83). CONCLUSIONS. Among women observed for at least 1 year after receiving a biopsy-based EH diagnosis, EIN and AH were both found to have similarly increased risks of progression to carcinoma. Cancer 2008;113:2073-81. (C) Published 2008 by the American Cancer Society* C1 [Lacey, James V., Jr.; Richesson, Douglas A.; Sherman, Mark E.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Mutter, George L.; Nucci, Marisa R.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. [Ronnett, Brigitte M.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Ioffe, Olga B.] Univ Maryland, Med Ctr, Dept Pathol, Baltimore, MD 21201 USA. [Rush, Brenda B.; Glass, Andrew G.] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Langholz, Bryan] Univ So Calif, Keck Sch Med, Div Biostat, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Lacey, JV (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. EM jimlacey@nih.gov RI Mutter, George/C-5819-2009 FU Division of Cancer Epidemiology and Genetics; NIH; NCI; Johns Hopkins Medical Institutions; University of Maryland Medical Center; Kaiser Foundation Research Institute FX The National Cancer Institute's intramural research program (Division of Cancer Epidemiology and Genetics) funded this study.; This research was supported by the Intramural Research Program of the NIH, NCI, through contracts with Brigham and Women's Hospital, The Johns Hopkins Medical Institutions, the University of Maryland Medical Center, and the Kaiser Foundation Research Institute.; We thank Stella Munuo, MSc, and Ruth Parsons, BA, at IMS, Inc for data management. We also thank J. Danny Carreon, MPH, at the Division of Cancer Epidemiology and Genetics of the National Cancer Institute for technical assistance. Finally, we thank Kris Bennett; Chris Eddy, BS; Beverly Battaglia; and the rest of the Kaiser Permanente Center for Health Research staff. NR 23 TC 29 Z9 30 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 15 PY 2008 VL 113 IS 8 BP 2073 EP 2081 DI 10.1002/cncr.23808 PG 9 WC Oncology SC Oncology GA 362LA UT WOS:000260198000011 PM 18720479 ER PT J AU Anderson, BO Yip, CH Smith, RA Shyyan, R Sener, SF Eniu, A Carlson, RW Azavedo, E Harford, J AF Anderson, Benjamin O. Yip, Cheng-Har Smith, Robert A. Shyyan, Roman Sener, Stephen F. Eniu, Alexandru Carlson, Robert W. Azavedo, Edward Harford, Joe TI Guideline Implementation for Breast Healthcare in Low-income and Middle-income Countries Overview of the Breast Health Global Initiative Global Summit 2007 SO CANCER LA English DT Article DE breast cancer; low-income countries; early detection; screening; diagnosis; treatment; healthcare systems; guideline; implementation; resource allocation; process metrics ID LIMITED-RESOURCE COUNTRIES; CANCER STATISTICS; WOMEN; RECOMMENDATIONS; RADIOTHERAPY; THERAPY; TRIAL; CHEMOTHERAPY; MAMMOGRAPHY; STRATEGIES AB Breast cancer outcomes in low- and middle-income countries (LMCs) correlate with the degree to which 1) cancers are detected at early stages, 2) newly detected cancers can be diagnosed correctly, and 3) appropriately selected multi-modality treatment can be provided properly in a timely fashion. The Breast Health Global Initiative (BHGI) invited international experts to review and revise previously developed BHGI resource-stratified guideline tables for early detection, diagnosis, treatment, and healthcare systems. Focus groups, addressed specific issues in breast pathology, radiation therapy, and management of locally advanced disease. Process metrics were developed based on the priorities established in the guideline stratification. The groups indicated that cancer prevention through health behavior modification could influence breast cancer incidence in LMCs, Diagnosing breast cancer at earlier stages will reduce breast cancer mortality. Programs to promote breast self-awareness and clinical breast examination and resource-adapted mammographic screening are important early detection steps. Breast imaging, initially with ultrasound and, at higher resource levels with diagnostic mammography, improves preoperative diagnostic assessment and permits image-guided needle sampling. Multimodality therapy includes surgery, radiation, and systemic therapies. Government intervention is needed to address drug-delivery problems relating to high cost and poor access. Guideline dissemination and implementation research plays a crucial role in improving care. Adaptation of technology is needed in LMCs, especially for breast imaging, pathology, radiation therapy, and systemic treatment. Curricula for education and training in LMCs should be developed. applied, and studied in LMC-based learning laboratories to aid information transfer of evidence-based BHGI guidelines. Cancer 2008;113(8 suppl):2221-43. Published 2008 41, the American Cancer Society C1 [Anderson, Benjamin O.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Anderson, Benjamin O.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Yip, Cheng-Har] Univ Malaya, Med Ctr, Kuala Lumpur, Malaysia. [Smith, Robert A.] Amer Canc Soc, Atlanta, GA 30329 USA. [Shyyan, Roman] Lviv Canc Ctr, Lvov, Ukraine. [Sener, Stephen F.] Evanston NW Healthcare, Evanston, IL USA. [Sener, Stephen F.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Eniu, Alexandru] Canc Inst I Chiricuta, Cluj Napoca, Romania. [Carlson, Robert W.] Stanford Univ, Stanford, CA 94305 USA. [Azavedo, Edward] Karolinska Univ Hosp, Dept Radiol, Stockholm, Sweden. [Harford, Joe] NCI, Bethesda, MD 20892 USA. RP Anderson, BO (reprint author), Univ Washington, Dept Surg, Box 356410, Seattle, WA 98195 USA. EM banderso@u.washington.edu RI Yip, Cheng-Har/B-1909-2010; Eniu, Alexandru Eugen/C-4067-2011 FU Fred Hutchinson Cancer Research Center; American Society of Clinical Oncology; US National Cancer Institute, Office of International Affairs (O1A); American Cancer Society; Lance Armstrong Foundation; US Agency for Healthcare Research and Quality [1 R13 HS017218-01]; US Centers for Disease Control and Prevention, Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion;; American Society of Breast Disease; US National Institutes of Health; Women's Health (ORWH); Global Summit on International Breast Health-Implementation [1 R13 HS017218-01]; Agency for Healthcare Research and Quality; Department of Health and Human Services; US Government FX Funding for the BHGI, 2007 Global Summit on international Breast Health-Implementation and Guidelines for International Breast Health and Cancer Control-Implementation publication came from partnering organizations who share a commitment to medically Underserved women. We thank and gratefully acknowledge these organizations and agencies for grants and conference Support: Fred Hutchinson Cancer Research Center; Susan G. Komen for the cure; American Society of Clinical Oncology (ASCO); US National Cancer Institute, Office of International Affairs (O1A); American Cancer Society; Lance Armstrong Foundation; US Agency for Healthcare Research and Quality (Grant 1 R13 HS017218-01); US Centers for Disease Control and Prevention, Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion; American Society of Breast Disease; Oncology Nursing Society: US National Cancer Institute, Office of Women's Health (OWH); and US National Institutes of Health, Office of Research on Women's Health (ORWH).; Funding for the 2007 Global Summit on International Breast Health-Implementation was made possible (in part) by Grant No. 1 R13 HS017218-01 from the Agency for Healthcare Research and Quality (AHRQ). The views expressed in written conference materials or publications and by speakers and moderators do not necessarilv reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the US Government. NR 88 TC 142 Z9 154 U1 4 U2 23 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 15 PY 2008 VL 113 IS 8 SU S BP 2221 EP 2243 DI 10.1002/cncr.23844 PG 23 WC Oncology SC Oncology GA 362LC UT WOS:000260198200003 PM 18816619 ER PT J AU Harford, J Azavedo, E Fischietto, M AF Harford, Joe Azavedo, Edward Fischietto, Mary CA Breast Hlth Global Initiative Heal TI Guideline Implementation for Breast Healthcare in Low- and Middle-Income Countries Breast Healthcare Program Resource Allocation SO CANCER LA English DT Article DE healthcare systems; breast care program; human resource allocation; patient navigation; capacity building ID FOLLOW-UP; PATIENT NAVIGATION; ABNORMAL MAMMOGRAM; UNINSURED ADULTS; CANCER; INSURANCE; WOMEN; MORTALITY; ACCESS; PERSPECTIVES AB Breast cancer is serious public health problem ill countries of all resource levels. Although major advances in the detection art treatment of the disease have Occurred in higher income settings, similar progress has been slow or scarce in most low- and middle-income countries (LMCs). The poorer outcomes in LMCs may relate to the limited capability of their healthcare systems (HCS) to provide successful early detection, diagnosis, and treatment of breast cancer. Impediments to bettei outcomes include insufficient numbers of appropriately trained healthcare workers, limited access to SCFeeniog/treatioerit facilities, inadequate supplies of occessary drugs, timeliness of treatment after diagnosis. Clearly these HCS deficiencies are broader than the scope of the Breast Health Global Initiative (BHGI) and are not unique to the issue of breast cancer. To address issues ill FICS that hinder the delivery Of breast health services, the BHGI Healthcare Systems and Public policy Panel explored HCS structures and Function needed to operate a breast care program (BCP). Like with all BHGI guidelines, those proposed by this planel were expressed in terms of' 4 strata of resource levels: basic, limited, enhanced, and maximal. The current report describes the issues and questions related to FICS that are important to consider when designing, implementing, and measuring the performance of' a BCP Health ministers, other policymakers. healthcare personnel, adimnistrators,arld anyooe else involved in developing it BCP Call Use and adapt this frame work to improve outcomes arld ensure the more effective Use of resources. Cancer 2008;113(8 suppl):2282-96. (C) 2008 American Cancer Society C1 [Harford, Joe; Fischietto, Mary] NCI, Off Int Affairs, Bethesda, MD 20892 USA. [Azavedo, Edward] Karolinska Univ Hosp, Dept Radiol, Stockholm, Sweden. RP Harford, J (reprint author), NCI, Off Int Affairs, Execut Plaza N,Suite 100,6130 Execut Blvd, Bethesda, MD 20892 USA. EM harfordj@nih.gov FU Fred Hutchinson Cancer Research Center; Susan G. Komen for the Cure; American Society of Clinical Oncology (ASCO); US National Cancer Institute, Office of International Affairs; American Cancer Society; Lance Armstrong Foundation; US Agency for Healthcare Research and Quality [1 R13 HS017218-01]; US Centers for Disease Control and Prevention, Division of Cancer Prevention and Control; American Society of Breast Disease; Oncology Nursing Society; US National Cancer Institute, Office of Women's Health (OWH); US National Institutes of Health, Office of Research on Women's Health (ORWH); National Center for Chronic Disease Prevention and Health Promotion FX Funding for the BHGI 2007 Global Summit on International Breast Health Implementation and Guidelines for International Breast Health and Cancer Control Implementation publication came from partnering organizations who share a commitment to medically underserved women. We thank and gratefully acknowledge these organizations and agencies for grants and conference support, Fred Hutchinson Cancer Research Center, Susan G. Komen for the Cure, American Society of Clinical Oncology, US National Cancer Institute, Office of International Affairs, American Cancer Society, Lance Armstrong Foundation, US Agency for Healthcare Research and Quality (AHRQ) (Grant 1 R13 HS017218-01), US Centers for Disease Control and Prevention, Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion,American Society of Breast Disease, Oncology Nursing Society, US National Cancer Institute, Office of Womens Health, and US National Institutes of Health, Office of Research on Womens Health. NR 72 TC 23 Z9 23 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2008 VL 113 IS 8 SU S BP 2282 EP 2296 DI 10.1002/cncr.23841 PG 15 WC Oncology SC Oncology GA 362LC UT WOS:000260198200007 PM 18837020 ER PT J AU Waalkes, MP Liu, J Germolee, DR Trempus, CS Cannon, RE Tokar, EJ Tennant, RW Ward, JM Diwan, BA AF Waalkes, Michael P. Liu, Jie Germolee, Dori R. Trempus, Carol S. Cannon, Ronald E. Tokar, Erik J. Tennant, Raymond W. Ward, Jerrold M. Diwan, Bhalchandra A. TI Arsenic Exposure In utero Exacerbates Skin Cancer Response in Adulthood with Contemporaneous Distortion of Tumor Stem Cell Dynamics SO CANCER RESEARCH LA English DT Article ID DNA HYPOMETHYLATION; CHRONIC STIMULATION; TRANSGENIC MOUSE; GROWTH-FACTORS; MICE; EXPRESSION; CARCINOGENESIS; IDENTIFICATION; ASSOCIATION; NEOPLASIA AB Arsenic is a carcinogen with transplacental activity that can affect human skin stem cell population dynamics in vitro by blocking exit into differentiation pathways. Keratinocyte stem cells (KSC) are probably a key target in skin carcinogenesis. Thus, we tested the effects of fetal arsenic exposure in Tg.AC mice, a strain sensitive to skin carcinogenesis via activation of the v-Ha-ras transgene likely in KSCs. After fetal arsenic treatment, offspring received topical 12-O-tetradecanoyl phorbol-13-acetate (TPA) through adulthood. Arsenic alone had no effect, whereas TPA alone induced papillomas and squamous cell carcinomas (SCC). However, fetal arsenic treatment before TPA increased SCC multiplicity 3-fold more than TPA alone, and these SCCs were much more aggressive (invasive, etc.). Tumor v-Ha-ras levels were 3-fold higher with arsenic plus TPA than TPA alone, and v-Ha-ras was overexpressed early on in arsenic-treated fetal skin. CD34, considered a marker for both KSCs and skin cancer stem cells, and Rac1, a key gene stimulating KSC self-renewal, were greatly increased in tumors produced by arsenic plus TPA exposure versus TPA alone, and both were elevated in arsenic-treated fetal skin. Greatly increased numbers of CD34-positive probable cancer stem cells and marked overexpression of RAC1 protein occurred in tumors induced by arsenic plus TPA compared with TPA alone. Thus, fetal arsenic exposure, although by itself oncogenically inactive in skin, facilitated cancer response in association with distorted skin tumor stem cell signaling and population dynamics, implicating stem cells as a target of arsenic in the fetal basis of skin cancer in adulthood. [Cancer Res 2008;68(20):8278-85] C1 [Waalkes, Michael P.; Liu, Jie; Tokar, Erik J.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. [Trempus, Carol S.; Cannon, Ronald E.; Tennant, Raymond W.] NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Germolee, Dori R.] NIEHS, Toxicol Branch, Res Triangle Pk, NC 27709 USA. [Ward, Jerrold M.] Global VetPathol, Montgomery Village, MD USA. [Diwan, Bhalchandra A.] NCI, Frederick Inc, Sci Applicat Int Corp, Basic Res Program, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NIH; National Cancer Institute [NO1-CO-12400]; Center for Cancer Research; National Institute of Environmental Health Sciences; NIAID FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (M.P. Waalkes, J. Liu, E.J. Tokar) and by the National Institute of Environmental Health Sciences (D.R. Germolec, C.S. Trempus, R.E. Cannon, R.W. Tennant). This research was funded in part with Federal funds from the National Cancer Institute under contract no. NO1-CO-12400 (B.A. Diwan) and an NIAID contract to SoBran, Inc., Bethesda, MD (J.M. Ward). NR 36 TC 55 Z9 55 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2008 VL 68 IS 20 BP 8278 EP 8285 DI 10.1158/0008-5472.CAN-08-2099 PG 8 WC Oncology SC Oncology GA 364GE UT WOS:000260323400011 PM 18922899 ER PT J AU Staquicini, FI Tandle, A Libutti, SK Sun, J Zigler, M Bar-Eli, M Aliperti, F Perez, EC Gershenwald, JE Mariano, M Pasqualini, R Arap, W Lopes, JD AF Staquicini, Fernanda I. Tandle, Anita Libutti, Steven K. Sun, Jessica Zigler, Maya Bar-Eli, Menashe Aliperti, Fabiana Perez, Elizabeth C. Gershenwald, Jeffrey E. Mariano, Mario Pasqualini, Renata Arap, Wadih Lopes, Jose Daniel TI A Subset of Host B Lymphocytes Controls Melanoma Metastasis through a Melanoma Cell Adhesion Molecule/MUC18-Dependent Interaction: Evidence from Mice and Humans SO CANCER RESEARCH LA English DT Article ID TUMOR-GROWTH; B-1 CELLS; RHEUMATOID-FACTOR; MUC18 EXPRESSION; IN-VIVO; ANTIBODY; INFLAMMATION; REPERTOIRE; MCAM/MUC18; INCREASE AB Host immunity affects tumor metastasis but the corresponding cellular and molecular mechanisms are not entirely clear. Here, we show that a subset of B lymphocytes (termed B-1 population), but not other lymphocytes, has prometastatic effects on melanoma cells in vivo through a direct heterotypic cell-cell interaction. In the classic B16 mouse melanoma model, one mechanism underlying this phenomenon is a specific up-regulation and subsequent homophilic interaction mediated by the cell surface glycoprotein MUC18 (also known as melanoma cell adhesion molecule). Presence of B-1 lymphocytes in a panel of tumor samples from melanoma patients directly correlates with MUC18 expression in melanoma cells, indicating that the same protein interaction exists in humans. These results suggest a new but as yet unrecognized functional role for host B-1 lymphocytes in tumor metastasis and establish a biochemical basis for such observations. Our findings support the counterintuitive central hypothesis in which a primitive layer of the immune system actually contributes to tumor progression and metastasis in a mouse model and in melanoma patients. Given that monoclonal antibodies against MUC18 are in preclinical development but the reason for their antitumor activity is not well understood, these translational results are relevant in the setting of human melanoma and perhaps of other cancers. [Cancer Res 2008;68(20):8419-28] C1 [Staquicini, Fernanda I.; Sun, Jessica; Zigler, Maya; Bar-Eli, Menashe; Gershenwald, Jeffrey E.; Pasqualini, Renata; Arap, Wadih] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Tandle, Anita; Libutti, Steven K.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Aliperti, Fabiana; Perez, Elizabeth C.; Mariano, Mario; Lopes, Jose Daniel] Univ Fed Sao Paulo, Sao Paulo, Brazil. RP Arap, W (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM rpasqual@mdanderson.org; warap@mdanderson.org; jdlopes@unifesp.br RI Perez, Elizabeth /E-8057-2012 OI Perez, Elizabeth /0000-0003-3038-9902 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo; Department of Defense; NCI; Gillson-Longenbaugh Foundation; AngelWorks FX Grant support: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (J.D. Lopes), Department of Defense (F.I. Staquicini, R. Pasqualim, and W. Arap), NCI (R. Pasqualini and W. Arap), Gillson-Longenbaugh Foundation, and AngelWorks. F.I. Staquicini received a predoctoral fellowship from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo. NR 41 TC 44 Z9 44 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2008 VL 68 IS 20 BP 8419 EP 8428 DI 10.1158/0008-5472.CAN-08-1242 PG 10 WC Oncology SC Oncology GA 364GE UT WOS:000260323400027 PM 18922915 ER PT J AU Haugen, AC Goel, A Yamada, K Marra, G Nguyen, TP Nagasaka, T Kanazawa, S Koike, J Kikuchi, Y Zhong, X Arita, M Shibuya, K Oshimura, M Hemmi, H Boland, CR Koi, M AF Haugen, Astrid C. Goel, Ajay Yamada, Kanae Marra, Giancarlo Nguyen, Thuy-Phuong Nagasaka, Takeshi Kanazawa, Shinsaku Koike, Junichi Kikuchi, Yoshinori Zhong, Xiaoling Arita, Michitsune Shibuya, Kazutoshi Oshimura, Mitsuo Hemmi, Hiromichi Boland, C. Richard Koi, Minoru TI Genetic Instability Caused by Loss of MutS Homologue 3 in Human Colorectal Cancer SO CANCER RESEARCH LA English DT Article ID LEVEL MICROSATELLITE INSTABILITY; DNA MISMATCH REPAIR; PROTEIN EXPRESSION; BLADDER-CANCER; LYNCH-SYNDROME; TUMOR-CELLS; HMUTS-BETA; MSH3; CARCINOMA; TRACT AB Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (NISI-L) exists; however, its molecular basis is unclear. There is another type of MSI-elevated microsatellite alterations at selected tetranucleotide repeats (EXAST)-where loci containing [AAAG](n) or [ATAG](n) repeats are unstable. EMAST is frequent in non-CRCs; however, the incidence of EMAST and its cause in CRC is not known. Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non-MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non-MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the total tumor cell population, the tissues exhibiting EXAST contained more MSH3-negative cells (average, 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of MSI at loci with dinucleotide repeats in CRC. [Cancer Res 2008;68(20):8465-721 C1 [Haugen, Astrid C.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC USA. [Goel, Ajay; Nguyen, Thuy-Phuong; Nagasaka, Takeshi; Boland, C. Richard; Koi, Minoru] Baylor Univ, Med Ctr, Gastrointestinal Canc Res Lab, Baylor Res Inst, Dallas, TX 75246 USA. [Goel, Ajay; Nguyen, Thuy-Phuong; Nagasaka, Takeshi; Boland, C. Richard; Koi, Minoru] Baylor Univ, Med Ctr, Sammons Canc Ctr, Dallas, TX 75246 USA. [Yamada, Kanae; Kikuchi, Yoshinori; Zhong, Xiaoling; Arita, Michitsune; Hemmi, Hiromichi] Toho Univ, Fac Med, Dept Mol Biol, Ohta Ku, Tokyo, Japan. [Kanazawa, Shinsaku; Koike, Junichi] Toho Univ, Fac Med, Dept Surg, Ohta Ku, Tokyo, Japan. [Shibuya, Kazutoshi] Toho Univ, Fac Med, Dept Surg Pathol, Ohta Ku, Tokyo, Japan. [Marra, Giancarlo] Univ Zurich, Inst Mol Canc Res, Zurich, Switzerland. [Oshimura, Mitsuo] Tottori Univ, Dept Biomed Sci, Inst Regenerat Med & Biofonct, Grad Sch Med Sci, Tottori 680, Japan. RP Boland, CR (reprint author), Baylor Univ, Med Ctr, Gastrointestinal Canc Res Lab Hoblitzelle 250, Baylor Res Inst, 3500 Gaston Ave, Dallas, TX 75246 USA. EM rickbo@baylorHealth.edu; minoruk@baylorHealth.edu RI Koi, Minoru/C-3489-2012; Koi, Minoru/G-9197-2014 FU NIH [1Z01ES023016-05, R01 CA72851]; Association for International Cancer Research [03-103]; Japan Society for the Promotion of Science [16591358]; Baylor University Medical Center FX Grant support: NIH intramural grant 1Z01ES023016-05, Association for International Cancer Research project grant 03-103 (M. Koi), grant-in-aid for Scientific Research of the Japan Society for the Promotion of Science 16591358 H. Hemmi), NIH grants R01 CA72851, and funds from Baylor University Medical Center (C.R. Boland). NR 40 TC 67 Z9 67 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2008 VL 68 IS 20 BP 8465 EP 8472 DI 10.1158/0008-5472.CAN-08-0002 PG 8 WC Oncology SC Oncology GA 364GE UT WOS:000260323400032 PM 18922920 ER PT J AU Taranova, AG Maldonado, D Vachon, CM Jacobsen, EA Abdala-Valencia, H McGarry, MP Ochkur, SI Protheroe, CA Doyle, A Grant, CS Cook-Mills, J Birnbaumer, L Lee, NA Lee, JJ AF Taranova, Anna G. Maldonado, David, III Vachon, Celine M. Jacobsen, Elizabeth A. Abdala-Valencia, Hiam McGarry, Michael P. Ochkur, Sergei I. Protheroe, Cheryl A. Doyle, Alfred Grant, Clive S. Cook-Mills, Joan Birnbaumer, Lutz Lee, Nancy A. Lee, James J. TI Allergic Pulmonary Inflammation Promotes the Recruitment of Circulating Tumor Cells to the Lung SO CANCER RESEARCH LA English DT Article ID ADHESION MOLECULE-1 VCAM-1; ENDOTHELIAL-CELLS; LYMPHOCYTE MIGRATION; T-LYMPHOCYTES; METASTASIS; CANCER; ASTHMA; MICROENVIRONMENT; EXTRAVASATION; EOSINOPHILS AB Allergen-induced respiratory inflammation facilitates and/or elicits the extravasation of proinflammatory leukocytes by well-understood mechanisms that mediate the movement of multiple cell types. The nonspecific character of these pathways led us to hypothesize that circulating cancer cells use similar mechanisms, promoting secondary tumor formation at distal sites. To test this hypothesis, the frequency of metastasis to the lung as a function of allergic pulmonary inflammation was assessed following the i.v. injection of B16-F10 melanoma cells in mice. These studies showed that allergen-induced pulmonary inflammation resulted in a >3-fold increase in lung metastases. This increase was dependent on CD4(+) T-cell activities; however, it occurred independent of the induced eosinophilia associated with allergen provocation. Interventional strategies showed that existing therapeutic modalities for asthma, such as inhaled corticosteroids, were sufficient to block the enhanced pulmonary recruitment of cancer cells from circulation. Additional mechanistic studies further suggested that the ability of circulating cancer cells to extravasate to surrounding lung tissues was linked to the activation of the vascular endothelium via one or more G alpha(i)-coupled receptors. Interestingly, a survey of a clinical breast cancer surgical database showed that the incidence of asthma was higher among patients with lung metastases. Thus, our data show that allergic respiratory inflammation may represent a risk factor for the development of lung metastases and suggest that amelioration of the pulmonary inflammation associated with asthma will have a direct and immediate benefit to the 7% to 8% of breast cancer patients with this lung disease. [Cancer Res 2008;68(20):8582-9] C1 [Lee, James J.] Mayo Clin, Div Pulm Med, Dept Biochem & Mol Biol, SCJMRB Res, Scottsdale, AZ 85259 USA. [Protheroe, Cheryl A.; Doyle, Alfred; Lee, Nancy A.] Mayo Clin, Div Hematol & Oncol, Dept Biochem & Mol Biol, Scottsdale, AZ 85259 USA. [Maldonado, David, III] Mayo Clin, Div Pulm & Crit Care Med, Dept Internal Med, Rochester, MN USA. [Grant, Clive S.] Mayo Clin, Ctr Comprehens Canc, Div Surg Oncol, Rochester, MN USA. [Abdala-Valencia, Hiam; Cook-Mills, Joan] Northwestern Univ, Div Allergy Immunol, Feinberg Sch Med, Chicago, IL 60611 USA. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC USA. RP Lee, JJ (reprint author), Mayo Clin, Div Pulm Med, Dept Biochem & Mol Biol, SCJMRB Res, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM jjlee@mayo.edu FU Mayo Foundation; NIH [R01CA112442, K26-RR019709, HL058723, F32HL83718] FX Grant support: Mayo Foundation; Intramural Research Program of the NIH (L. Birnbaumer); and NIH grants R01CA112442 and K26-RR019709 (J.J. Lee), HL058723 (N.A. Lee), and F32HL83718 (A.G. Taranova). NR 42 TC 26 Z9 26 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2008 VL 68 IS 20 BP 8582 EP 8589 DI 10.1158/0008-5472.CAN-08-1673 PG 8 WC Oncology SC Oncology GA 364GE UT WOS:000260323400046 PM 18922934 ER PT J AU Kim, HH Gorospe, M AF Kim, Hyeon Ho Gorospe, Myriam TI Phosphorylated HuR shuttles in cycles SO CELL CYCLE LA English DT Article DE HuR; post-transcriptional gene regulation; cell cycle; cyclins ID MESSENGER-RNA STABILITY; BINDING PROTEIN HUR; NUCLEAR IMPORT; STABILIZATION; SENESCENCE; EXPRESSION; EXPORT; CELLS; AUF1; CDK1 AB HuR is a ubiquitous RNA-binding protein (RBP) that associates with many mRNAs encoding proliferative proteins. Although predominantly nuclear, HuR translocation to the cytoplasm is linked to its ability to stabilize target mRNAs and modulate their translation. We recently reported that HuR phosphorylation by Cdk1 at S202 (within the HuR hinge region that is necessary for nucleocytoplasmic shuttle) increases HuR association with 14-3-3 and contributes to its nuclear retention. In the next issue of Cell Cycle we report that residue S242 also regulates HuR's cytoplasmic localization, influences cyclin expression, and modulates cell proliferation. Together with evidence of other post-translational HuR modifications, we propose that HuR phosphorylation ensures the timely mobilization of HuR across the nuclear envelope. In this manner, HuR helps to schedule gene expression programs in a cell cycle-dependent manner. C1 [Kim, Hyeon Ho; Gorospe, Myriam] NIA, LCMB, IRP, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, LCMB, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov FU National Institute on Aging; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 34 TC 41 Z9 41 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2008 VL 7 IS 20 BP 3124 EP 3126 DI 10.4161/cc.7.20.6884 PG 3 WC Cell Biology SC Cell Biology GA 363JI UT WOS:000260263200004 PM 18927508 ER PT J AU Bagnyukova, TV Tryndyak, VP Muskhelishvili, L Ross, SA Beland, FA Pogribny, IP AF Bagnyukova, Tetyana V. Tryndyak, Volodymyr P. Muskhelishvili, Levan Ross, Sharon A. Beland, Frederick A. Pogribny, Igor P. TI Epigenetic downregulation of the suppressor of cytokine signaling 1 (Socs1) gene is associated with the STAT3 activation and development of hepatocellular carcinoma induced by methyl-deficiency in rats SO CELL CYCLE LA English DT Article DE hepatocellular carcinoma; STAT3; Socs1; DNA methylation; histone lysine methylation ID HEPATIC STELLATE CELLS; GROWTH-FACTOR-BETA; LIVER FIBROSIS; PDGF-D; MOLECULAR PATHOGENESIS; DNA METHYLATION; RECEPTOR-ALPHA; CANCER; EXPRESSION; HEPATOCARCINOGENESIS AB The members of the platelet-derived growth factor (PDGF) and the transforming growth factor-beta (TGF beta) pathways are important in the induction of liver fibrosis and cirrhosis; however, their role in the subsequent progression to hepatocellular carcinoma (HCC) remains elusive. Our study provides new insights into mechanisms of dysregulation of PDGFs, TGF beta and signal transducer and activator of transcription (STAT) pathways in the pathogenesis of methyl-deficient rodent liver carcinogenesis, a remarkably relevant model to the development of HCC in humans. We demonstrated a progressive increase in the Pdgfs and TGF beta expression in preneoplastic tissue and liver tumors indicating their promotional role in carcinogenesis, particularly in progression of liver fibrosis and cirrhosis. However, activation of the STAT3 occurred only in fully developed HCC and was associated with downregulation of the Socs1 gene. The inhibition of the Socs1 expression in HCC was associated with an increase in histone H3 lysine 9, H3 lysine 27, and H4 lysine 20 trimethylation at the Socs1 promoter, but not with promoter methylation. The results of our study suggest the following model of events in hepatocarcinogenesis: during early stages, overexpression of the Socs1 effectively inhibits TGF beta- and PDGF-induced STAT3 activation, whereas, during the advanced stages of hepatocarcinogenesis, the Socs1 downregulation resulted in loss of its ability to attenuate the signal from the upregulated TGF beta and PDGFs leading to oncogenic STAT3 activation and malignant cell transformation. This model illustrates that the Socs1 acts as classic tumor suppressor by preventing activation of the STAT3 and downregulation of Socs1 and consequent activation of STAT3 may be a crucial events leading to formation of HCC. C1 [Bagnyukova, Tetyana V.; Tryndyak, Volodymyr P.; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Muskhelishvili, Levan] Natl Ctr Toxicol Res, Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Ross, Sharon A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov FU Oak Ridge Institute for Science and Education FX This work is supported in part (VT, TB) by the Postgraduate Research Program administered by the Oak Ridge Institute for Science and Education. NR 53 TC 20 Z9 23 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2008 VL 7 IS 20 BP 3202 EP 3210 DI 10.4161/cc.7.20.6816 PG 9 WC Cell Biology SC Cell Biology GA 363JI UT WOS:000260263200016 PM 18843197 ER PT J AU Aune, GJ Takagi, K Sordet, O Guirouilh-Barbat, J Antony, S Bohr, VA Pommier, Y AF Aune, Gregory J. Takagi, Kazutaka Sordet, Olivier Guirouilh-Barbat, Josee Antony, Smitha Bohr, Vilhelm A. Pommier, Yves TI Von Hippel-Lindau - Coupled and Transcription-Coupled Nucleotide Excision Repair - Dependent Degradation of RNA Polymerase 11 in Response to Trabectendin SO CLINICAL CANCER RESEARCH LA English DT Article ID II LARGEST SUBUNIT; DNA-REPAIR; CARIBBEAN TUNICATE; ANTITUMOR-ACTIVITY; HUMAN-CELLS; ECTEINASCIDIN-743 ET-743; INDUCED UBIQUITINATION; CRYSTAL-STRUCTURES; MINOR-GROOVE; GENE AB Purpose: Ecteinascidin 743 (Et743; trabectedin,Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II. Experimental Design and Results: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation.We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency. Conclusion: These results suggest that both TC-NER - induced and VHL-mediated Pol II degradation play a role in cell killing by Et743. C1 [Aune, Gregory J.; Takagi, Kazutaka; Sordet, Olivier; Guirouilh-Barbat, Josee; Antony, Smitha; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Room 5068,Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Sordet, Olivier/M-3271-2014; Aune, Gregory/I-5895-2015 OI Aune, Gregory/0000-0002-2750-6461 FU NIH; National Cancer Institute; Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 50 TC 22 Z9 22 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 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2008 VL 14 IS 20 BP 6449 EP 6455 DI 10.1158/1078-0432.CCR-08-0730 PG 7 WC Oncology SC Oncology GA 364TZ UT WOS:000260359600013 PM 18927284 ER PT J AU Ross, DT Kim, CY Tang, G Bohn, OL Beck, RA Ring, BZ Seitz, RS Paik, S Costantino, JP Wolmark, N AF Ross, Douglas T. Kim, Chung-yeul Tang, Gong Bohn, Olga L. Beck, Rodney A. Ring, Brian Z. Seitz, Robert S. Paik, Soonmyung Costantino, Joseph P. Wolmark, Norman TI Chemosensitivity and Stratification by a Five Monoclonal Antibody Immunohistochemistry Test in the NSABP B14 and B20 Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID POSITIVE BREAST-CANCER; SURGICAL ADJUVANT BREAST; UPDATED FINDINGS; GENE-EXPRESSION; CLINICAL-TRIALS; TAMOXIFEN; CHEMOTHERAPY; PREDICTORS AB Purpose: To test the association between risk stratification and outcome in a prospectively designed, blinded retrospective study using tissue arrays of available paraffin blocks from the estrogen receptor-expressing, node-negative samples from the National Surgical Adjuvant Breast and Bowel Project B14 and B20 tamoxifen and chemotherapy trials. Experimental Design: Tissue arrays were stained by immunohistochemistry targeting p53, NDRG1, SLC7A5, CEACAM5, and HTF9C. Risk stratification was done using predefined scoring rules, algorithm for combining scores, and cutoff points for low-risk, moderate-risk, and high-risk patient strata. Results: In a univariate Cox model, this test was significantly associated with recurrence-free interval [HR, 1.3 (95% confidence interval, 1.1-1.6); P = 0.006]. In a multivariate model it contributed information independent of age, tumor size, and menopausal status (P = 0.007). The Kaplan-Meier estimates of the proportion of recurrence-free after 10 years were 73%, 86%, and 85% for the high-risk, moderate-risk, and low-risk groups (P = 0.001). The Kaplan-Meier estimates of the breast-cancer-specific-death rate were 23%, 10%, and 9% (P < 0.0001). Exploratory analysis in patients >= 60 years old showed Kaplan-Meier estimates of the proportion of recurrence-free of 78%, 89%, and 92%. Both high-risk and low-risk groups showed significant improvement on treatment with cytotoxic chemotherapy, Conclusions: Immunohistochemistry using five monoclonal antibodies assigns breast cancer patients to a risk index that was significantly associated with clinical outcome among the estrogen receptor-expressing, node-negative tamoxifen-treated patients. It seems that the test may be able to identify patients who have greater absolute benefit from adjuvant chemotherapy compared with unstratified patient populations. Exploratory analysis suggests that this test will be most useful in clinical decision making for postmenopausal patients. C1 [Ross, Douglas T.; Ring, Brian Z.] Appl Genom Inc, Burlingame, CA 94010 USA. [Kim, Chung-yeul; Bohn, Olga L.; Paik, Soonmyung] Univ Pittsburgh, Div Pathol, Pittsburgh, PA 15260 USA. [Tang, Gong; Costantino, Joseph P.] Univ Pittsburgh, Ctr Biostat, Pittsburgh, PA 15260 USA. [Wolmark, Norman] Univ Pittsburgh, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15260 USA. [Tang, Gong; Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15260 USA. [Wolmark, Norman] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Beck, Rodney A.; Seitz, Robert S.] Appl Genom Inc, Huntsville, AL USA. RP Ross, DT (reprint author), Appl Genom Inc, 863 Mitten Ave,Suite 103, Burlingame, CA 94010 USA. EM dross@applied-genomics.com FU NCI NIH HHS [U10 CA069651, U10 CA069651-15, U10 CA012027, U10 CA012027-38, U24 CA114732, U24 CA114732-04] NR 17 TC 30 Z9 30 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2008 VL 14 IS 20 BP 6602 EP 6609 DI 10.1158/1078-0432.CCR-08-0647 PG 8 WC Oncology SC Oncology GA 364TZ UT WOS:000260359600030 PM 18927301 ER PT J AU Christensen, PB Engle, RE Hjort, C Homburg, KM Vach, W Georgsen, J Purcell, RH AF Christensen, Peer B. Engle, Ronald E. Hjort, Charlotte Homburg, Keld M. Vach, Werner Georgsen, Jorgen Purcell, Robert H. TI Time trend of the prevalence of hepatitis e antibodies among farmers and blood donors: A potential zoonosis in Denmark SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID E VIRUS-INFECTION; UNITED-STATES; WILD BOAR; SWINE; IDENTIFICATION; TRANSMISSION; COUNTRIES; HEV; SEROREACTIVITY; NETHERLANDS AB Background. Antibody to hepatitis E virus (anti-HEV) is prevalent in Western countries, where clinical hepatitis E is rarely reported. The aim of this study was to determine the prevalence of anti-HEV among Danish blood donors and Danish farmers. In addition, we compared the prevalence among 2 sets of serum samples obtained from blood donors 20 years apart. Methods. Samples from 291 Danish farmers and 169 blood donors that were collected in 1983 and samples from 461 blood donors that were collected in 2003 were tested for anti-HEV. Relevant information on HEV exposure was collected by self-administered questionnaire. Results. Anti-HEV testing was performed on samples after 20 years of storage at -20 degrees C. The prevalence of anti-HEV was 50.4% among farmers and 32.9% among donors in 1983 and 20.6% among donors in 2003 (P<). Presence of anti-HEV was significantly correlated with increasing age in all 3 groups (P<.05). Among donors who had serum samples obtained in 2003, age, contact with horses, and the presence of antibody to hepatitis A virus were associated with the presence of anti-HEV in multivariate analysis. Among farmers, only age was independently associated with the presence of anti-HEV. Conclusion. Anti-HEV was highly prevalent among Danes but has decreased in prevalence over the past 50 years. Our study supports the hypothesis that HEV infection in Denmark may be an asymptomatic zoonotic infection. C1 [Christensen, Peer B.] Odense Univ Hosp, Dept Infect Dis, DK-5000 Odense C, Denmark. [Georgsen, Jorgen] Odense Univ Hosp, Dept Clin Immunol, DK-5000 Odense C, Denmark. [Vach, Werner] Univ So Denmark, Dept Stat, Odense, Denmark. [Hjort, Charlotte] Univ Aarhus, Dept Environm & Occupat Med, Inst Publ Hlth, Aarhus, Denmark. [Homburg, Keld M.] Hosp South, Dept Clin Immunol, Naestved, Denmark. [Engle, Ronald E.; Purcell, Robert H.] NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. RP Christensen, PB (reprint author), Odense Univ Hosp, Dept Infect Dis, Sdr Blvd 29, DK-5000 Odense C, Denmark. EM peer.christensen@dadlnet.dk RI Vach, Werner/F-2512-2011; Christensen, Peer/B-8042-2015 OI Vach, Werner/0000-0003-1865-8399; FU National Institute of Allergy and Infectious Diseases; National Institutes of Health FX Director of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 39 TC 107 Z9 109 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 15 PY 2008 VL 47 IS 8 BP 1026 EP 1031 DI 10.1086/591970 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 349XA UT WOS:000259315400007 PM 18781880 ER PT J AU Satyanarayana, A Berthet, C Lopez-Molina, J Coppola, V Tessarollo, L Kaldis, P AF Satyanarayana, Ande Berthet, Cyril Lopez-Molina, Javier Coppola, Vincenzo Tessarollo, Lino Kaldis, Philipp TI Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2 SO DEVELOPMENT LA English DT Article DE cell cycle regulation; cyclin; cyclin-dependent kinase (Cdk); meiosis; mouse genetics ID CYCLIN-DEPENDENT KINASES; CELL-CYCLE; LIVER-REGENERATION; CDC2 KINASE; PROTEIN; MICE; PHASE; PHOSPHORYLATION; HEPATECTOMY; REPLACEMENT AB It was believed that Cdk2-cyclin E complexes are essential to drive cells through the G1-S phase transition. However, it was discovered recently that the mitotic kinase Cdk1 (Cdc2a) compensates for the loss of Cdk2. In the present study, we tested whether Cdk2 can compensate for the loss of Cdk1. We generated a knockin mouse in which the Cdk2 cDNA was knocked into the Cdk1 locus (Cdk1(Cdk2KI)). Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality, even though Cdk2 was expressed from the Cdk1 locus. In addition, we generated Cdk2(-/-) Cdk1(+/Cdk2KI) mice in which one copy of Cdk2 and one copy of Cdk1 were expressed from the Cdk1 locus and the Cdk2 gene was deleted from the endogenous Cdk2 locus. We found that both male and female Cdk2(-/-) Cdk1(+/Cdk2KI) mice were sterile, similar to Cdk2(-/-) mice, even though they expressed the Cdk2 protein from the Cdk1 locus in testes. The translocational and cell cycle properties of knockin Cdk2 in Cdk2(-/-) Cdk1(+/Cdk2KI) cells were comparable to those of endogenous Cdk2, but we detected premature transcriptional activation of Cdk1 during liver regeneration in the absence of Cdk2. This study provides evidence of the molecular differences between Cdk2 and Cdk1 and highlights that the timing of transcriptional activation and the genetic locus play important roles in determining the function of Cdk proteins in vivo. C1 [Satyanarayana, Ande; Berthet, Cyril; Coppola, Vincenzo; Tessarollo, Lino; Kaldis, Philipp] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Lopez-Molina, Javier] Whitehead Inst, Cambridge, MA 02142 USA. [Kaldis, Philipp] IMCB, Singapore 138673, Singapore. RP Kaldis, P (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560-22-56,1050 Boyles St, Frederick, MD 21702 USA. EM kaldis@imcb.a-star.edu.sg RI Coppola, Vincenzo/E-2917-2011; Kaldis, Philipp/G-2714-2010; ASTAR, IMCB/E-2320-2012 OI Coppola, Vincenzo/0000-0001-6163-1779; Kaldis, Philipp/0000-0002-7247-7591; FU NIH; National Cancer Institute; Center for Cancer Research FX We thank Mary Beth Hilton, Matt McCollum and Angie Smith for animal care; Eileen Southon and Susan Reid for technical help generating the knockin mice; Donna Butcher, Roberta Smith and the Pathology/Histotechnology Laboratory, LASP, NCI-Frederick, for tissue sectioning and staining; Scott Lawrence and Richard Frederickson for helping with embryo photographs; members of the Kaldis laboratory and David Page for discussions and support. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 34 TC 33 Z9 33 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD OCT 15 PY 2008 VL 135 IS 20 BP 3389 EP 3400 DI 10.1242/dev.024919 PG 12 WC Developmental Biology SC Developmental Biology GA 353LH UT WOS:000259568600008 PM 18787066 ER PT J AU Vallelian, F Pimenova, T Pereira, CP Abraham, B Mikolajczyk, MG Schoedon, G Zenobi, R Alayash, AI Buehler, PW Schaer, DJ AF Vallelian, Florence Pimenova, Tatiana Pereira, Claudia P. Abraham, Bindu Mikolajczyk, Malgorzata G. Schoedon, Gabriele Zenobi, Renato Alayash, Abdu I. Buehler, Paul W. Schaer, Dominik J. TI The reaction of hydrogen peroxide with hemoglobin induces extensive alpha-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Hemoglobin; Haptoglobin; CD163; Hydrogen peroxide; Oxidative stress ID HEME UPTAKE; INTRAPLAQUE HEMORRHAGE; CARDIOVASCULAR-DISEASE; MACROPHAGES; HAPTOGLOBIN; MYOGLOBIN; RECEPTOR; CD163; DETERMINES; ACTIVATION AB Cell-free hemoglobin (Hb) enhances the oxidation-related toxicity associated with inflammation, ischemia, and hemolytic disorders. Hb is highly vulnerable to oxidative damage, and irreversible structural changes involving iron/heme oxidation, heme-adduct products, and amino acid oxidation have been reported. Specific structural features of Hb, such as unconstrained a-chains and molecular size, determine the efficiency of interactions between the endogenous Hb scavengers haptoglobin (Hp) and CD163. Using HPLC, mass spectrometry, and Western blotting, we show that H2O2-mediated Hb oxidation results in the formation of covalently stabilized globin multimers, with prominent intramolecular crosslinking between a-globin chains. These structural alterations are associated with reduced Hp binding, reduced CD163 interaction, and severely impaired endocytosis of oxidized Hb by the Hp-CD163 pathway. As a result, when exposed to oxidized Hb, CD163-positive HEK293 cells and human macrophages do not increase hemeoxygenase-1 (HO-1) expression, the physiological anti-oxidative macrophage response to Hb exposure. Failed Hb clearance, inadequate HO-1 expression, and the subsequent accumulation of oxidatively damaged Hb species might thus contribute to pathologies related to oxidative stress. (C) 2008 Elsevier Inc. All rights reserved. C1 [Abraham, Bindu; Mikolajczyk, Malgorzata G.; Alayash, Abdu I.; Buehler, Paul W.; Schaer, Dominik J.] US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Vallelian, Florence; Pereira, Claudia P.; Schoedon, Gabriele; Schaer, Dominik J.] Univ Zurich, Internal Med Res Unit, Zurich, Switzerland. [Pimenova, Tatiana; Zenobi, Renato] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Zurich, Switzerland. RP Buehler, PW (reprint author), NIH, LBUB, CBER, FDA, Bldg 29,8800 Rockville Pike, Bethesda, MD 20892 USA. EM paul.buehler@fda.hhs.gov; dominik.schaer@usz.ch RI Zenobi, Renato/F-1113-2010 FU Swiss National Science Foundation [310000-120658, 200020-111831]; Hartmann Muller Foundation; Helmut-Horten Foundation FX The work described in this article was supported by the Swiss National Science Foundation (SNF grant 310000-120658 to DJ.S. and SNF grant 200020-111831 to R.Z.), the Hartmann Muller Foundation (F.V.), and the Helmut-Horten Foundation (D.J.S.). NR 38 TC 36 Z9 36 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT 15 PY 2008 VL 45 IS 8 BP 1150 EP 1158 DI 10.1016/j.freeradbiomed.2008.07.013 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 361XO UT WOS:000260161300012 PM 18708138 ER PT J AU Pascual-Garcia, P Govind, CK Queralt, E Cuenca-Bono, B Llopis, A Chavez, S Hinnebusch, AG Rodriguez-Navarro, S AF Pascual-Garcia, Pau Govind, Chhabi K. Queralt, Ethel Cuenca-Bono, Bernardo Llopis, Ana Chavez, Sebastian Hinnebusch, Alan G. Rodriguez-Navarro, Susana TI Sus1 is recruited to coding regions and functions during transcription elongation in association with SAGA and TREX2 SO GENES & DEVELOPMENT LA English DT Article DE Sus1; SAGA; TREX2; transcription elongation; mRNA export ID MESSENGER-RNA EXPORT; HISTONE ACETYLTRANSFERASE ACTIVITY; IN-VIVO; SACCHAROMYCES-CEREVISIAE; COTRANSCRIPTIONAL RECRUITMENT; H2B UBIQUITYLATION; CELL-CYCLE; COMPLEX; PROTEIN; UBP8 AB Gene transcription, RNA biogenesis, and mRNA transport constitute a complicated process essential for all eukaryotic cells. The transcription/ export factor Sus1 plays a key role in coupling transcription activation with mRNA export, and it resides in both the SAGA and TREX2 complexes. Moreover, Sus1 is responsible for GAL1 gene gating at the nuclear periphery, which is important for its transcriptional status. Here, we show that Sus1 is required during transcription elongation and is associated with the elongating form of RNA Polymerase II (RNAP II) phosphorylated on Ser5 and Ser2 of the C-terminal domain (CTD). In addition, Sus1 copurifies with the essential mRNA export factors Yra1 and Mex67, which bind to the mRNA cotranscriptionally. Consistently, ChIP analysis reveals that Sus1 is present at coding regions dependent on transcription in a manner stimulated by Kin28-dependent CTD phosphorylation. Strikingly, eliminating the TREX2 component Sac3 or the SAGA subunit Ubp8 partially impairs Sus1 targeting to coding sequences and upstream activating sequences (UAS). We found, unexpectedly, that Sgf73 is necessary for association of Sus1 with both SAGA and TREX2, and that its absence dramatically reduces Sus1 occupancy of UAS and ORF sequences. Our results reveal that Sus1 plays a key role in coordinating gene transcription and mRNA export by working at the interface between the SAGA and TREX2 complexes during transcription elongation. C1 [Pascual-Garcia, Pau; Queralt, Ethel; Cuenca-Bono, Bernardo; Llopis, Ana; Rodriguez-Navarro, Susana] CIPE, E-46012 Valencia, Spain. [Govind, Chhabi K.; Hinnebusch, Alan G.] NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Chavez, Sebastian] Univ Seville, Dept Genet, E-41012 Seville, Spain. RP Rodriguez-Navarro, S (reprint author), CIPE, E-46012 Valencia, Spain. EM srodriguez@cipf.es RI Chavez, Sebastian/F-7574-2011; Queralt, Ethel/D-8090-2015; Rodriguez-Navarro, Susana/B-5182-2014; IBIS, GENICA/O-1906-2015 OI Chavez, Sebastian/0000-0002-8064-4839; Queralt, Ethel/0000-0003-0045-0039; Rodriguez-Navarro, Susana/0000-0001-7472-3111; FU MEC [BFU2007-67575-C03-02, BFU200506856]; Andalusian Government [CVI-271]; NIH; GV [ACOMP06/165, ACOMP07/013]; CIPF FX We are grateful to Dr. J. Workman, Dr C. Dargemont, and Dr. P. Sanz for yeast strains, antibodies, or plasmids. We thank Dr. Jimeno for her contribution. The excellent technical assistance of the Mass Spectrometry service in the CIPF (ProteoRed Network), especially Dr. Valero, is acknowledged. S. C. is supported by MEC (BFU2007-67575-C03-02) and the Andalusian Government (CVI-271). This work was supported partly by the Intramural Research Program of the NIH. S. R.-N. is supported by the Ramon y Cajal program and funded by the MEC (BFU200506856) and the GV (ACOMP06/165 and ACOMP07/013). P. P.G. and B. C.-B. are holders of predoctoral fellowships from the CIPF and MEC, respectivelly. NR 48 TC 62 Z9 65 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD OCT 15 PY 2008 VL 22 IS 20 BP 2811 EP 2822 DI 10.1101/gad.483308 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 360QT UT WOS:000260073200009 PM 18923079 ER PT J AU Xu, DY Guo, R Sobeck, A Bachrati, CZ Yang, J Enomoto, T Brown, GW Hoatlin, ME Hickson, ID Wang, WD AF Xu, Dongyi Guo, Rong Sobeck, Alexandra Bachrati, Csanad Z. Yang, Jay Enomoto, Takemi Brown, Grant W. Hoatlin, Maureen E. Hickson, Ian D. Wang, Weidong TI RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability SO GENES & DEVELOPMENT LA English DT Article DE Bloom syndrome; BLM; BLAP75; RMI1; RMI2; Topoisomerase 3 alpha ID TOPOISOMERASE-III-ALPHA; HOMOLOGOUS RECOMBINATION; SYNDROME HELICASE; BRANCH MIGRATION; REPLICATION FORK; DNA-REPLICATION; FANCONI-ANEMIA; BLM HELICASE; D-LOOPS; REPAIR AB BLM, the helicase mutated in Bloom syndrome, associates with topoisomerase 3 alpha, RMI1 (RecQ-mediated genome instability), and RPA, to form a complex essential for the maintenance of genome stability. Here we report a novel component of the BLM complex, RMI2, which interacts with RMI1 through two oligonucleotide-binding (OB)- fold domains similar to those in RPA. The resulting complex, named RMI, differs from RPA in that it lacks obvious DNA-binding activity. Nevertheless, RMI stimulates the dissolution of a homologous recombination intermediate in vitro and is essential for the stability, localization, and function of the BLM complex in vivo. Notably, inactivation of RMI2 in chicken DT40 cells results in an increased level of sister chromatid exchange ( SCE) - the hallmark feature of Bloom syndrome cells. Epistasis analysis revealed that RMI2 and BLM suppress SCE within the same pathway. A point mutation in the OB domain of RMI2 disrupts the association between BLM and the rest of the complex, and abrogates the ability of RMI2 to suppress elevated SCE. Our data suggest that multi-OB-fold complexes mediate two modes of BLM action: via RPA-mediated protein-DNA interaction, and via RMI-mediated protein-protein interactions. C1 [Xu, Dongyi; Guo, Rong; Wang, Weidong] NIA, Genet Lab, NIH, Ctr Biomed Res, Baltimore, MD 21224 USA. [Sobeck, Alexandra; Hoatlin, Maureen E.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Bachrati, Csanad Z.; Hickson, Ian D.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [Yang, Jay; Brown, Grant W.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Enomoto, Takemi] Tohoku Univ, Grad Sch Pharmaceut Sci, Mol Cell Biol Lab, Sendai, Miyagi 9808578, Japan. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, Ctr Biomed Res, Baltimore, MD 21224 USA. EM wangw@grc.nia.nih.gov OI Bachrati, Csanad Z./0000-0003-1703-5894; Xu, Dongyi/0000-0001-5711-2618 FU National Institute on Aging [Z01 AG000657-08]; National Institutes of Health; Canadian Institutes of Health Research [MOP-79368] FX We thank Drs. A. R. Meetei for communicating unpublished data, G. Li for recombinant RPA, and D. Schlessinger for critical reading of the manuscript. This work was supported in part by the Intramural Research Program of the National Institute on Aging (Z01 AG000657-08), National Institutes of Health; and by the Canadian Institutes of Health Research (MOP-79368). NR 41 TC 108 Z9 118 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD OCT 15 PY 2008 VL 22 IS 20 BP 2843 EP 2855 DI 10.1101/gad.1708608 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 360QT UT WOS:000260073200012 PM 18923082 ER PT J AU Strasak, AM Pfeiffer, RM Klenk, J Hilbe, W Oberaigner, W Gregory, M Concin, H Diem, G Pfeiffer, KP Ruttmann, E Ulmer, H AF Strasak, Alexander M. Pfeiffer, Ruth M. Klenk, Jochen Hilbe, Wolfgang Oberaigner, Willi Gregory, Martin Concin, Hans Diem, Guenter Pfeiffer, Karl P. Ruttmann, Elfriede Ulmer, Hanno CA VHM TI Prospective study of the association of gamma-glutamyltransferase with cancer incidence in women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE gamma-glutamyltransferase; cancer incidence; risk factor; epidemiology; women ID CARDIOVASCULAR RISK-FACTORS; MIDDLE-AGED MEN; SERUM URIC-ACID; ALCOHOL-CONSUMPTION; METABOLIC SYNDROME; PROGNOSTIC VALUE; DRUG-RESISTANCE; NATIONAL-HEALTH; HEART-DISEASE; TRANSPEPTIDASE AB Although several epidemiologic studies have shown that gamma-glutamyltransferase (GGT) is associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In experimental models the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it may thus play a role in tumor progression. In the present study, we investigated the association of GGT with overall and site-specific cancer incidence in a population-based cohort of 92,843 Austrian women with 349,674 serial GGT measurements, prospectively followed-up for a median of 13.5 years. The relationship between GGT and cancer incidence was analyzed using adjusted Cox regression models with age as underlying time metric with age as underlying time metric including GGT concentrations at baseline and incorporating repeated GGT measurements as a time-dependent variable. During follow-up, 4,884 incidence cancers were observed. Compared to normal low GGT (<17.99 U/L), cancer risk was elevated for all other GGT categories (p for trend < 0.0001), with adjusted hazard ratios (95% confidence intervals) of 1.06 (0.99-1.13) for GGT levels between 18.00 and 35.99 U/L (normal high), 1.12 (1.02-1.22) for GGT levels between 36.00 and 71.99 U/L (elevated) and 1.43 (1.28-1.61) for highly elevated GGT (>72.00 U/L). Very similar results were seen when GGT was analyzed as a time-dependent variable. In cancer-site specific models, elevated GGT statistically significantly increased the risk for malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, breast and female genital organs and lymphoid and haematopoietic cancers (all, p < 0.006). Our study is the first to demonstrate in a large population-based cohort that high GGT levels significantly increased cancer risk in women. Published 2008 Wiley-Liss, Inc. This article is a US Government work, and, as such. is in the public domain in the United States of America. C1 [Strasak, Alexander M.; Pfeiffer, Karl P.; Ulmer, Hanno] Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria. [Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Klenk, Jochen] Univ Ulm, Inst Epidemiol, Ulm, Germany. [Hilbe, Wolfgang] Innsbruck Med Univ, Dept Haematol & Oncol, A-6020 Innsbruck, Austria. [Oberaigner, Willi] Tyrolean State Hosp Ltd, Dept Clin Epidemiol, Canc Registry Tyrol, Innsbruck, Austria. [Gregory, Martin] SAS Inst Inc, Heidelberg, Germany. [Ruttmann, Elfriede] Innsbruck Med Univ, Dept Cardiac Surg, A-6020 Innsbruck, Austria. RP Strasak, AM (reprint author), Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Schoepfstr 41, A-6020 Innsbruck, Austria. EM alexander.strasak@i-med.ac.at RI Ruttmann, Elfriede/D-6501-2011; Pfeiffer, Ruth /F-4748-2011; vhmpp, aks/F-9756-2012; Klenk, Jochen/C-2164-2012; Ulmer, Hanno/C-3488-2011; OI Ulmer, Hanno/0000-0001-5911-1002; Klenk, Jochen/0000-0002-5987-447X FU Austrian National Bank [OENB-12737]; Government of the State of Vorarlberg, Austria FX Grant sponsor: Austrian National Bank; Grant number: OENB-12737. Grant sponsor: Government of the State of Vorarlberg, Austria. NR 46 TC 40 Z9 44 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2008 VL 123 IS 8 BP 1902 EP 1906 DI 10.1002/ijc.23714 PG 5 WC Oncology SC Oncology GA 352TA UT WOS:000259519100022 PM 18688855 ER PT J AU Huang, TTK Glass, TA AF Huang, Terry T. -K. Glass, Thomas A. TI Transforming research strategies for understanding and preventing obesity SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HEALTH C1 [Huang, Terry T. -K.] NICHHD, Obes Res Strateg Core, NIH, Bethesda, MD 20892 USA. [Glass, Thomas A.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Huang, TTK (reprint author), NICHHD, Obes Res Strateg Core, NIH, 6100 Execut Blvd,4B11, Bethesda, MD 20892 USA. EM huangter@mail.nih.gov OI Glass, Thomas/0000-0003-4399-612X NR 15 TC 73 Z9 73 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 15 PY 2008 VL 300 IS 15 BP 1811 EP 1813 DI 10.1001/jama.300.15.1811 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 359QA UT WOS:000260002000034 PM 18854544 ER PT J AU Kotsyfakis, M Anderson, JM Andersen, JF Calvo, E Francischetti, IMB Mather, TN Valenzuela, JG Ribeiro, JMC AF Kotsyfakis, Michalis Anderson, Jennifer M. Andersen, John F. Calvo, Eric Francischetti, Ivo M. B. Mather, Thomas N. Valenzuela, Jesus G. Ribeiro, Jose M. C. TI Cutting edge: Immunity against a "Silent" salivary antigen of the Lyme vector Ixodes scapularis impairs its ability to feed SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TICK SALIVA; INHIBITOR; PATHOGEN; GLAND; TRANSMISSION; PROTEIN; CLONING; HOST AB Ixodes scapularis ticks transmit the Lyme disease agent in the United States. Although strong antitick immunity mediates tick rejection by certain vertebrates, only a few Ags have been molecularly characterized. We show that guinea pig vaccination against a secreted tick salivary immunomodulator, sialostatin L2, can lead to decreased feeding ability of L scapularis nymphs. Increased rejection rate, prolonged feeding time, and apparent signs of inflammation were observed for nymphs attached to vaccinated animals, indicating a protective host immune response. Interestingly, sialostatin L2 humoral recognition does not take place upon repeated tick exposure in control animals, but only in the vaccinated animals that neutralize sialostatin L2 action. Therefore, we demonstrate an essential sialostatin L2 role upon nymphal infestation that can be blocked by vertebrate immunity and propose the discovery of similarly "silent" Ags toward the development of a multicomponent vaccine that will protect against tick bites and the pathogens theytransmit. C1 [Kotsyfakis, Michalis; Andersen, John F.; Calvo, Eric; Francischetti, Ivo M. B.; Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Anderson, Jennifer M.; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Mather, Thomas N.] Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. RP Kotsyfakis, M (reprint author), NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM mkotsyfakis@mail.nih.gov RI Kotsyfakis, Michail/G-9525-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) [2R01 A137230] FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and was also partially supported by NIH Extramural Grant 2R01 A137230 to T.N.M. NR 18 TC 44 Z9 44 U1 0 U2 6 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 OCT 15 PY 2008 VL 181 IS 8 BP 5209 EP 5212 PG 4 WC Immunology SC Immunology GA 359YX UT WOS:000260025300008 PM 18832673 ER PT J AU Wang, L van Panhuys, N Hu-Li, J Kim, SH Le Gros, G Min, BK AF Wang, Lu van Panhuys, Nicholas Hu-Li, Jane Kim, Sohee Le Gros, Graham Min, Booki TI Blimp-1 induced by IL-4 plays a critical role in suppressing IL-2 production in activated CD4 T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTIONAL REPRESSOR BLIMP-1; GENE-EXPRESSION; TH2 DIFFERENTIATION; B-LYMPHOCYTES; PLASMA-CELLS; TNF-ALPHA; INTERLEUKIN-4; MECHANISMS; GATA-3; HOMEOSTASIS AB Although an inhibitory function of IL-4 in CD4 T cell IL-2 production has long been recognized, a mechanism mediating the inhibition remains unclear. In this study we demonstrate that IL-4 displays a potent suppressive function in IL-2 production of activated CD4 T cells through STAT6. IL-4-induced IL-2 suppression required IL-2 because IL-2 neutralization restored the production of IL-2 even in the presence of IL-4. In vivo, enhanced IL-2 production was found in nematode-infected IL-4- or STAT6-deficient animals, whereas immunization in the presence of IL-4 substantially diminished IL-2 production by Ag-specific CD4 T cells. IL-2 mRNA expression was reduced when T cells were stimulated in the presence of IL-4, whereas IL-2 mRNA decay was unaltered, suggesting that IL-4 mediates the suppression at a transcriptional level. Blimp-1 induced by IL-4 stimulation in activated CD4 T cells was found to be necessary to mediate the IL-2 inhibition as IL-4-mediated IL-2 suppression was less pronounced in activated CD4 T cells deficient in Blimp-1. Taken together, our results demonstrate a potential link with IL-4, Blimp-1, and IL-2 production, suggesting that Blimp-1 may play an important role in controlling IL-2 production in activated T cells and in adaptive T cell immunity. C1 [Wang, Lu; Kim, Sohee; Min, Booki] Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, Cleveland, OH 44195 USA. [van Panhuys, Nicholas; Le Gros, Graham] Malaghan Inst Med Res, Wellington, New Zealand. [Hu-Li, Jane] NIAID, Natl Inst Hlth, Immunol Lab, Bethesda, MD 20892 USA. RP Min, BK (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, NB30,9500 Euclid Ave, Cleveland, OH 44195 USA. EM minb@ccf.org RI Le Gros, Graham/C-6725-2011; van Panhuys, Nicholas/E-1812-2011; OI van Panhuys, Nicholas/0000-0003-2199-852X FU Cleveland Clinic Foundation; American Heart Associations FX This work was supported by startup funds from the Cleveland Clinic Foundation and in part by a Scientist Development grant from the American Heart Associations (to B.M.). NR 46 TC 9 Z9 10 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2008 VL 181 IS 8 BP 5249 EP 5256 PG 8 WC Immunology SC Immunology GA 359YX UT WOS:000260025300014 PM 18832679 ER PT J AU Nguyen, KD Fohner, A Booker, JD Dong, C Krensky, AM Nadeau, KC AF Nguyen, Khoa D. Fohner, Alison Booker, Jerome D. Dong, Chen Krensky, Alan M. Nadeau, Kari C. TI XCL1 enhances regulatory activities of CD4(+)CD25(high)CD127(low/-) T cells in human allergic asthma SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSGENE EXPRESSION; LYMPHOTACTIN; CD4(+); ACTIVATION; CHEMOKINE; AIRWAY; ACCUMULATION; SUPPRESSION; PHENOTYPE; CYTOKINE AB Chemokine-mediated recruitment of regulatory cell subsets to the airway during inflammation and enhancement of their activities are potential strategies for therapeutic development in allergic asthma (AA). In this study, we aim to explore the role of XCL1, a chemokine associated with immune suppression and allergy, on CD4(+)CD25(high)CD127(low/-) regulatory T cell (Treg) function in AA. Flow cytometry and PCR analysis showed a reduction in XCL1 and XCR1 expression in AA Treg compared with healthy control and nonallergic asthmatic counterparts. This reduction in XCL1 expression was associated with the suboptimal regulatory function of Treg in AA. Interestingly, incubation with recombinant human XCL1 significantly increased Treg-mediated suppression and cytotoxicity by up-regulating expression of XCL1 and chief effector molecules of Treg function. Altogether, these results suggest an association between dysregulated XCL1 expression and reduced Treg activities in AA, as well as a potential role of XCL1 in reversing defective Treg function in the disease. C1 [Nguyen, Khoa D.; Fohner, Alison; Booker, Jerome D.; Dong, Chen; Nadeau, Kari C.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Krensky, Alan M.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Nadeau, KC (reprint author), Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. EM knadeau@stanford.edu FU Mary Hewitt Loveless Foundation; Parker B. Francis Foundation FX This work was supported by grants from the Mary Hewitt Loveless Foundation and the Parker B. Francis Foundation. NR 34 TC 29 Z9 32 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2008 VL 181 IS 8 BP 5386 EP 5395 PG 10 WC Immunology SC Immunology GA 359YX UT WOS:000260025300030 PM 18832695 ER PT J AU Kawamura, K Yao, K Shukaliak-Quandt, JA Huh, J Baig, M Quigley, L Ito, N Necker, A McFarland, HF Muraro, PA Martin, R Ito, K AF Kawamura, Kazuyuki Yao, Karen Shukaliak-Quandt, Jacqueline A. Huh, Jaebong Baig, Mirza Quigley, Laura Ito, Naoko Necker, Antje McFarland, Henry F. Muraro, Paolo A. Martin, Roland Ito, Kouichi TI Different development of myelin basic protein agonist- and antagonist-specific human TCR transgenic T cells in the thymus and periphery SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR-ALPHA CHAINS; MULTIPLE-SCLEROSIS; POSITIVE SELECTION; RHEUMATOID-ARTHRITIS; CLASS-I; MICE; EXPRESSION; COMPLEX; HLA-DR4; REPERTOIRE AB Myelin basic protein (MBP)-specific T cells are thought to play a role in the development of multiple sclerosis. MBP residues 111-129 compose an immunodominant epitope cluster restricted by HLA-DRB1*0401. The sequence of residues 111-129 of MBP (MBP(111-129)) differs in humans (MIBP122:Arg) and mice (MBP122:Lys) at aa 122. We previously found that similar to 50% of human MBP(111-129) (MBP122: Arg)-specific T cell clones, including MS2-3C8 can proliferate in response to mouse MBP(111-129) (MBP122:Lys). However, the other half of T cell clones, including HD4-1C2, cannot proliferate in response to MBP(111-129) (MBP122:Lys). We found that MBP(111-129) (MBP122: Lys) is an antagonist for HD4-1C2 TCR, therefore, MS2-3C8 and HD4-1C2 TCRs are agonist- and antagonist-specific TCRs in mice, respectively. Therefore, we examined the development of HD4-1C2 TCR and MS2-3C8 TCR transgenic (Tg) T cells in the thymus and periphery. We found that dual TCR expression exclusively facilitates the development of MBP(111-129) TCR Tg T cells in the periphery of HD4-1C2 TCR/HLA-DRB1*0401 Tg mice although it is not required for their development in the thymus. We also found that MS2-3C8 TCR Tg CD8(+) T cells develop along with MS2-3C8 TCR Tg CD4(+) T cells, and that dual TCR expression was crucial for the development of MS2-3C8 TCR Tg CD4(+) and CD8(+) T cells in the thymus and periphery, respectively. These results suggest that thymic and peripheral development of MBP-specific T cells are different; however, dual TCR expression can facilitate their development. C1 [Ito, Kouichi] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, Piscataway, NJ 08854 USA. [Kawamura, Kazuyuki; Yao, Karen; Shukaliak-Quandt, Jacqueline A.; Huh, Jaebong; Baig, Mirza; Quigley, Laura; McFarland, Henry F.; Muraro, Paolo A.; Martin, Roland; Ito, Kouichi] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Necker, Antje] Beckman Coulter, Antibody Dept, Marseille, France. [Muraro, Paolo A.] Univ London Imperial Coll Sci Technol & Med, Dept Cellular & Mol Neurosci, London, England. [Martin, Roland] Univ Med Ctr Eppendorf, Inst Neuroimmunol & Clin Multiple Sclerosis Res, Hamburg, Germany. RP Ito, K (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, Res Bldg Room 182,683 Hoes Lane, Piscataway, NJ 08854 USA. EM itoko@umdnj.edu FU National Multiple Sclerosis Society; Canadian Multiple Sclerosis Society FX This work was supported by the National Multiple Sclerosis Society (K.K.) and by the Canadian Multiple Sclerosis Society (J.A.S.-Q.). NR 47 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2008 VL 181 IS 8 BP 5462 EP 5472 PG 11 WC Immunology SC Immunology GA 359YX UT WOS:000260025300038 PM 18832703 ER PT J AU Li, CKF Wu, H Yan, HP Ma, SW Wang, LL Zhang, MX Tang, XP Temperton, NJ Weiss, RA Brenchley, JM Douek, DC Mongkolsapaya, J Tran, BH Lin, CLS Screaton, GR Hou, JL McMichael, AJ Xu, XN AF Li, Chris Ka-fai Wu, Hao Yan, Huiping Ma, Shiwu Wang, Lili Zhang, Mingxia Tang, Xiaoping Temperton, Nigel J. Weiss, Robin A. Brenchley, Jason M. Douek, Daniel C. Mongkolsapaya, Juthathip Tran, Bac-Hai Lin, Chen-lung Steve Screaton, Gavin R. Hou, Jin-lin McMichael, Andrew J. Xu, Xiao-Ning TI T cell responses to whole SARS coronavirus in humans SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACUTE RESPIRATORY SYNDROME; NEUTRALIZING ANTIBODY-RESPONSE; VIRAL LOAD; IDENTIFICATION; EPITOPES; VACCINE; INFECTION; DISEASE; PROTEIN; MICE AB Effective vaccines should confer long-term protection against future outbreaks of severe acute respiratory syndrome (SARS) caused by a novel zoonotic coronavirus (SARS-CoV) with unknown animal reservoirs. We conducted a cohort study examining multiple parameters of immune responses to SARS-CoV infection, aiming to identify the immune correlates of protection. We used a matrix of overlapping peptides spanning whole SARS-CoV proteome to determine T cell responses from 128 SARS convalescent samples by ex vivo IFN-gamma ELISPOT assays. Approximately 50% of convalescent SARS patients were positive for T cell responses, and 90% possessed strongly neutralizing Abs. Fifty-five novel T cell epitopes were identified, with spike protein dominating total T cell responses. CD8(+) T cell responses were more frequent and of a greater magnitude than CD4(+) T cell responses (p < 0.001). Polychromatic cytometry analysis indicated that the virus-specific T cells from the severe group tended to be a central memory phenotype (CD27(+)/CD45RO(+)) with a significantly higher frequency of polyfunctional CD4(+) T cells producing IFN-gamma, TNF-alpha, and IL-2, and CD8(+) T cells producing IFN-gamma, TNF-alpha, and CD107a (degranulation), as compared with the mild-moderate group. Strong T cell responses correlated significantly (p < 0.05) with higher neutralizing Ab. The serum cytokine profile during acute infection indicated a significant elevation of innate immune responses. Increased Th2 cytokines were observed in patients with fatal infection. Our study provides a roadmap for the immunogenicity of SARS-CoV and types of immune responses that may be responsible for the virus clearance, and should serve as a benchmark for SARS-CoV vaccine design and evaluation. C1 [Li, Chris Ka-fai; Wang, Lili; McMichael, Andrew J.; Xu, Xiao-Ning] Univ Oxford, Weatherall Inst Mol Med, MRC, Human Immunol Unit, Oxford, England. [Wu, Hao; Yan, Huiping] Capital Univ Med Sci, Beijing You An Hosp, Beijing, Peoples R China. [Ma, Shiwu; Zhang, Mingxia; Hou, Jin-lin] So Med Univ, Nan Fang Hosp, Dept Infect Dis, Guangzhou, Guangdong, Peoples R China. [Tang, Xiaoping] Guangzhou 8 Hosp, Guangzhou, Guangdong, Peoples R China. [Temperton, Nigel J.; Weiss, Robin A.] UCL, MRC, Ctr Med Mol Virol, Div Infect & Immun, London, England. [Brenchley, Jason M.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Mongkolsapaya, Juthathip; Tran, Bac-Hai; Lin, Chen-lung Steve; Screaton, Gavin R.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. RP Xu, XN (reprint author), John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DU, England. EM jlhou@fimmu.com; xiaoning.xu@imm.ox.ac.uk RI Temperton, Nigel/K-5158-2013 OI Temperton, Nigel/0000-0002-7978-3815 FU Beijing Municipal Government; National Science Fund for Distinguished Young Scholars; Medical Research Council U.K.; European Commission [SP22-CT-2004-511064] FX This work was support by Beijing Municipal Government, National Science Fund for Distinguished Young Scholars, Medical Research Council U.K., and the Euro-Asian SARS-DTV Network (SP22-CT-2004-511064) from the European Commission specific research and technological development Program "Integrating and strengthening the European Research area." NR 35 TC 32 Z9 34 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2008 VL 181 IS 8 BP 5490 EP 5500 PG 11 WC Immunology SC Immunology GA 359YX UT WOS:000260025300041 PM 18832706 ER PT J AU Jennewein, C Kuhn, AM Schmidt, MV Meilladec-Jullig, V von Knethen, A Gonzalez, FJ Brune, B AF Jennewein, Carla Kuhn, Anne-Marie Schmidt, Martina Victoria Meilladec-Jullig, Virginie von Knethen, Andreas Gonzalez, Frank J. Bruene, Bernhard TI Sumoylation of peroxisome proliferator-activated receptor gamma by apoptotic cells prevents lipopolysaccharide-induced NCoR removal from kappa B binding sites proinflammatory cytokines SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PPAR-GAMMA; GENE-EXPRESSION; LIGAND-BINDING; MACROPHAGES; TRANSCRIPTION; RECOGNITION; MICE; TRANSREPRESSION; ADIPOGENESIS; CONSEQUENCES AB Efficient clearance of apoptotic cells (AC) by professional phagocytes is crucial for tissue homeostasis and resolution of inflammation. Macrophages respond to AC with an increase in antiinflammatory cytokine production but a diminished release of proinflammatory mediators. Mechanisms to explain attenuated proinflammatory cytokine formation remain elusive. We provide evidence that peroxisome proliferator-activated receptor gamma (PPAR gamma) coordinates antiinflammatory responses following its activation by AC. Exposing murine RAW264.7 macrophages to AC before LPS stimulation reduced NF-kappa B transactivation and lowered target gene expression of, that is, TNF-alpha and IL-6 compared with controls. In macrophages overexpressing a dominant negative mutant of PPAR gamma, NF-kappa B transactivation in response to LPS was restored, while macrophages from myeloid lineage-specific conditional PPAR gamma knockout mice proved that PPAR gamma transmitted an antiinflammatory response, which was delivered by AC. Expressing a PPAR gamma-Delta aa32-250 deletion mutant, we observed no inhibition of NF-kappa B. Analyzing the PPAR gamma domain structures within aa 32-250, we anticipated PPAR-gamma sumoylation in mediating the antiinflammatory effect in response to AC. Interfering with sumoylation of PPAR gamma by mutating the predicted sumoylation site (K77R), or knockdown of the small ubiquitin-like modifier (SUMO) E3 ligase PIAS1 (protein inhibitor of activated STAT1), eliminated the ability of AC to suppress NF-kappa B Chromatin immunoprecipitation analysis demonstrated that AC prevented the LPS-induced removal of nuclear receptor corepressor (NCoR) from the kappa B site within the TNF-alpha promoter. We conclude that AC induce PPAR gamma sumoylation to attenuate the removal of NCoR, thereby blocking transactivation of NF-kappa B This contributes to an antiinflammatory phenotype shift in macrophages responding to AC by lowering proinflammatory cytokine production. C1 [Jennewein, Carla; Kuhn, Anne-Marie; Schmidt, Martina Victoria; Meilladec-Jullig, Virginie; von Knethen, Andreas; Bruene, Bernhard] Univ Frankfurt, Fac Med, Inst Biochem, ZAFES, D-60590 Frankfurt, Germany. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Brune, B (reprint author), Univ Frankfurt, Fac Med, Inst Biochem, ZAFES, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM bruene@zbc.kgu.de RI Jennewein, Carla/C-2199-2013 FU Deutsche Forschungsgemeinschaft [Br 999, FOG 784]; Deutsche Krebshilfe; Sander Foundation; LiFF; European Community (PROLIGEN) FX This work was supported by grants from Deutsche Forschungsgemeinschaft (Br 999, FOG 784, Excellence Cluster Cardiopulmonary System), Deutsche Krebshilfe, Sander Foundation, LiFF, and European Community (PROLIGEN). NR 35 TC 58 Z9 67 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2008 VL 181 IS 8 BP 5646 EP 5652 PG 7 WC Immunology SC Immunology GA 359YX UT WOS:000260025300058 PM 18832723 ER PT J AU Tross, D Klinman, DM AF Tross, Debra Klinman, Dennis M. TI Effect of CpG oligonucleotides on vaccine-induced B cell memory SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LICENSED ANTHRAX VACCINE; BACILLUS-ANTHRACIS; BACTERIAL-DNA; PROTECTIVE ANTIGEN; INTERFERON-GAMMA; DENDRITIC CELLS; RHESUS MACAQUES; OLIGODEOXYNUCLEOTIDES; INFECTION; STIMULATION AB Adding synthetic oligodeoxynucleotides containing unmethylated CpG motifs to Anthrax vaccine adsorbed (AVA, the licensed human vaccine) increases the speed and magnitude of the resultant Ab response. Ab titers persist in the protective range for > 1 year, significantly longer than in animals vaccinated with AVA alone. Unexpectedly, a majority of mice immunized with CpG-adjuvanted AVA maintained resistance to anthrax infection even after their Ab titers had declined into the subprotective range. The survival of these animals was mediated by the de novo production of protective Abs by high affinity memory B cells re-stimulated immediately after challenge. Thus, a previously unrecognized benefit of CpG oligodeoxynucleotides adjuvants is their ability to expand the long-lived memory B cell population. Current findings demonstrate that CpG-adjuvanted AVA mediates protection both by stimulating a strong/persistent serum Ab response and by generating a high-affinity long-lived pool of memory B cells. C1 [Tross, Debra; Klinman, Dennis M.] Natl Canc Inst, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), Natl Canc Inst, Bldg 567,Room 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Joint Science and Technology Office for Chemical and Biological Defense of the Defense Threat Reduction Agency FX This work was supported in part by the Joint Science and Technology Office for Chemical and Biological Defense of the Defense Threat Reduction Agency. NR 39 TC 32 Z9 37 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2008 VL 181 IS 8 BP 5785 EP 5790 PG 6 WC Immunology SC Immunology GA 359YX UT WOS:000260025300073 PM 18832738 ER PT J AU Shepherd, JC Jacobson, LP Qiao, W Jamieson, BD Phair, JP Piazza, P Quinn, TC Margolick, JB AF Shepherd, James C. Jacobson, Lisa P. Qiao, Wei Jamieson, Beth D. Phair, John P. Piazza, Paolo Quinn, Thomas C. Margolick, Joseph B. TI Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the Multicenter AIDS Cohort Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 16th International AIDS Conference CY AUG 13-18, 2006 CL Toronto, CANADA ID IMMUNODEFICIENCY-VIRUS TYPE-1; SYNCYTIUM-INDUCING PHENOTYPE; T-CELL HOMEOSTASIS; ANTIRETROVIRAL THERAPY; CORECEPTOR USAGE; TROPISM; PROGRESSION; INFECTION; INDIVIDUALS; DISEASE AB We examined the emergence of CXCR4 (i.e., X4) tropism in 67 male human immunodeficiency virus type 1 (HIV-1) seroconverters from the Multicenter AIDS Cohort Study (MACS) who were selected to reflect the full spectrum of rates of HIV-1 disease progression. A mean of 10 serial samples per donor were evaluated by a laboratory-validated, commercially available assay to determine phenotypic coreceptor use. A total of 52% of men had dual-or mixed-tropic HIV-1 detected at 1 or more of the time points tested. Use of X4 by HIV-1 was detected more frequently among men who developed AIDS (defined as a CD4(+) T cell count of < 200 cells/mu L and/or an AIDS-defining illness) <= 11 years after seroconversion than among those who did not ( P=.005), as well as among men who exhibited a total T cell count decline (i.e., a CD3(+) inflection point), compared with those who did not (P=.03). For men in whom both X4 virus and an inflection point were detected, emergence of X4 virus preceded the inflection point by a median of 0.83 years. The median CD4(+) T cell count at first detection of X4 viruses before the onset of AIDS was 475 cells/mu L. We conclude that HIV-1 variants that used X4 frequently emerged at high CD4(+) T cell counts and may contribute to the decrease in T cell numbers during late HIV-1 infection. C1 [Shepherd, James C.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Jacobson, Lisa P.; Qiao, Wei; Margolick, Joseph B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Shepherd, James C.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Quinn, Thomas C.] NIAID, Bethesda, MD 20892 USA. [Jamieson, Beth D.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Phair, John P.] Northwestern Univ, Howard Brown Hlth Ctr, Chicago, IL 60611 USA. [Phair, John P.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Piazza, Paolo] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Margolick, JB (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, 615 N Wolfe St,Rm E5153, Baltimore, MD 21205 USA. EM jmargoli@jhsph.edu FU Intramural NIH HHS [Z01 AI000361-25]; NCRR NIH HHS [M01 RR000722, M01 RR000722-23]; NIAID NIH HHS [U01 AI037984-07, U01 AI035039, U01 AI035039-17, U01 AI035040, U01 AI035040-17, U01 AI035041, U01 AI035041-17, U01 AI035042, U01 AI035042-07, U01 AI035042-08, U01 AI035042-09, U01 AI035042-09S1, U01 AI035042-10, U01 AI035042-11, U01 AI035042-12, U01 AI035042-13, U01 AI035042-14, U01 AI035042-15, U01 AI035042-16, U01 AI035042-17, U01 AI035043, U01 AI037613, U01 AI037984, U01 AI037984-04, U01 AI037984-04S1, U01 AI037984-05, U01 AI037984-06, U01 AI037984-08] NR 31 TC 55 Z9 57 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2008 VL 198 IS 8 BP 1104 EP 1112 DI 10.1086/591623 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 358BQ UT WOS:000259891800004 PM 18783316 ER PT J AU Rigaud, M Borkowsky, W Muresan, P Weinberg, A LaRussa, P Fenton, T Read, JS Jean-Philippe, P Fergusson, E Zimmer, B Smith, D Kraimer, J AF Rigaud, Mona Borkowsky, William Muresan, Petronella Weinberg, Adriana LaRussa, Phillip Fenton, Terry Read, Jennifer S. Jean-Philippe, Patrick Fergusson, Elaine Zimmer, Bonnie Smith, Dorothy Kraimer, Joyce CA Pediat AIDS Clinical Trials Grp P1 TI Impaired immunity to recall antigens and neoantigens in severely immunocompromised children and adolescents during the first year of effective highly active antiretroviral therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 13th Conference on Retroviruses and Opportunistic Infections CY FEB 05-09, 2006 CL Denver, CO ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED CHILDREN; HIV-1-INFECTED CHILDREN; COMBINATION THERAPY; TYPE-1 INFECTION; RECONSTITUTION; RESPONSES; TETANUS; MORTALITY; VACCINE AB Background. We studied whether severely immunocompromised, human immunodeficiency virus (HIV)-infected children who were beginning highly active antiretroviral therapy (HAART) or changing HAART regimens could spontaneously respond to a recall antigen (tetanus toxoid [TT] vaccine) or respond to a recall antigen and neoantigen (hepatitis A virus [HAV] vaccine) after 3 vaccinations. Methods. A total of 46 children who had CD4 cell percentages < 15% and who demonstrated a > 0.75-log reduction in plasma HIV RNA levels within 4 weeks of starting HAART were randomized to receive vaccinations with either TT or HAV vaccines during the first 6 months of HAART. Study subjects then received the alternate vaccine during the next 6 months of HAART. Results. Despite the early decline in viremia and the later increase in the percentage of CD4 T cells, spontaneous recovery of cell-mediated immunity (CMI) was not seen for TT. Serologic responses to TT required 3 vaccinations and were comparable in both groups. Serologic responses to HAV were infrequent and of low titer, although the group that received HAV vaccine after receiving TT vaccine performed somewhat better. CMI to HAV was virtually absent. Conclusions. Severely immunocompromised children who are receiving HAART develop CMI and antibody to a recall antigen independent of the timing of vaccination, but they require a primary series of vaccinations. Antibodies to a neoantigen, HAV, developed when vaccination was delayed after initiation of HAART. CMI to a neoantigen was difficult to establish. Trial registration. Clinicaltrials.gov identifier: NCT00004735/PACTG P1006. C1 [Rigaud, Mona] NYU, Sch Med, Dept Pediat, New York, NY 10016 USA. [LaRussa, Phillip] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Zimmer, Bonnie] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Muresan, Petronella; Fenton, Terry] Harvard Univ, Sch Publ Hlth, Frontier Sci & Technol Res Fdn, Boston, MA 02115 USA. [Smith, Dorothy] Univ Massachusetts Mem Hlth Ctr, Worcester, MA USA. [Weinberg, Adriana] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Read, Jennifer S.] NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. [Jean-Philippe, Patrick] Henry M Jackson Fdn, Pediat Med Branch, Bethesda, MD USA. [Fergusson, Elaine] Pharmaceut Affairs Branch, Div Aids, Bethesda, MD USA. [Fergusson, Elaine] NIAID, NIH, Bethesda, MD 20892 USA. [Kraimer, Joyce] Social & Sci Syst, Silver Spring, MD USA. RP Rigaud, M (reprint author), NYU, Sch Med, Dept Pediat, 550 1St Ave, New York, NY 10016 USA. EM mona.rigaud@med.nyu.edu FU NIAID NIH HHS [U01 AI027553, U01 AI068632, U01AI068632]; NICHD NIH HHS [N01-HD-3-3365] NR 23 TC 16 Z9 17 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2008 VL 198 IS 8 BP 1123 EP 1130 DI 10.1086/592050 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 358BQ UT WOS:000259891800006 PM 18752430 ER PT J AU An, P Thio, CL Kirk, GD Donfield, S Goedert, JJ Winkler, CA AF An, Ping Thio, Chloe L. Kirk, Gregory D. Donfield, Sharyne Goedert, James J. Winkler, Cheryl A. TI Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 57th Annual Meeting of the American-Society-of-Human-Genetics CY OCT 23-27, 2007 CL San Diego, CA SP Amer Soc Human Genet ID SINGLE-NUCLEOTIDE POLYMORPHISMS; NECROSIS-FACTOR-ALPHA; GENE POLYMORPHISMS; RACIAL-DIFFERENCES; LIVER-INJURY; VIRAL CLEARANCE; INFECTION; IL-18; DISEASE; MICE AB The immune response is critical in determining the outcome of hepatitis C virus (HCV) infection. Interleukin (IL)-18 is a pivotal mediator of the Th1/Th2-driven immune response. Two IL-18 promoter polymorphisms (-607C/A and -137G/C) and their haplotypes were known to affect IL-18 expression. We examined the role played by these polymorphisms in determining HCV clearance or persistence. Genotyping was performed among African American injection drug users with HCV clearance (n = 91) or HCV persistence ( n = 182) and among European Americans with hemophilia who were mainly infected through plasma transfusion. Among injection drug users, IL18 -607A (odds ratio [OR], 3.68 [95% confidence interval{CI}, 1.85-7.34]) and IL18 -137C ( OR, 2.33 [95% CI, 1.24-4.36]) were significantly associated with HCV clearance. A haplotype carrying -607A and -137C (OR, 4.53 [95% CI, 1.77-11.6]) was also strongly associated with viral clearance. No association was found among those with hemophilia. These results suggest that IL-18 promoter polymorphism may affect the outcome of HCV infection in certain groups. C1 [An, Ping; Winkler, Cheryl A.] Sci Applicat Int Corp, Lab Genom Divers, Frederick, MD USA. [Thio, Chloe L.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Kirk, Gregory D.] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Goedert, James J.] NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Donfield, Sharyne] Rho Inc, Chapel Hill, NC USA. RP Winkler, CA (reprint author), NCI FCRDC, Bldg 560, Frederick, MD 21702 USA. EM winkler@ncifcrf.gov RI Kirk, Gregory/A-8484-2009 FU Intramural NIH HHS [Z01 BC010297-10]; NCI NIH HHS [HHSN261200800001E, N01 CO012400, N01-CO-12400, N01CO12400]; NIDA NIH HHS [R01 DA013324, R01 DA013324-09, R01 DA13324] NR 44 TC 34 Z9 37 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2008 VL 198 IS 8 BP 1159 EP 1165 DI 10.1086/592047 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 358BQ UT WOS:000259891800010 PM 18781864 ER PT J AU Wardenburg, JB Palazzolo-Ballance, AM Otto, M Schneewind, O DeLeo, FR AF Wardenburg, Juliane Bubeck Palazzolo-Ballance, Amy M. Otto, Michael Schneewind, Olaf DeLeo, Frank R. TI Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID NECROTIZING PNEUMONIA; INFECTIONS; EMERGENCE; GENOME; GENES; CLONE; SKIN AB Increases in the incidence and severity of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have spawned efforts to define unique virulence properties among prevalent strains. Panton-Valentine leukocidin (PVL), a pore-forming cytotoxin, has garnered attention because of its epidemiologic association with CA-MRSA. Using both the clinical isolate LAC, which is representative of the epidemic USA300 strain, and its isogenic PVL-negative strain in murine models of staphylococcal skin infection and pneumonia, we expanded upon recent studies by assessing the contribution of PVL in the genetic background of BALB/c mice. The data presented in this report support the observation that PVL does not contribute to the pathogenesis of staphylococcal infection of mice. C1 [Palazzolo-Ballance, Amy M.; Otto, Michael; DeLeo, Frank R.] NIAID, LHBP, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Wardenburg, Juliane Bubeck; Schneewind, Olaf] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. RP DeLeo, FR (reprint author), NIAID, LHBP, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM oschnee@bsd.uchicago.edu; fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program; National Institute of Allergy and Infectious Diseases (NIAID) [AI52747]; National Institutes of Health (NIH); Division of Microbiology and Infectious Diseases; National Institute of Child Health and Human Development (NICHD) [K12-HD00850] FX Intramural Research Program, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Division of Microbiology and Infectious Diseases, NIAID ( grant AI52747 to O. S.). J. B. W. is a National Institute of Child Health and Human Development (NICHD) Fellow of the Pediatric Scientist Development Program (NICHD grant K12-HD00850). NR 15 TC 148 Z9 153 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2008 VL 198 IS 8 BP 1166 EP 1170 DI 10.1086/592053 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 358BQ UT WOS:000259891800011 PM 18729780 ER PT J AU Cheng, K Saha, B Mahadevan, A Razdan, RK Kunos, G Jacobson, AE Rice, KC AF Cheng, Kejun Saha, Bijali Mahadevan, A. Razdan, Raj K. Kunos, George Jacobson, Arthur E. Rice, Kenner C. TI Synthesis of 2-(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenamidoethyl-d(4) dihydrogen phosphate, tetra-deuterated pAEA SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE deuterium labeling; deuterated phospho-anandamide; pAEA; endocannabinoid ID CANNABINOID RECEPTOR; ANANDAMIDE; BIOSYNTHESIS AB A labile intermediate phospho-anandamide (2-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidoethyl dihydrogen phosphate, pAEA) has been identified in mouse brain and macrophages, but its precise quantitation was difficult because of its low concentration and chemical instability. We report the synthesis of tetra-deuterated pAEA from 2-aminoethyl dihydrogen phosphate-1,1,2,2-d(4) and (5Z,8Z,11Z,14Z)-2,5-dioxopyrrolidin-1-yl icosa-5,8,11,14-tetraenoate. The compound will be used to quantitate the pAEA necessary for a novel biosynthetic pathway. C1 [Cheng, Kejun; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, Drug Design & Synth Sect, Chem Biol Res Branch, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. [Saha, Bijali; Mahadevan, A.; Razdan, Raj K.] Organix Inc, Woburn, MA 01801 USA. [Kunos, George] NIAAA, Neuroendocrinol Sect, Lab Physiol Studies, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. RP Rice, KC (reprint author), NIAAA, Drug Design & Synth Sect, Chem Biol Res Branch, Dept Hlth & Human Serv,NIH, 5625 Fishers Lone,Room 4N03,MSC 9145, Rockville, MD 20852 USA. EM kr21f@nih.gov FU NIDA [DA-05488] FX We would like to thank Dr Klaus Gawrisch and Dr Walter Teague of the Laboratory of Membrane Biochemistry and Biophysics (LMBB) in NIAAA for 2 H NMR spectral data. The authors also express their appreciation to Noel Whittaker and Wesley White of the Laboratory of Analytical Chemistry for mass spectral data and 31 P NMR spectral data. The work of the Drug Design and Synthesis Section, CBRB, NIDA, & NIAAA, was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism, and the work of the Neuroenclocrinology Section, Laboratory of Physiologic Studies, was supported by the NIH Intramural Research Programs of the National Institute of Alcohol Abuse and Alcoholism. The authors (B.S., A.M., R.K.R.) thank NIDA Grant DA-05488 for financial support. NR 7 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD OCT 15 PY 2008 VL 51 IS 11-12 BP 389 EP 390 DI 10.1002/jlcr.1540 PG 2 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 383CQ UT WOS:000261652100005 PM 19823563 ER PT J AU Scimemi, A AF Scimemi, Annalisa TI Anchors aweigh: NMDA receptors set sail from their presynaptic port SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material C1 NINDS, Synapt Physiol Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Scimemi, A (reprint author), NINDS, Synapt Physiol Unit, Porter Neurosci Res Ctr, NIH, 35 Convent Dr,Bldg 35,Room 3C-1006, Bethesda, MD 20892 USA. EM scimemia@ninds.nih.gov RI Scimemi, Annalisa/O-5396-2014 OI Scimemi, Annalisa/0000-0003-4975-093X NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD OCT 15 PY 2008 VL 586 IS 20 BP 4787 EP 4787 DI 10.1113/jphysiol.2008.162784 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 360JM UT WOS:000260053800003 PM 18854432 ER PT J AU Phillips, RS Miles, EW McPhie, P Marchal, S Georges, C Dupont, Y Lange, R AF Phillips, Robert S. Miles, Edith W. McPhie, Peter Marchal, Stephane Georges, Cedric Dupont, Yves Lange, Reinhard TI Pressure and temperature jump relaxation kinetics of the conformational change in Salmonella typhimurium tryptophan synthase L-Serine complex: Large activation compressibility and heat capacity changes demonstrate the contribution of solvation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID BIENZYME COMPLEX; ALPHA(2)BETA(2) COMPLEX; ESCHERICHIA-COLI; MONOVALENT CATIONS; ALLOSTERIC REGULATION; CATALYTIC MECHANISM; ALPHA-SUBUNITS; ACTIVE-SITES; BETA; SUBSTRATE AB Tryptophan synthase is an alpha(2)beta(2) multienzyme complex that exhibits coupling of the alpha- and P-subunit reactions by tightly controlled allosteric interactions. A wide range of parameters can affect the allosteric interactions, including monovalent cations, pH, alpha-site and beta-site ligands, temperature, and pressure. Rapid changes in hydrostatic pressure (P-jump) and temperature (T-jump) were used to examine the effects of pressure and temperature on the rates of the interconversion of external aldimine and aminoacrylate intermediates in the Tryptophan synthase-L-Ser complex. The intense fluorescence emission of the Tryptophan synthase L-Ser external aldimine complex at 495 rim, with 420 nm excitation, provides a probe of the conformational state of Trp synthase. P-jump measurements allowed the determination of rate constants for the reactions in the presence of Na+, Na+ with benzimidazole (BZI), and NH4+. The data require a compressibility term, beta(double dagger)(o), to obtain good fits, especially for the NH4(+) and BZI/Na+ data. The compressibility changes are consistent with changes in solvation in the transition state. The transition state for the relaxation is more similar in volume to the closed aminoacrylate complex in the presence of Na+, while it is more similar to the open external aldimine in the presence of NH4(+). Differences between the relaxations for positive and negative P-jumps may arise from changing relative populations of microstates with pressure. T-jump experiments of the Na+ form of the tryptophan synthase-L-Ser complex show large changes in rate and amplitude over the temperature range from 7 to 45 degrees C. The Arrhenius plots show strong curvature, and hence require a heat capacity term, Delta C-p(double dagger), to obtain good fits. The values of Delta C-p(double dagger) are very large and negative (-3.6 to -4.4 kJ mol(-1) K-1). These changes are also consistent with large changes in solvation in the transition state for interconversion of external aldimine and aminoacrylate intermediates in the Tryptophan synthase-L-Ser complex. C1 [Phillips, Robert S.] Univ Georgia, Dept Chem, Athens, GA 30602 USA. [Phillips, Robert S.] Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA. [Miles, Edith W.; McPhie, Peter] NIDDK, NIH, Bethesda, MD 20892 USA. [Marchal, Stephane; Lange, Reinhard] Univ Montpellier 2, INSERM, U710, F-34095 Montpellier, France. [Marchal, Stephane; Lange, Reinhard] EPHE, F-75007 Paris, France. [Georges, Cedric; Dupont, Yves] BioL SAS 1, F-38640 Claix, France. RP Phillips, RS (reprint author), Univ Georgia, Dept Chem, Athens, GA 30602 USA. OI Phillips, Robert/0000-0001-8710-562X FU NIH; NIDDK (EWM, PM) FX This research was supported in part by the intramural research program of the NIH, NIDDK (EWM, PM). NR 47 TC 11 Z9 11 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 15 PY 2008 VL 130 IS 41 BP 13580 EP 13588 DI 10.1021/ja8018466 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 358NK UT WOS:000259924000026 PM 18795779 ER PT J AU Shen, Y Costantino, JP Qin, J AF Shen, Yu Costantino, Joseph P. Qin, Jing TI Tamoxifen Chemoprevention Treatment and Time to First Diagnosis of Estrogen Receptor-Negative Breast Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SCREEN-DETECTED CANCERS; MAMMOGRAPHIC DENSITY; FOLLOW-UP; RISK; PREVENTION; TRIAL; EFFICACY; PATTERNS; WOMEN AB Background Tamoxifen's effect of reducing the risk of estrogen receptor (ER)-positive breast cancer is well established. Its effect on the time to first diagnosis of breast cancer has not been reported. We used information from the randomized, placebo-controlled Breast Cancer Prevention Trial (BCPT) to make that evaluation. Methods A total of 13388 women enrolled in BCPT, of whom 174 were diagnosed with ER-positive tumors and 69 were diagnosed with ER-negative tumors. A flexible semiparametric cure rate model was used to assess the effects of tamoxifen vs placebo treatment on the time to disease diagnosis. Multivariable logistic regression, adjusted for age and tumor size at diagnosis, was used to assess the association between the mammography detection rate and treatment with tamoxifen. All statistical tests were two-sided. Results The median times to diagnosis of ER- positive tumors were similar in both treatment groups (43 months for the placebo arm and 51 months for the treatment arm). Times to diagnosis of ER- negative tumors, however, differed between treatment groups, with median times to diagnosis of 36 months in the placebo arm vs 24 months in the tamoxifen arm (difference = 12 months, 95% confidence interval [CI] = 3 to 17 months, P = .037). ER- negative breast cancers in the tamoxifen arm were more likely than those in the placebo arm to be detected by mammography than by clinical breast examination alone after adjustment for age and tumor size, but the increase was only marginally statistically significant (odds ratio for mammography detection = 4.68, 95% CI = 0.86 to 25.32, P = .073). No differences were found in the mammography detection rates for ER- positive tumors by treatment arm. Conclusion Although tamoxifen treatment does not reduce the incidence of ER- negative breast cancer, it may have advanced detection of such tumors by approximately 1 year, compared with that in the placebo arm. The time to diagnosis of ER- positive breast cancer was similar in both treatment arms. C1 [Shen, Yu] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Qin, Jing] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Shen, Y (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Biostat, 1515 Holcombe Blvd,Unit 1411, Houston, TX 77030 USA. EM yshen@mdanderson.org OI Shen, Yu/0000-0002-3899-7868 FU National Cancer Institute [R01-CA079466, U10-CA-37377, U10-CA69974] FX This project was supported in part by the National Cancer Institute grants (R01-CA079466 to Y. S., U10-CA-37377 and U10-CA69974 to J. P. C.). NR 25 TC 8 Z9 8 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 15 PY 2008 VL 100 IS 20 BP 1448 EP 1453 DI 10.1093/jnci/djn320 PG 6 WC Oncology SC Oncology GA 361CU UT WOS:000260105900009 PM 18840821 ER PT J AU Brinton, LA Richesson, DA Gierach, GL Lacey, JV Park, Y Hollenbeck, AR Schatzkin, A AF Brinton, Louise A. Richesson, Douglas A. Gierach, Gretchen L. Lacey, James V., Jr. Park, Yikyung Hollenbeck, Albert R. Schatzkin, Arthur TI Prospective Evaluation of Risk Factors for Male Breast Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BONE-MINERAL DENSITY; LIFE-STYLE FACTORS; KLINEFELTERS-SYNDROME; OCCUPATIONAL EXPOSURES; ELECTROMAGNETIC-FIELDS; TESTOSTERONE LEVELS; SERUM ANDROGENS; UNITED-STATES; MEN; POPULATION AB Most risk factors for male breast cancer have been derived from retrospective studies that may reflect selective recall. In the prospective National Institutes of Health AARP Diet and Health Study, we studied 324 920 men, among whom 121 developed breast cancer. Men who reported a first-degree relative with breast cancer had an increased risk of breast cancer (relative risk [RR] = 1.92, 95% confidence interval [CI] = 1.19 to 3.09). Among the medical conditions examined, a new finding emerged regarding increased male breast cancer risk associated with a history of a bone fracture (RR = 2.20, 95% CI = 1.24 to 3.91). Obesity was positively related to risk (RR = 1.79, 95% CI = 1.10 to 2.91, for body mass indices of = 30 vs <25 kg/m(2)) and physical activity inversely related, even after adjustment for body mass index. Smokers were at somewhat elevated risk, although trends with smoking characteristics were inconsistent. Alcohol consumption was not related to risk. The identified risk factors show some commonalities with female breast cancer and indicate the importance of hormonal mechanisms. Differences in risk factors may reflect unique mechanisms associated with androgens and their ratio to bioavailable estrogens. C1 [Brinton, Louise A.; Richesson, Douglas A.; Gierach, Gretchen L.; Lacey, James V., Jr.] AARP, Hormonal & Reprod Epidemiol Branch, Washington, DC USA. [Park, Yikyung; Schatzkin, Arthur] AARP, Nutr Epidemiol Branch, Washington, DC USA. [Hollenbeck, Albert R.] AARP, Knowledge Management, Washington, DC USA. RP Brinton, LA (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 550,Rm 5018, Rockville, MD 20852 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016; OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522; Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health; National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The authors had responsibility for the design of the study, collection of data, analysis and interpretation of data, decision to submit the manuscript for publication, and writing of the manuscript. NR 58 TC 51 Z9 52 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 15 PY 2008 VL 100 IS 20 BP 1477 EP U9 DI 10.1093/jnci/djn329 PG 5 WC Oncology SC Oncology GA 361CU UT WOS:000260105900012 PM 18840816 ER PT J AU Zhang, SH Blech-Hermoni, Y Faravelli, L Seltzer, Z AF Zhang, Shi-Hong Blech-Hermoni, Yotam Faravelli, Laura Seltzer, Ze'ev TI Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat SO PAIN LA English DT Article DE Neuropathic pain; Nerve-end neuroma; Autotomy; Spontaneous pain behavior; Preemptive analgesia; Na(I) channel blocker; Ca(+3) ID MULTIPLE DORSAL RHIZOTOMY; FALSE DISCOVERY RATE; PERIPHERAL-NERVE; INJURY DISCHARGE; ONGOING DISCHARGES; AUTOTOMY BEHAVIOR; CHANNEL BLOCKER; SELECTIVE LOSS; MODEL; NEURONS AB Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague-Dawley male rats (N = 10-20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80 mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting 'preemptive analgesia' was found in ats treated with ralfinamide preoperatively, expressed by delayed autotomy onset (P = 0.009) and reduced scores on d63 (P = 0.01). Rats treated with ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P = 0.05, P = 0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na(+) and Ga(++) currents in Nav1.3, Nav1.7. Nav1.8, and Cav2.2 channel in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes. NMDA receptor antagonism and neuroprotection. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 [Zhang, Shi-Hong] Zhejiang Univ, Sch Med, Dept Pharmacol, Hangzhou 310003, Zhejiang, Peoples R China. [Zhang, Shi-Hong; Blech-Hermoni, Yotam; Seltzer, Ze'ev] Univ Toronto, Ctr Study Pain, Fac Dent, Toronto, ON M5G 1G6, Canada. [Zhang, Shi-Hong; Blech-Hermoni, Yotam; Seltzer, Ze'ev] Univ Toronto, Fac Med, Ctr Study Pain, Toronto, ON M5G 1G6, Canada. [Blech-Hermoni, Yotam] NHGRI, NIH, Bethesda, MD 20892 USA. [Faravelli, Laura] Newron Pharmaceut SpA, Discovery Dept, Bresso, MI, Italy. RP Seltzer, Z (reprint author), Univ Toronto, Ctr Study Pain, Fac Dent, 124 Edward St, Toronto, ON M5G 1G6, Canada. EM zeev.seltzer@utoronto.ca NR 46 TC 16 Z9 19 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD OCT 15 PY 2008 VL 139 IS 2 BP 293 EP 305 DI 10.1016/j.pain.2008.04.020 PG 13 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 368UT UT WOS:000260648900009 PM 18583049 ER PT J AU Sun, Y Li, H Liu, Y Mattson, MP Rao, MS Zhan, M AF Sun, Yu Li, Huai Liu, Ying Mattson, Mark P. Rao, Mahendra S. Zhan, Ming TI Evolutionarily Conserved Transcriptional Co-Expression Guiding Embryonic Stem Cell Differentiation SO PLOS ONE LA English DT Article AB Background: Understanding the molecular mechanisms controlling pluripotency in embryonic stem cells (ESCs) is of central importance towards realizing their potentials in medicine and science. Cross-species examination of transcriptional co-expression allows elucidation of fundamental and species-specific mechanisms regulating ESC self-renewal or differentiation. Methodology/Principal Findings: We examined transcriptional co-expression of ESCs from pathways to global networks under the framework of human-mouse comparisons. Using generalized singular value decomposition and comparative partition around medoids algorithms, evolutionarily conserved and divergent transcriptional co-expression regulating pluripotency were identified from ESC-critical pathways including ACTIVIN/NODAL, ATK/PTEN, BMP, CELL CYCLE, JAK/STAT, PI3K, TGF beta and WNT. A set of transcription factors, including FOX, GATA, MYB, NANOG, OCT, PAX, SOX and STAT, and the FGF response element were identified that represent key regulators underlying the transcriptional co-expression. By transcriptional intervention conducted in silico, dynamic behavior of pathways was examined, which demonstrate how much and in which specific ways each gene or gene combination effects the behavior transition of a pathway in response to ESC differentiation or pluripotency induction. The global co-expression networks of ESCs were dominated by highly connected hub genes such as IGF2, JARID2, LCK, MYCN, NASP, OCT4, ORC1L, PHC1 and RUVBL1, which are possibly critical in determining the fate of ESCs. Conclusions/Significance: Through these studies, evolutionary conservation at genomic, transcriptomic, and network levels is shown to be an effective predictor of molecular factors and mechanisms controlling ESC development. Various hypotheses regarding mechanisms controlling ESC development were generated, which could be further validated by in vitro experiments. Our findings shed light on the systems-level understanding of how ESC differentiation or pluripotency arises from the connectivity or networks of genes, and provide a "road-map'' for further experimental investigation. C1 [Sun, Yu; Li, Huai; Zhan, Ming] NIA, Bioinformat Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Liu, Ying; Rao, Mahendra S.] Invitrogen Corp, CRL, Carlsbad, CA USA. [Mattson, Mark P.] NIA, Lab Neurosci, NIH, Baltimore, MD USA. RP Sun, Y (reprint author), NIA, Bioinformat Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. EM zhanmi@mail.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural Research Program at the National Institute on Aging, NIH FX This work was supported by the Intramural Research Program at the National Institute on Aging, NIH. NR 83 TC 33 Z9 34 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 15 PY 2008 VL 3 IS 10 AR e3406 DI 10.1371/journal.pone.0003406 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 432GP UT WOS:000265121800005 PM 18923680 ER PT J AU Gezmu, M AF Gezmu, Misrak TI Special issue on HIV/AIDS including Papers from the MAID Workshop on Statistical Methods in HIV/AIDS Research and its Practical Application - Preface SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Gezmu, M (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 15 PY 2008 VL 27 IS 23 SI SI BP 4634 EP 4634 DI 10.1002/sim.3252 PG 1 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 353FB UT WOS:000259550400002 PM 18407560 ER PT J AU Dixon, D AF Dixon, Dennis TI Statistical methods in HIV/AIDS - Foreword SO STATISTICS IN MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Dixon, D (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 15 PY 2008 VL 27 IS 23 SI SI BP 4635 EP 4635 DI 10.1002/sim.3258 PG 1 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 353FB UT WOS:000259550400003 PM 18335569 ER PT J AU Bura, E Pfeiffer, R AF Bura, E. Pfeiffer, R. TI On the distribution of the left singular vectors of a random matrix and its applications SO STATISTICS & PROBABILITY LETTERS LA English DT Article ID SLICED INVERSE REGRESSION; DIMENSION REDUCTION AB In several dimension reduction techniques, the original variables are replaced by a smaller number of linear combinations. The coefficients of these linear combinations are typically the elements of the left singular vectors of a random matrix. We derive the asymptotic distribution of the left singular vectors of a random matrix that has a normal limit distribution. This result is then used to develop a Wald-type test for testing variable importance in Sliced Inverse Regression (SIR) and Sliced Average Variance Estimation (SAVE), two popular sufficient dimension reduction methods. (C) 2008 Elsevier B.V. All rights reserved. C1 [Bura, E.] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Pfeiffer, R.] NCI, Biostat Branch, DCEG, Bethesda, MD 20892 USA. RP Bura, E (reprint author), George Washington Univ, Dept Stat, Washington, DC 20052 USA. EM ebura@gwu.edu; pfeiffer@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 NR 14 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7152 J9 STAT PROBABIL LETT JI Stat. Probab. Lett. PD OCT 15 PY 2008 VL 78 IS 15 BP 2275 EP 2280 DI 10.1016/j.spl.2008.01.097 PG 6 WC Statistics & Probability SC Mathematics GA 369MJ UT WOS:000260698300001 ER PT J AU Puliyath, N Ray, S Milton, J Mage, RG AF Puliyath, Nandakumar Ray, Satyajit Milton, Jacqueline Mage, Rose G. TI Genetic contributions to the autoantibody profile in a rabbit model of systemic lupus erythematosus (SLE) SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE Rabbits; Autoantibodies; Antibody heavy chain allotypes; Genetics; Lupus ID ANTI-DNA ANTIBODY; ACTIVATE B-CELLS; NEUROPSYCHIATRIC LUPUS; AUTOIMMUNE MICE; NMDA RECEPTORS; SUSCEPTIBILITY; COMPLEXES; DISEASE; BINDING; REGION AB For the development of rabbit models of Systemic Lupus Erythematosus (SLE), immunoglobulin allotype-defined pedigreed rabbits from the National Institute of Allergy and Infectious Diseases rabbit resource more closely approximate human populations due to their non-inbred pedigreed structure. In an initial study from this laboratory, peptides (SM and GR) from the spliceosomal Smith (Sm) and the NMDA glutamate receptor NR2b, on branched polylysine backbones (BB) elicited antinuclear and anti-dsDNA autoantibodies typical of SLE, as well as seizures and nystagmus sometimes observed as neurological manifestations in SLE patients. This suggested the feasibility of further selective breeding to develop a more reproducible rabbit model for investigations of SLE. Here we report the results of GR-MAP-8 and control BB immunization on autoantibody responses in a group of 24 rabbits specifically bred and developed from parents and ancestors tested for autoantibody responses. The changes in hematological profile and blood chemistry in the experimental rabbits were evaluated along with autoantibody responses. Elevations of total white blood cell (WBC), monocyte, eosinophil and basophil counts that developed following immunizations were moderately influenced by litter and presence of the antibody heavy chain allotype VH1a1. Autoantibody development followed a sequential pattern with anti-nuclear antibodies (ANA) followed by anti-dsDNA and subsequently anti-Sm and anti-RNP similar to SLE patients. High autoantibody levels to one autoantigen were not always associated with antibody response to another. Female rabbits had higher prevalence and levels of autoantibodies similar to human SLE. Higher autoantibody levels of anti-dsDNA and -ANA were observed among some full sibs and the presence of high responder ancestors in the pedigree was associated the augmented responses. We observed significant association between highest antibody responses to GR-MAP-8 and highest anti-dsDNA levels. Naturally occurring autoantibodies were found in some pre-immune sera and some unique ANA fluorescent staining patterns within the experimental group were observed. Background immunofluorescence in pre-immune sera, distinct patterns of programmed autoantibody responses unique among individual rabbits may have been modulated by genetic constitution, gender and environmental factors including exposure to antigens. The high incidence and intensity of autoantibody responses among descendants of high responders suggest that there may be an additive mode of inheritance with high heritability. It is conceivable that further rigorous pedigree selection for autoantibody responses could lead to development of rabbit models with spontaneous occurrence of SLE like serology and disease phenotypes. Published by Elsevier B.V. C1 [Puliyath, Nandakumar; Ray, Satyajit; Milton, Jacqueline; Mage, Rose G.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Mage, RG (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM rmage@comcast.net FU Intramural Research Program of the NIH; NIAID; Senior Fellowship Program at National Institutes of Health; Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S.; Department of Energy; National Institutes of Health FX This research was supported by the Intramural Research Program of the NIH, NIAID. This research was also supported in part by appointment (N.P.) to the Senior Fellowship Program at National Institutes of Health. This program is administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the U.S. Department of Energy and the National Institutes of Health. We thank Dr. Richard Pospisil for helpful technical advice about ELISA, Cornelius Alexander and Barbara Newman of the Laboratory of Immunology, NIAID and Paula DeGrange and Robyn Shaw of Spring Valley Laboratories, Woodbine MD for technical assistance, and Drs. Geeta Rai, Michael Mage and Jiahui Yang for helpful suggestions about the manuscript. We are grateful to Shirley Starnes for editorial assistance. NR 50 TC 6 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD OCT 15 PY 2008 VL 125 IS 3-4 BP 251 EP 267 DI 10.1016/j.vetimm.2008.05.020 PG 17 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 363SD UT WOS:000260286100006 PM 18602165 ER PT J AU Parry, CS Brooks, BR AF Parry, Christian S. Brooks, Bernard R. TI A new model defines the minimal set of polymorphism in HLA-DQ and -DR that determines susceptibility and resistance to autoimmune diabetes SO BIOLOGY DIRECT LA English DT Article ID CLASS-II MOLECULES; MYELIN BASIC-PROTEIN; CRYSTAL-STRUCTURE; BETA-CHAIN; STRUCTURAL BASIS; PEPTIDE-BINDING; ASPARTIC-ACID; NOD MICE; T-CELLS; MELLITUS AB Background: The mechanism underlying autoimmune diabetes has been difficult to define. There is a strong genetic contribution and numerous studies associate the major histocompatibility complex, especially the class II region, with predisposition or resistance. However, how these molecules are implicated remains obscure. Presentation of the hypothesis: We have supplemented structural analysis with computational biophysical and sequence analyses and propose an heuristic for distinguishing between human leukocyte antigen molecules that predispose to insulin dependent diabetes mellitus and those that are protective. Polar residues at both beta 37 and beta 9 suffice to distinguish accurately between class II alleles that predispose to type I diabetes and those that do not. The electrostatic potential within the peptide binding pocket exerts a strong influence on diabetogenic epitopes with basic residues. Diabetes susceptibility alleles are predicted to bind autoantigens strongly with tight affinity, prolonged association and altered cytokine expression profile. Protective alleles bind moderately, and neutral alleles poorly or not at all. Non-Asp beta 57 is a modifier that supplements disease risk but only in the presence of the polymorphic, polar pair at beta 9 and beta 37. The nature of beta 37 determines resistance on one hand, and susceptibility or dominant protection on the other. Conclusion: The proposed ideas are illustrated with structural, functional and population studies from the literature. The hypothesis, in turn, rationalizes their results. A plausible mechanism of immune mediated diabetes based on binding affinity and peptide kinetics is discussed. The number of the polymorphic markers present correlates with onset of disease and severity. The molecular elucidation of disease susceptibility and resistance paves the way for risk prediction, treatment and prevention of disease based on analogue peptides. C1 [Parry, Christian S.; Brooks, Bernard R.] NHLBI, Computat Biophys Sect, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Parry, CS (reprint author), NHLBI, Computat Biophys Sect, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM csparry@helix.nih.gov; brb@nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health FX This research was supported in part by the Intramural Research program of the National Heart, Lung and Blood Institute, National Institutes of Health. NR 59 TC 6 Z9 6 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD OCT 14 PY 2008 VL 3 AR 42 DI 10.1186/1745-6150-3-42 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 381AV UT WOS:000261508100001 PM 18854049 ER PT J AU Franceschini, N Almasy, L MacCluer, JW Goering, HHH Cole, SA Diego, VP Laston, S Howard, BV Lee, ET Best, LG Fabsitz, RR North, KE AF Franceschini, Nora Almasy, Laura MacCluer, Jean W. Goering, Harald H. H. Cole, Shelley A. Diego, Vincent P. Laston, Sandra Howard, Barbara V. Lee, Elisa T. Best, Lyle G. Fabsitz, Richard R. North, Kari E. TI Diabetes-specific genetic effects on obesity traits in American Indian populations: the Strong Heart Family Study SO BMC MEDICAL GENETICS LA English DT Article ID CARDIOVASCULAR-DISEASE RISK; BY-SEX INTERACTION; GENOME-WIDE SCAN; LINKAGE ANALYSIS; INSULIN-RESISTANCE; ENCODING ADIPONECTIN-RECEPTOR-1; METABOLIC SYNDROME; FASTING INSULIN; PHENOTYPES; POLYMORPHISMS AB Background: Body fat mass distribution and deposition are determined by multiple environmental and genetic factors. Obesity is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes. We previously identified evidence for genotype-by-diabetes interaction on obesity traits in Strong Heart Family Study (SHFS) participants. To localize these genetic effects, we conducted genome-wide linkage scans of obesity traits in individuals with and without type 2 diabetes, and in the combined sample while modeling interaction with diabetes using maximum likelihood methods (SOLAR 2.1.4). Methods: SHFS recruited American Indians from Arizona, North and South Dakota, and Oklahoma. Anthropometric measures and diabetes status were obtained during a clinic visit. Marker allele frequencies were derived using maximum likelihood methods estimated from all individuals and multipoint identity by descent sharing was estimated using Loki. We used variance component linkage analysis to localize quantitative trait loci (QTLs) influencing obesity traits. We tested for evidence of additive and QTL-specific genotype-by-diabetes interactions using the regions identified in the diabetes-stratified analyses. Results: Among 245 diabetic and 704 non-diabetic American Indian individuals, we detected significant additive gene-by-diabetes interaction for weight and BMI (P < 0.02). In analysis accounting for QTL-specific interaction (P < 0.001), we detected a QTL for weight on chromosome 1 at 242 cM (LOD = 3.7). This chromosome region harbors the adiponectin receptor 1 gene, which has been previously associated with obesity. Conclusion: These results suggest distinct genetic effects on body mass in individuals with diabetes compared to those without diabetes, and a possible role for one or more genes on chromosome 1 in the pathogenesis of obesity. C1 [Franceschini, Nora; MacCluer, Jean W.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA. [Almasy, Laura; MacCluer, Jean W.; Goering, Harald H. H.; Cole, Shelley A.; Diego, Vincent P.; Laston, Sandra] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Howard, Barbara V.] MedStar Res Inst, Washington, DC USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Fabsitz, Richard R.] NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. [North, Kari E.] Univ N Carolina, Ctr Genome Sci, Chapel Hill, NC USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA. EM noraf@unc.edu; almasy@sfbrgenetics.org; jean@sfbrgenetics.org; hgoring@sfbrgenetics.org; scole@sfbrgenetics.org; vdiego@sfbrgenetics.org; slaston@sfbrgenetics.org; Barbara.V.Howard@medstar.net; Elisa-Lee@ouhsc.edu; sbest@utma.com; fabsitzr@nhlbi.nih.gov; Kari_North@unc.edu OI Diego, Vincent/0000-0002-0007-2085 FU NHLBI NIH HHS [U01 HL41642, U01 HL041642, U01 HL041652, U01 HL041654, U01 HL065520, U01 HL065521, U01 HL41652, U01 HL41654, U01 HL65520, U01 HL65521]; NIMH NIH HHS [MH059490, R01 MH059490, R37 MH059490] NR 34 TC 6 Z9 6 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD OCT 14 PY 2008 VL 9 AR 90 DI 10.1186/1471-2350-9-90 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 370EE UT WOS:000260744700001 PM 18854016 ER PT J AU Zhang, P Pazin, MJ Schwartz, CM Becker, KG Wersto, RP Dilley, CM Mattson, MP AF Zhang, Peisu Pazin, Michael J. Schwartz, Catherine M. Becker, Kevin G. Wersto, Robert P. Dilley, Caroline M. Mattson, Mark P. TI Nontelomeric TRF2-REST Interaction Modulates Neuronal Gene Silencing and Fate of Tumor and Stem Cells SO CURRENT BIOLOGY LA English DT Article ID HUMAN TELOMERES; DIFFERENTIATION; SENESCENCE; UBIQUITIN; SUBTYPE; YEAST; REST AB Removal of TRF2, a telomere shelterin protein, recapitulates key aspects of telomere attrition including the DNA-damage response and cell-cycle arrest [1]. Distinctfrorn the response of proliferating cells to loss of TRF2 [2, 3], in rodent noncycling cells, TRF2 inhibition promotes differentiation and growth [4, 5]. However, the mechanism that couples telomere gene-silencing features [6-8] to differentiation programs has yet to be elucidated. Here we describe an extratelomeric function of TRF2 in the regulation of neuronal genes mediated by the interaction of TRF2 with repressor element 1-silencing transcription factor (REST), a master repressor of gene networks devoted to neuronal functions [9-12]. TRF2-REST complexes are readily detected by coimmunoprecipitation assays and are localized to aggregated PML-nuclear bodies in undifferentiated pluripotent human NTera2 stem cells. Inhibition of TRF2, either by a dominant-negative mutant or by RNA interference, dissociates TRF2-REST complexes resulting in ubiquitin-proteasomal degradation of REST. Consequentially, REST-targeted neural genes (OCAM, beta 3-tubulin, synaptophysin, and others) are derepressed, resulting in acquisition of neuronal phenotypes. Notably, selective damage to telomeres without affecting TRF2 levels causes neither REST degradation nor cell differentiation. Thus, in addition to protecting telomeres, TRF2 possesses a novel role in stabilization of REST thereby controlling neural tumor and stem cell fate. C1 [Zhang, Peisu; Schwartz, Catherine M.; Dilley, Caroline M.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Pazin, Michael J.] NIA, Cellular & Mol Biol Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Becker, Kevin G.; Wersto, Robert P.] NIA, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Schwartz, Catherine M.] Karolinska Inst, Mol Neurobiol Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; OI Becker, Kevin/0000-0002-6794-6656; Pazin, Michael/0000-0002-7561-3640 FU National Institute on Aging Intramural Research Program FX We thank G. Mandel for REST plasmids, F. Dantzer for GST-TRF2 plasmids, and V.M. Vishva Dixit for HA-ubiquitin plasmids; Kazuo Shin-ya for telomestatin; C. Morris for help with flow cytometry analysis; and V. Bohr, Y. Liu, H. Tahara, and O. Taeko for valuable comments on the paper and technical support. This research was supported by the National Institute on Aging Intramural Research Program. NR 24 TC 41 Z9 41 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD OCT 14 PY 2008 VL 18 IS 19 BP 1489 EP 1494 DI 10.1016/j.cub.2008.08.048 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 361OV UT WOS:000260137900025 PM 18818083 ER PT J AU Isik, N Brzostowski, JA Jin, T AF Isik, Nilgun Brzostowski, Joseph A. Jin, Tian TI An Elmo-like Protein Associated with Myosin II Restricts Spurious F-Actin Events to Coordinate Phagocytosis and Chemotaxis SO DEVELOPMENTAL CELL LA English DT Article ID SIGNALING EVENTS; CELL MOTILITY; DICTYOSTELIUM; DYNAMICS; REORGANIZATION; ENGULFMENT; MIGRATION; FILAMENTS; POLARITY; COMPLEX AB Elmo proteins positively regulate actin polymerization during cell migration and phagocytosis through activation of the small G protein Rac. We identified an Elmo-like protein, ElmoA, in Dictyostelium discoideum that unexpectedly functions as a negative regulator of actin polymerization. Cells lacking ElmoA display an elevated rate of phagocytosis, increased pseudopod formation, and excessive F-actin localization within pseudopods. ElmoA associates with cortical actin and myosin II. TIRF microscopic observations of functional ElmoA-GFP reveal that a fraction of ElmoA localizes near the presumptive actin/myosin II cortex and the levels of ElmoA and myosin II negatively correlate with that of polymerizing F-actin. F-actin-regulated dynamic dispersions of ElmoA and myosin II are interdependent. Taken together, our data suggest that ElmoA modulates actin/myosin II at the cortex to prevent excessive F-actin polymerization around the cell periphery, thereby maintaining proper cell shape during phagocytosis and chemotaxis. C1 [Isik, Nilgun; Jin, Tian] NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil 2, Rockville, MD 20852 USA. [Brzostowski, Joseph A.] NIAID, Lab Immunogenet Light Imaging Facil, NIH, Twinbrook Facil 2, Rockville, MD 20852 USA. RP Jin, T (reprint author), NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil 2, 12331 Parklawn Dr, Rockville, MD 20852 USA. EM tjin@niaid.nih.gov FU NIAID/NIH intramural funds FX We thank Michael March. Jun Fang, Pavel Tolar, Francisco Borrego, Xuehua Xu. Gordon Joyce. Julie Kim, and members in T. Jin's lab at LIG MAID for help: G. Gerisch and A. Muller-Taubenberger for providing Delta limE-RFP plasmid and N. Glenn and M. Zhao at NIAID/NIH for mass spectrometry analysis. We thank T. Egelhoff for the anti-myosin antibody, We also thank S, Shu,X. Liu, and E. Korn for help and for providing Myoll-GFP plasmid and myosin 11 null cells. We thank X. Xiang for critical comments. The study is supported by NIAID/NIH intramural funds. NR 40 TC 16 Z9 18 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD OCT 14 PY 2008 VL 15 IS 4 BP 590 EP 602 DI 10.1016/j.devcel.2008.08.006 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 363BP UT WOS:000260241200014 PM 18854143 ER PT J AU Hallett, M Evinger, C Jankovic, J Stacy, M Ali, M Berardelli, A Daroff, RB Defazio, G Delong, M Eidelberg, D Foote, K Hattori, N Katz, B Nguyen, QT Lehericy, S Meunier, S Morecraft, RJ Ozelius, LJ Patrinely, JR Peckham, E Perl, DP Perlmutter, JS Scott, AB Singleton, A Tolosa, E Valente, EM Valls-Sole, J Wang, JJ AF Hallett, Mark Evinger, Craig Jankovic, Joseph Stacy, Mark Ali, M. Berardelli, A. Daroff, R. B. Defazio, G. Delong, M. Eidelberg, D. Foote, K. Hattori, N. Katz, B. Nguyen, Q. T. Lehericy, S. Meunier, S. Morecraft, R. J. Ozelius, L. J. Patrinely, J. R. Peckham, E. Perl, D. P. Perlmutter, J. S. Scott, A. B. Singleton, A. Tolosa, E. Valente, E. M. Valls-Sole, J. Wang, J. J. TI Update on blepharospasm - Report from the BEBRF International Workshop SO NEUROLOGY LA English DT Review ID PRIMARY TORSION DYSTONIA; LONG-TERM POTENTIATION; DEEP BRAIN-STIMULATION; FOCAL HAND DYSTONIA; MEIGE-SYNDROME; CERVICAL DYSTONIA; BOTULINUM TOXIN; BLINK REFLEX; DRY EYE; ONSET AB This review updates understanding and research on blepharospasm, a subtype of focal dystonia. Topics covered include clinical aspects, pathology, pathophysiology, animal models, dry eye, photophobia, epidemiology, genetics, and treatment. Blepharospasm should be differentiated from apraxia of eyelid opening. New insights into pathology and pathophysiology are derived from different types of imaging, including magnetic resonance studies. Physiologic studies indicate increased plasticity and trigeminal sensitization. While botulinum neurotoxin injections are the mainstay of therapy, other therapies are on the horizon. C1 [Hallett, Mark; Ali, M.; Berardelli, A.; Daroff, R. B.; Defazio, G.; Delong, M.; Eidelberg, D.; Foote, K.; Hattori, N.; Katz, B.; Nguyen, Q. T.; Lehericy, S.; Meunier, S.; Morecraft, R. J.; Ozelius, L. J.; Patrinely, J. R.; Peckham, E.; Perl, D. P.; Perlmutter, J. S.; Scott, A. B.; Singleton, A.; Tolosa, E.; Valente, E. M.; Valls-Sole, J.; Wang, J. J.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Evinger, Craig] SUNY Stony Brook, Dept Neurobiol & Behav, Stony Brook, NY 11794 USA. [Jankovic, Joseph] Baylor Coll Med, Parkinsons Dis Ctr, Houston, TX 77030 USA. [Jankovic, Joseph] Baylor Coll Med, Movement Disorders Clin, Dept Neurol, Houston, TX 77030 USA. [Stacy, Mark] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Singleton, Andrew/C-3010-2009; meunier, sabine/G-7622-2014 OI meunier, sabine/0000-0002-6167-4602 FU NIH Intramural Program; Control of eyelids in normal and pathological states [EY07391]; Advanced Neuromodulation Systems; Allergan, Inc.; Boehringer-Ingelheim; Ceregene, Inc.; EMD; Eisai; Ipsen Limited; Huntington's Disease Society of America; Kyowa Pharmaceuticals; Medtronic; Merz Pharmaceuticals; National Institutes of Health; National Parkinson Foundation; Novartis; Ortho-McNeil; Parkinson Study Group; Prestwick Pharmaceuticals; Schering; Schwarz Pharma/UCB; Teva FX Supported by the NIH Intramural Program (M.H.) and NIH grant EY07391 (Control of eyelids in normal and pathological states) (C.E.). Dr. Jankovic has received research grants from the following: Advanced Neuromodulation Systems; Allergan, Inc.; Boehringer-Ingelheim; Ceregene, Inc.; EMD; Eisai; Ipsen Limited; Huntington's Disease Society of America; Kyowa Pharmaceuticals; Medtronic; Merz Pharmaceuticals; National Institutes of Health; National Parkinson Foundation; Novartis; Ortho-McNeil; Parkinson Study Group; Prestwick Pharmaceuticals; Schering; Schwarz Pharma/UCB; Teva. NR 52 TC 64 Z9 66 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 14 PY 2008 VL 71 IS 16 BP 1275 EP 1282 DI 10.1212/01.wnl.0000327601.46315.85 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 359KT UT WOS:000259986300011 PM 18852443 ER PT J AU Dudko, OK Hummer, G Szabo, A AF Dudko, Olga K. Hummer, Gerhard Szabo, Attila TI Theory, analysis, and interpretation of single-molecule force spectroscopy experiments SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE atomic force microscope; optical tweezers; nanopore unzipping Kramers theory; rupture force distribution ID CELL-ADHESION MOLECULES; REACTION COORDINATE; UNFOLDING KINETICS; SYSTEMATIC-ERRORS; BONDS; DYNAMICS; PROTEIN; DNA; LANDSCAPES; TRANSITION AB Dynamic force spectroscopy probes the kinetic and thermodynamic properties of single molecules and molecular assemblies. Here, we propose a simple procedure to extract kinetic information from such experiments. The cornerstone of our method is a transformation of the rupture-force histograms obtained at different force-loading rates into the force-dependent lifetimes measurable in constant-force experiments. To interpret the force-dependent lifetimes, we derive a generalization of Bell's formula that is formally exact within the framework of Kramers theory. This result complements the analytical expression for the lifetime that we derived previously for a class of model potentials. We illustrate our procedure by analyzing the nanopore unzipping of DNA hairpins and the unfolding of a protein attached by flexible linkers to an atomic force microscope. Our procedure to transform rupture-force histograms into the force-dependent lifetimes remains valid even when the molecular extension is a poor reaction coordinate and higher-dimensional free-energy surfaces must be considered. In this case the microscopic interpretation of the lifetimes becomes more challenging because the lifetimes can reveal richer, and even nonmonotonic, dependence on the force. C1 [Dudko, Olga K.] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA. [Dudko, Olga K.] Univ Calif San Diego, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA. [Hummer, Gerhard; Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Dudko, OK (reprint author), Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA. EM dudko@physics.ucsd.edu RI Szabo, Attila/H-3867-2012; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Center for Theoretical Biological Physics; National Science Foundation [PHY-0822283]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX We thank Prof. Amit Meller and Prof. Matthias Rief for sharing their data. O.K.D. was supported by the Center for Theoretical Biological Physics, National Science Foundation Grant PHY-0822283. G.H. and A.S. were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 38 TC 272 Z9 275 U1 9 U2 109 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 14 PY 2008 VL 105 IS 41 BP 15755 EP 15760 DI 10.1073/pnas.0806085105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363BM UT WOS:000260240900023 PM 18852468 ER PT J AU Raychaudhuri, S Prinz, WA AF Raychaudhuri, Sumana Prinz, William A. TI Nonvesicular phospholipid transfer between peroxisomes and the endoplasmic reticulum SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ER; lipid transport; membrane; organelle biogenesis ID PERFORMANCE LIQUID-CHROMATOGRAPHY; SACCHAROMYCES-CEREVISIAE; PREEXISTING PEROXISOMES; ZELLWEGER-SYNDROME; MEMBRANE-PROTEINS; SECRETORY PATHWAY; VESICLE FORMATION; BINDING PROTEIN; YEAST; TRANSPORT AB The endoplasmic reticulum (ER) plays an important role in peroxisome biogenesis; some peroxisomal membrane proteins are inserted into the ER and trafficked to peroxisomes in vesicles. These vesicles could also provide the phospholipids required for the growth of peroxisomal membranes, because peroxisomes lack phospholipid biosynthesis enzymes. To test this, we established a novel assay to monitor phospholipid transfer between the ER and peroxisomes and found that phospholipids are rapidly trafficked between these compartments. This transport is not blocked in mutants with conditional defects in Sec proteins required for vesicular trafficking from the ER or in Pex3p, a protein required for peroxisome membrane biogenesis. ER to peroxisome lipid transport was reconstituted in vitro and does not require cytosolic factors or ATP. Our findings indicate that lipids are directly transferred from the ER to peroxisomes by a nonvesicular pathway and suggest that ER to peroxisome vesicular transport is not required to provide lipids for peroxisomal growth. C1 [Raychaudhuri, Sumana; Prinz, William A.] NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), NIDDKD, Lab Cell Biochem & Biol, NIH, 8 Ctr Dr,Bldg 8,Room 301, Bethesda, MD 20892 USA. EM wprinz@helix.nih.gov OI Raychaudhuri, Sumana/0000-0002-3164-0057 FU National Institute of Diabetes and Digestive and Kidney Diseases FX We thank S. Gould for plasmids and advice, and O. Cohen-Fix, T. Schulz, and J. Hanover for critical reading of the manuscript. This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 42 TC 39 Z9 39 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 14 PY 2008 VL 105 IS 41 BP 15785 EP 15790 DI 10.1073/pnas.0808321105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363BM UT WOS:000260240900028 PM 18836080 ER PT J AU Cereghetti, GM Stangherlin, A de Brito, OM Chang, CR Blackstone, C Bernardi, P Scorrano, L AF Cereghetti, G. M. Stangherlin, A. de Brito, O. Martins Chang, C. R. Blackstone, C. Bernardi, P. Scorrano, L. TI Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fission phosphatase; subcellular localization; calcium; cyclosporine A ID SYNAPTIC VESICLE ENDOCYTOSIS; DEPENDENT PROTEIN-KINASE; PERMEABILITY TRANSITION; CELL-DEATH; GTPASE ACTIVITY; CYCLOSPORINE-A; CYTOCHROME-C; PHOSPHORYLATION; MORPHOLOGY; APOPTOSIS AB Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca2+ rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca2+ rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle. C1 [Cereghetti, G. M.; Stangherlin, A.; de Brito, O. Martins; Scorrano, L.] Dulbecco Telethon Inst, I-35129 Padua, Italy. [Cereghetti, G. M.; Stangherlin, A.; de Brito, O. Martins; Scorrano, L.] Venetian Inst Mol Med, I-35129 Padua, Italy. [Chang, C. R.; Blackstone, C.] NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. [Bernardi, P.] Univ Padua, Dept Biomed Sci, I-35121 Padua, Italy. RP Scorrano, L (reprint author), Univ Geneva, Sch Med, Dept Cell Physiol & Metab, 1 Rue M Servet, CH-1205 Geneva, Switzerland. EM luca.scorrano@medecine.unige.ch RI Bernardi, Paolo/C-3656-2008; stangherlin, alessandra/E-9669-2011; Chang, Chuang-Rung /C-1815-2012; Scorrano, Luca/A-6652-2008 OI Bernardi, Paolo/0000-0001-9187-3736; stangherlin, alessandra/0000-0001-7296-1183; Scorrano, Luca/0000-0002-8515-8928 FU Telethon Italy; AIRC Italy; Compagnia di San Paolo Italy; Human Frontier Science Program Organization; Swiss National Science Foundation FX This study was supported by Telethon Italy, AIRC Italy, Compagnia di San Paolo Italy, Human Frontier Science Program Organization, Swiss National Science Foundation (to L.S.); and by Telethon Italy and AIRC Italy (to P.B.). G.M.C. was supported by a grant for prospective researchers of the Swiss National Science Foundation. NR 33 TC 394 Z9 405 U1 3 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 14 PY 2008 VL 105 IS 41 BP 15803 EP 15808 DI 10.1073/pnas.0808249105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363BM UT WOS:000260240900031 PM 18838687 ER PT J AU Than, NG Romero, R Erez, O Weckle, A Tarca, AL Hotra, J Abbas, A Han, YM Kim, SS Kusanovic, JP Gotsch, F Hou, ZC Santolaya-Forgas, J Benirschke, K Papp, Z Grossman, LI Goodman, M Wildman, DE AF Than, Nanclor Gabor Romero, Roberto Erez, Offer Weckle, Amy Tarca, Adi L. Hotra, John Abbas, Asad Han, Yu Mi Kim, Sung-Su Kusanovic, Juan Pedro Gotsch, Francesca Hou, Zhuocheng Santolaya-Forgas, Joaquin Benirschke, Kurt Papp, Zoltan Grossman, Lawrence I. Goodman, Morris Wildman, Derek E. TI Emergence of hormonal and redox regulation of galectin-1 in placental mammals: Implication in maternal-fetal immune tolerance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE decidua; estrogen; glycocode; immune-endocrine cross-talk; pregnancy ID GALACTOSIDE-BINDING LECTIN; SITE-DIRECTED MUTAGENESIS; T-CELLS; PHYLOGENETIC ANALYSIS; ESTROGEN-RECEPTOR; GENE-EXPRESSION; FAMILY; EVOLUTION; LOCALIZATION; INTERFACE AB Galectin-1 is an anti-inflammatory lectin with pleiotropic regulatory functions at the crossroads of innate and adaptive immunity. It is expressed in immune privileged sites and is implicated in establishing maternal-fetal immune tolerance, which is essential for successful pregnancy in eutherian mammals. Here, we show conserved placental localization of galectin-1 in primates and its predominant expression in maternal decidua. Phylogenetic foot-printing and shadowing unveil conserved cis motifs, including an estrogen responsive element in the 5' promoter of LGALS1, that were gained during the emergence of placental mammals and could account for sex steroid regulation of LGALS1 expression,thus providing additional evidence for the role of galectin-1 in immune-endocrine cross-talk. Maximum parsimony and maximum likelihood analyses of 27 publicly available vertebrate and seven newly sequenced primate LGALS1 coding sequences reveal that intense purifying selection has been acting on residues in the carbohydrate recognition domain and dimerization interface that are involved in immune functions. Parsimony- and codon model-based phylogenetic analysis of coding sequences show that amino acid replacements occurred in early mammalian evolution on key residues, including gain of cysteines, which regulate immune functions by redox status-mediated conformational changes that disable sugar binding and dimerization, and that the acquired immunoregulatory functions of galectin-1 then became highly conserved in eutherian lineages, suggesting the emergence of hormonal and redox regulation of galectin-1 in placental mammals may be implicated in maternal-fetal immune tolerance. C1 [Than, Nanclor Gabor; Romero, Roberto; Erez, Offer; Tarca, Adi L.; Hotra, John; Abbas, Asad; Han, Yu Mi; Kim, Sung-Su; Kusanovic, Juan Pedro; Gotsch, Francesca; Wildman, Derek E.] NICHHD, Perinatol Res Branch, Detroit, MI 48201 USA. [Than, Nanclor Gabor; Romero, Roberto; Erez, Offer; Tarca, Adi L.; Hotra, John; Abbas, Asad; Han, Yu Mi; Kim, Sung-Su; Kusanovic, Juan Pedro; Gotsch, Francesca; Wildman, Derek E.] US Dept HHS, Detroit, MI 48201 USA. [Than, Nanclor Gabor; Papp, Zoltan] Semmelweis Univ, Dept Obstet & Gynecol 1, H-1088 Budapest, Hungary. [Romero, Roberto; Erez, Offer; Kusanovic, Juan Pedro] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Weckle, Amy; Hou, Zhuocheng; Grossman, Lawrence I.; Goodman, Morris; Wildman, Derek E.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Goodman, Morris] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Benirschke, Kurt] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Santolaya-Forgas, Joaquin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. RP Romero, R (reprint author), NICHHD, Perinatol Res Branch, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; dwildman@med.wayne.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Department of Health and Human Services FX We acknowledge the valuable contributions of Dr. Chong Jai Kim, Sandy Field, Nancy Hauff, Gerardo Rodriguez, and the nursing staff of the Perinatology Research Branch. The authors thank Dr. Susan Land and Daniel Lott at the Applied Genomics Technology Center of Wayne State University for performing the qRT-PCR reactions, and Sara Tipton for critical reading of the manuscript. The following kindly provided DNA and/or tissue samples: Dr. Caro-Beth Stewart (SUNY, Albany, NY), Dr. Kathy Neiswanger (University of Pittsburgh, Pittsburgh, PA), the New England Regional Primate Center (Southborough, MA), the Duke University Primate Center (Durham, INC), and the San Diego Zoo (San Diego, CA). This research was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services. NR 51 TC 33 Z9 34 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 14 PY 2008 VL 105 IS 41 BP 15819 EP 15824 DI 10.1073/pnas.0807606105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363BM UT WOS:000260240900034 PM 18824694 ER PT J AU Chowdhury, M Forouhi, O Dayal, S McCloskey, N Gould, HJ Felsenfeld, G Fear, DJ AF Chowdhury, Muslima Forouhi, Omid Dayal, Sandeep McCloskey, Natalie Gould, Hannah J. Felsenfeld, Gary Fear, David J. TI Analysis of intergenic transcription and histone modification across the human immunoglobulin heavy-chain locus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE human B cells; immunoglobulin class switching; chromatin ID B-CELL DEVELOPMENT; IL-4/IL-13 GENE-CLUSTER; SINGLE-STRANDED-DNA; BETA-GLOBIN LOCUS; SWITCH REGIONS; SOMATIC HYPERMUTATION; CHROMOSOME 13Q14; HUMAN GENOME; IGH LOCUS; C-MYC AB Ig class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID) mediated deamination of the switch (S) regions; the resultant mismatch is processed to yield the DNA breaks required for recombination. Whereas many of the pathways involved in the mechanism of recombination have been identified, little is known about how CSR is regulated. AID action is known to require transcription of the Ig heavy-chain genes. However, it is not understood how AID is restricted to the Ig genes. Many aspects of gene expression are known to be regulated by modification of chromatin structure. In turn, chromatin is known to be regulated by several RNA-dependent activities. We have mapped the transcriptional and chromatin landscape of the human Ig heavy-chain locus to investigate the effect these activities have on CSR. We demonstrate that the Ig heavy-chain constant genes and 3'-regulatory regions are in an active chromatin conformation in unstimulated total human B cells: the locus undergoes both genic and intergenic transcription and possesses histone modifications associated with "active" chromatin (acetylated H3 and H4 and lysine 4 trimethylated H3). However, on cytokine stimulation, these modifications spread into the 9 regions, demonstrating a chromatin remodeling activity associated with switching. Surprisingly, after stimulation, the S regions also accumulate lysine 9 trimethylated H3, a modification previously associated with gene silencing. These data demonstrates that the Ig locus is maintained with a complex pattern of both positive and negative histone marks and suggest that some of these marks may have dual functions. C1 [Dayal, Sandeep; Felsenfeld, Gary] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chowdhury, Muslima; McCloskey, Natalie; Gould, Hannah J.] Kings Coll London, Randall Div Cel & Mol Biophys, London SE1 1UL, England. [McCloskey, Natalie; Gould, Hannah J.; Fear, David J.] Kings Coll London, Guys Hosp London, Asthma UK Ctr Allerg Mech Asthma, London SE1 9RT, England. [McCloskey, Natalie; Gould, Hannah J.; Fear, David J.] Kings Coll London, MRC, London SE1 9RT, England. [Forouhi, Omid; Fear, David J.] Kings Coll London, Div Asthma Allergy & Lung Biol, London SE1 9RT, England. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, 5 Ctr Dr, Bethesda, MD 20892 USA. EM garyf@intra.niddk.nih.gov; david.fear@kcl.ac.uk OI Gould, Hannah/0000-0003-0411-688X FU Medical Research Council (MRC) [G0400106]; MRC Asthma U.K. FX We thank the staff at the Evelina Children's Hospital Guy's and St. Thomas' National Health Service Foundation Trust for their help with the collection of tonsils, We also thank Dr. M Gellert for critical reading of this manuscript. D.F. is supported by a Research Councils U.K. fellowship. This work was supported by Medical Research Council (MRC) Project Grant G0400106, Asthma U.K. funded core support for the MRC & Asthma U.K. Centre for Allergic Mechanisms of Asthma, and the Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases. NR 63 TC 26 Z9 27 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 14 PY 2008 VL 105 IS 41 BP 15872 EP 15877 DI 10.1073/pnas.0808462105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363BM UT WOS:000260240900043 PM 18836073 ER PT J AU Capell, BC Olive, M Erdos, MR Cao, K Faddah, DA Tavarez, UL Conneely, KN Qu, X San, H Ganesh, SK Chen, X Avallone, H Kolodgie, FD Virmani, R Nabel, EG Collins, FS AF Capell, Brian C. Olive, Michelle Erdos, Michael R. Cao, Kan Faddah, Dina A. Tavarez, Urraca L. Conneely, Karen N. Qu, Xuan San, Hong Ganesh, Santhi K. Chen, Xiaoyan Avallone, Hedwig Kolodgie, Frank D. Virmani, Renu Nabel, Elizabeth G. Collins, Francis S. TI A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; Hutchinson-Gilford progeria syndrome; lamin; atherosclerosis; translation ID HUTCHINSON-GILFORD-PROGERIA; MUTANT LAMIN-A; DEFECTS; ATHEROSCLEROSIS; ISOPRENYLATION; MISREGULATION; FARNESYLATION; PRECURSOR; MUTATION; STATINS AB Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form of human premature aging. Death occurs at a mean age of 13 years, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A (LMNA) gene that results in production of a mutant lamin A protein termed progerin. This protein is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has been shown to prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. We have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. Here we show that the dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease. C1 [Capell, Brian C.; Olive, Michelle; Erdos, Michael R.; Cao, Kan; Faddah, Dina A.; Tavarez, Urraca L.; Qu, Xuan; San, Hong; Ganesh, Santhi K.; Chen, Xiaoyan; Nabel, Elizabeth G.; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Conneely, Karen N.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Avallone, Hedwig; Kolodgie, Frank D.; Virmani, Renu] CVPath, Gaithersburg, MD 20878 USA. [Nabel, Elizabeth G.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM 4rancis@mail.nih.gov OI Capell, Brian/0000-0002-7036-8359 FU NIA NIH HHS [K99 AG029761, K99 AG029761-01A1, R00 AG029761, R00 AG029761-02] NR 32 TC 96 Z9 99 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 14 PY 2008 VL 105 IS 41 BP 15902 EP 15907 DI 10.1073/pnas.0807840105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363BM UT WOS:000260240900048 PM 18838683 ER PT J AU Gogtay, N Lu, A Leow, AD Klunder, AD Lee, AD Chavez, A Greenstein, D Giedd, JN Toga, AW Rapoport, JL Thompson, PM AF Gogtay, Nitin Lu, Allen Leow, Alex D. Klunder, Andrea D. Lee, Agatha D. Chavez, Alex Greenstein, Deanna Giedd, Jay N. Toga, Arthur W. Rapoport, Judith L. Thompson, Paul M. TI Three-dimensional brain growth abnormalities in childhood-onset schizophrenia visualized by using tensor-based morphometry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE development; imaging; MRI; white matter ID WHITE-MATTER ABNORMALITIES; CORTICAL DEVELOPMENT; DEFORMATION; ADOLESCENCE; MRI; CONNECTIVITY; EXPRESSION; PATTERNS; DISORDER; DEFICITS AB Earlier studies revealed progressive cortical gray matter (GM) loss in childhood-onset schizophrenia (COS) across both lateral and medial surfaces of the developing brain. Here, we use tensor-based morphometry to visualize white matter (WM) growth abnormalities in COS throughout the brain. Using high-dimensional elastic image registration, we compared 3D maps of local WM growth rates in COS patients and healthy children over a 5-year period, based on analyzing longitudinal brain MRIs from 12 COS patients and 12 healthy controls matched for age, gender, and scan interval. COS patients showed up to 2.2% slower growth rates per year than healthy controls in WM (P = 0.02, all P values corrected). The greatest differences were in the right hemisphere (P = 0.006). This asymmetry was attributable to a right slower than left hemisphere growth rate mapped in COS patients (P = 0.037) but not in healthy controls. WM growth rates reached 2.6% per year in healthy controls (P = 0.0002). COS patients showed only a 1.3% per year trend for growth in the left hemisphere (P = 0.066). In COS, WM growth rates were associated with improvement in the Children's Global Assessment Scale (R = 0.64, P = 0.029). Growth rates were reduced throughout the brain in COS, but this process appeared to progress in a front-to-back (frontal-parietal) fashion, and this effect was not attributable to lower IQ. Growth rates were correlated with functional prognosis and were visualized as detailed 3D maps. Finally, these findings also confirm that the progressive GM deficits seen in schizophrenia are not the result of WM overgrowth. C1 [Gogtay, Nitin; Chavez, Alex; Greenstein, Deanna; Giedd, Jay N.; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Lu, Allen; Leow, Alex D.; Klunder, Andrea D.; Lee, Agatha D.; Toga, Arthur W.; Thompson, Paul M.] Univ Calif Los Angeles, Sch Med, Lab Neuro Imaging, Los Angeles, CA 90095 USA. [Leow, Alex D.] Univ Calif Los Angeles, Sch Med, Semel Inst Neurosci, Los Angeles, CA 90095 USA. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, 10-3N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM gogtayn@mail.nih.gov RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Leow, Alex/K-3236-2014; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Leow, Alex/0000-0002-5660-8651; Giedd, Jay/0000-0003-2002-8978; Chavez, Alexis/0000-0003-1322-4532 FU National Institute for Biomedical Imaging and Bioengineering; National Center for Research Resources; National institute on Aging; National Library of Medicine [EB01651, RR019771, AG016570] FX This research was partially supported by the National Institute for Biomedical Imaging and Bioengineering, the National Center for Research Resources, the National institute on Aging, and the National Library of Medicine Grants EB01651, RR019771, and AG016570 (to PMT). NR 42 TC 76 Z9 77 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 14 PY 2008 VL 105 IS 41 BP 15979 EP 15984 DI 10.1073/pnas.0806485105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 363BM UT WOS:000260240900061 PM 18852461 ER PT J AU Vinogradov, E Kubler-Kielb, J Korenevsky, A AF Vinogradov, Evgeny Kubler-Kielb, Joanna Korenevsky, Anton TI The structure of the carbohydrate backbone of the LPS from Shewanella spp. MR-4 SO CARBOHYDRATE RESEARCH LA English DT Article DE LPS; Structure; NMR; Shewanella ID ACID; LIPOOLIGOSACCHARIDE; LIPOPOLYSACCHARIDES AB The rough type lipopolysaccharide isolated from Shewanella spp. strain MR-4 was analyzed using NMR, mass spectroscopy, and chemical methods. Two structural variants have been found, both contained 8-amino-3,8-dideoxy-D-rnanno-octulosonic acid and lacked L-glycero-D-manno-heptose. A minor variant of the LPS contained phosphoramide substituent. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Vinogradov, Evgeny] Natl Res Council Canada, Inst Biol Sci, Ottawa, ON K1A 0R6, Canada. [Kubler-Kielb, Joanna] NICHHD, NIH, Bethesda, MD 20892 USA. [Korenevsky, Anton] Univ Guelph, Coll Biol Sci, Dept Microbiol, Guelph, ON N1G 2W1, Canada. RP Vinogradov, E (reprint author), Natl Res Council Canada, Inst Biol Sci, 100 Sussex Dr, Ottawa, ON K1A 0R6, Canada. EM evguenii.vinogradov@nrc.ca OI Vinogradov, Evgeny/0000-0002-5364-1376 FU US-DOE Natural and Accelerated Bioremediation Research; Intramural Research Program of the NIH, NICHD FX The research was partially supported by a US-DOE Natural and Accelerated Bioremediation Research Grant and by the Intramural Research Program of the NIH, NICHD. Authors thank J. Stupak (NRC, Canada) for the ESIMS analysis. NR 13 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD OCT 13 PY 2008 VL 343 IS 15 BP 2701 EP 2705 DI 10.1016/j.carres.2008.06.006 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 362QE UT WOS:000260211400027 PM 18619581 ER PT J AU Lehotzky, A Tokesi, N Gonzalez-Alvarez, I Merino, V Bermejo, M Orosz, F Lau, P Kovacs, GG Ovadi, J AF Lehotzky, A. Tokesi, N. Gonzalez-Alvarez, I. Merino, V. Bermejo, M. Orosz, F. Lau, P. Kovacs, G. G. Ovadi, J. TI Progress in the development of early diagnosis and a drug with unique pharmacology to improve cancer therapy SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES LA English DT Review DE cancer; anti-mitotic drug; KAR-2; bioavailability; anti-mitotic protein; TPPP/p25 ID DEVELOPING RAT-BRAIN; CELL-LINE; P-GLYCOPROTEIN; PROTEIN TPPP/P25; GENE-EXPRESSION; CACO-2 CELLS; MODEL SYSTEM; TUBULIN; OLIGODENDROCYTES; MICROTUBULES AB Cancer continues to be one of the major health and socio-economic problems worldwide, despite considerable efforts to improve its early diagnosis and treatment. The identification of new constituents as biomarkers for early diagnosis of neoplastic cells and the discovery of new type of drugs with their mechanistic actions are crucial to improve cancer therapy. New drugs have entered the market, thanks to industrial and legislative efforts ensuring continuity of pharmaceutical development. New targets have been identified, but cancer therapy and the anti-cancer drug market still partly depend on anti-mitotic agents. The objective of this paper is to show the effects of KAR-2, a potent anti-mitotic compound, and TPPP/p25, a new unstructured protein, on the structural and functional characteristics of the microtubule system. Understanding the actions of these two potential effectors on the microtubule system could be the clue for early diagnosis and improvement of cancer therapy. C1 [Lehotzky, A.; Tokesi, N.; Orosz, F.; Ovadi, J.] Hungarian Acad Sci, Inst Enzymol, Biol Res Ctr, H-1113 Budapest, Hungary. [Gonzalez-Alvarez, I.; Merino, V.; Bermejo, M.] Univ Valencia, Dept Pharmaceut & Pharmaceut Technol, Valencia 46010, Spain. [Lau, P.] Natl Inst Neurol Disorders & Stroke, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. [Kovacs, G. G.] Med Univ Vienna, Inst Neurol, A-1097 Vienna, Austria. RP Ovadi, J (reprint author), Hungarian Acad Sci, Inst Enzymol, Biol Res Ctr, Karolina Ut 29, H-1113 Budapest, Hungary. EM ovadi@enzim.hu RI Bermejo, Marival/A-4163-2009; Lehotzky, Attila/B-1837-2009; Kovacs, Gabor/A-7468-2013; GONZALEZ-ALVAREZ, ISABEL/N-3614-2013; OI Bermejo, Marival/0000-0001-5022-0544; Kovacs, Gabor/0000-0003-3841-5511; GONZALEZ-ALVAREZ, ISABEL/0000-0002-1685-142X; Attila, Lehotzky/0000-0001-5235-1812 FU BioSim and NKFP-MediChem2 [1/A/005/2004]; Hungarian National Scientific Research Fund [T-046071, T-67963, T-049247]; Ministerio de Educacion y Ciencia (SAF); Conselleria de Cultura, Educacion y Ciencia and Conselleria de Empresa, Universidad y Ciencia from Generalitat Valenciana (ACOMP); [FP6-2003-LIFESCIHEALTH-I]; [SAF2006-2749-E]; [ACOMP2007/180]; [AE 2007-005]; [ACOMP2006/156] FX This work was supported by FP6-2003-LIFESCIHEALTH-I: BioSim and NKFP-MediChem2 1/A/005/2004 to J.O.; and by the Hungarian National Scientific Research Fund grants OTKA T-046071 and T-67963 to J.O. and T-049247 to F.O. Part of this study was supported by the grants SAF2006-2749-E, ACOMP2007/180, AE 2007-005 and ACOMP2006/156 awarded by Ministerio de Educacion y Ciencia (SAF) and Conselleria de Cultura, Educacion y Ciencia and Conselleria de Empresa, Universidad y Ciencia from Generalitat Valenciana (ACOMP), respectively. We thank Pharsight Corporation for the academic license of WINNONLIN v. 5.2. NR 42 TC 10 Z9 11 U1 0 U2 14 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1364-503X J9 PHILOS T R SOC A JI Philos. Trans. R. Soc. A-Math. Phys. Eng. Sci. PD OCT 13 PY 2008 VL 366 IS 1880 BP 3599 EP 3617 DI 10.1098/rsta.2008.0106 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 343PQ UT WOS:000258866400009 PM 18644768 ER PT J AU Gorbach, AM Wang, HL Elster, E AF Gorbach, Alexander M. Wang, Hengliang Elster, Eric TI Thermal oscillations in rat kidneys: an infrared imaging study SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES LA English DT Article DE infrared imaging; blood flow; thermal oscillations; autoregulation; synchrony ID SMOOTH-MUSCLE-CELLS; SARCOPLASMIC-RETICULUM; THERMOGENESIS; CA2+-ATPASE; TIME; CA2+ AB A high-resolution infrared (IR) camera was used to assess rhythmicity in localized renal blood flow, including the extent of regions containing nephrons with spontaneous oscillations in their individual blood flow. The IR imaging was able to follow changes in rat renal perfusion during baseline conditions, during occlusion of the main renal artery and during the administration of either saline or papaverine. Concurrent recordings were made of tubular pressure in superficial nephrons. Spontaneous vascular oscillations centred around 0.02 0.05 Hz and approximately 0.01 Hz could be detected reproducibly by IR imaging. Their spectral characteristics and their response to papaverine were in line with tubular pressure measurements. The intensity of and synchrony between thermal signals from different local areas of the kidney may allow, after surgical exposure, non-invasive imaging of functional clusters involved in renal cortical blood flow. Through visualization of the spatial extent of thermal oscillations, IR imaging holds promise in assessing kidney autoregulatory mechanisms. C1 [Gorbach, Alexander M.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Wang, Hengliang; Elster, Eric] USN, Med Res Ctr, Silver Spring, MD 20910 USA. RP Gorbach, AM (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bldg 13,Room 3N-11, Bethesda, MD 20892 USA. EM gorbach@helix.nih.gov FU NIH FX We thank N. Holstein-Rathlou (University of Copenhagen, Denmark) and D. Marsh (Brown University, Providence, RI, USA) for important support in experimental design and preparation of this manuscript. The authors would like to thank Henry Eden MD, PhD, for his invaluable critique and insightful comments during the preparation of this manuscript. This research was supported in part by the Intramural Research Program of the NIH. NR 20 TC 6 Z9 6 U1 0 U2 3 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1364-503X J9 PHILOS T R SOC A JI Philos. Trans. R. Soc. A-Math. Phys. Eng. Sci. PD OCT 13 PY 2008 VL 366 IS 1880 BP 3633 EP 3647 DI 10.1098/rsta.2008.0117 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 343PQ UT WOS:000258866400011 PM 18650199 ER PT J AU Volkow, ND Wang, GJ Fowler, JS Telang, F AF Volkow, Nora D. Wang, Gene-Jack Fowler, Joanna S. Telang, Frank TI Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Royal-Society-Discussion Meeting on Neurobiology of Drug Addiction CY FEB 25-26, 2008 CL London, ENGLAND SP Royal Soc Discuss DE dopamine; positron emission tomography; imaging; self-control; compulsion ID ORBITOFRONTAL CORTEX; DOPAMINE-D-2 RECEPTORS; DRUG-ADDICTION; HUMAN BRAIN; VENTRAL STRIATUM; COCAINE ABUSERS; DORSAL STRIATUM; FOOD STIMULI; ACTIVATION; METABOLISM AB Drugs and food exert their reinforcing effects in part by increasing dopamine (DA) in limbic regions, which has generated interest in understanding how drug abuse/addiction relates to obesity. Here, we integrate findings from positron emission tomography imaging studies on DA's role in drug abuse/addiction and in obesity and propose a common model for these two conditions. Both in abuse/addiction and in obesity, there is an enhanced value of one type of reinforcer (drugs and food, respectively) at the expense of other reinforcers, which is a consequence of conditioned learning and resetting of reward thresholds secondary to repeated stimulation by drugs (abuse/addiction) and by large quantities of palatable food (obesity) in vulnerable individuals (i.e. genetic factors). In this model, during exposure to the reinforcer or to conditioned cues, the expected reward (processed by memory circuits) overactivates the reward and motivation circuits while inhibiting the cognitive control circuit, resulting in an inability to inhibit the drive to consume the drug or food despite attempts to do so. These neuronal circuits, which are modulated by DA, interact with one another so that disruption in one circuit can be buffered by another, which highlights the need of multiprong approaches in the treatment of addiction and obesity. C1 [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. [Volkow, Nora D.; Telang, Frank] NIAAA, Bethesda, MD 20892 USA. [Wang, Gene-Jack; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Volkow, ND (reprint author), NIDA, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 55 TC 313 Z9 320 U1 8 U2 69 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD OCT 12 PY 2008 VL 363 IS 1507 BP 3191 EP 3200 DI 10.1098/rstb.2008.0107 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 345AW UT WOS:000258969400009 PM 18640912 ER PT J AU Crombag, HS Bossert, JM Koya, E Shaham, Y AF Crombag, Hans S. Bossert, Jennifer M. Koya, Eisuke Shaham, Yavin TI Context-induced relapse to drug seeking: a review SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Royal-Society-Discussion Meeting on Neurobiology of Drug Addiction CY FEB 25-26, 2008 CL London, ENGLAND SP Royal Soc Discuss DE conditioned cues; drug self-administration; extinction; reinstatement; renewal; relapse ID METABOTROPIC GLUTAMATE RECEPTORS; VENTRAL TEGMENTAL AREA; DORSOMEDIAL PREFRONTAL CORTEX; EXTRACELLULAR DOPAMINE LEVELS; NUCLEUS-ACCUMBENS SHELL; COCAINE-SEEKING; HEROIN-SEEKING; BASOLATERAL AMYGDALA; ALCOHOL-SEEKING; INDUCED REINSTATEMENT AB In humans, exposure to environmental contexts previously associated with drug intake often provokes relapse to drug use, but the mechanisms mediating this relapse are unknown. Based on early studies by Bouton & Bolles on context-induced 'renewal' of learned behaviours, we developed a procedure to study context-induced relapse to drug seeking. In this procedure, rats are first trained to self-administer drug in one context. Next, drug-reinforced lever responding is extinguished in a different (non-drug) context. Subsequently, context-induced reinstatement of drug seeking is assessed by re-exposing rats to the drug-associated context. Using variations of this procedure, we and others reported reliable context-induced reinstatement in rats with a history of heroin, cocaine, heroin-cocaine combination, alcohol and nicotine self-administration. Here, we first discuss potential psychological mechanisms of context-induced reinstatement, including excitatory and inhibitory Pavlovian conditioning, and occasion setting. We then summarize results from pharmacological and neuroanatomical studies on the role of several neurotransmitter systems (dopamine, glutamate, serotonin and opioids) and brain areas (ventral tegmental area, accumbens shell, dorsal striatum, basolateral amygdala, prefrontal cortex, dorsal hippocampus and lateral hypothalamus) in context-induced reinstatement. We conclude by discussing the clinical implications of rat studies on context-induced reinstatement of drug seeking. C1 [Bossert, Jennifer M.; Koya, Eisuke; Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Crombag, Hans S.] Univ Sussex, Sch Life Sci, Dept Psychol, Behav & Clin Neurosci Grp, Brighton BN1 9RH, E Sussex, England. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014 FU Intramural NIH HHS NR 88 TC 203 Z9 204 U1 1 U2 17 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD OCT 12 PY 2008 VL 363 IS 1507 BP 3233 EP 3243 DI 10.1098/rstb.2008.0090 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 345AW UT WOS:000258969400013 PM 18640922 ER PT J AU Yuan, X Waterworth, D Perry, JRB Lim, N Song, K Chambers, JC Zhang, W Vollenweider, P Stirnadel, H Johnson, T Bergmann, S Beckmann, ND Li, Y Ferrucci, L Melzer, D Hernandez, D Singleton, A Scott, J Elliott, P Waeber, G Cardon, L Frayling, TM Kooner, JS Mooser, V AF Yuan, Xin Waterworth, Dawn Perry, John R. B. Lim, Noha Song, Kijoung Chambers, John C. Zhang, Weihua Vollenweider, Peter Stirnadel, Heide Johnson, Toby Bergmann, Sven Beckmann, Noam D. Li, Yun Ferrucci, Luigi Melzer, David Hernandez, Dena Singleton, Andrew Scott, James Elliott, Paul Waeber, Gerard Cardon, Lon Frayling, Timothy M. Kooner, Jaspal S. Mooser, Vincent TI Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ALKALINE-PHOSPHATASE ACTIVITY; CARBOXYPEPTIDASE-N; ADIPONUTRIN GENE; RISK-FACTORS; PROTEINS; DISEASE; HEMOCHROMATOSIS; EXPRESSION; MUTATIONS; MEMBRANE AB Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present Study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGTI locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases. C1 [Yuan, Xin; Waterworth, Dawn; Lim, Noha; Song, Kijoung; Cardon, Lon; Mooser, Vincent] GlaxoSmithKline Inc, Div Genet, King Of Prussia, PA 19406 USA. [Stirnadel, Heide; Li, Yun] GlaxoSmithKline Inc, Worldwide Epidemiol, Harlow EX2 5DW, Essex, England. [Perry, John R. B.; Melzer, David; Frayling, Timothy M.] Univ Exeter, Penn Coll Med & Dent, Inst Biomed & Clin Sci, Exeter CM19 5AW, Devon, England. [Chambers, John C.; Zhang, Weihua; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 11G, England. [Vollenweider, Peter; Waeber, Gerard] CHUV Univ Hosp, Dept Med, CH-1011 Lausanne, Switzerland. [Johnson, Toby; Bergmann, Sven; Beckmann, Noam D.] CHUV Univ Hosp, Div Med Genet, CH-1011 Lausanne, Switzerland. [Johnson, Toby] CHUV Univ Hosp, Inst Social & Preventat Med, CH-1011 Lausanne, Switzerland. [Johnson, Toby; Bergmann, Sven] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Ferrucci, Luigi] NIA, Gerontol Res Ctr, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Hernandez, Dena; Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W12 0NN, England. [Li, Yun] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Mooser, V (reprint author), GlaxoSmithKline Inc, Div Genet, King Of Prussia, PA 19406 USA. EM vincent.2.mooser@gsk.com RI Singleton, Andrew/C-3010-2009; Colaus, PsyColaus/K-6607-2013; OI Johnson, Toby/0000-0002-5998-3270; Bergmann, Sven/0000-0002-6785-9034; Melzer, David/0000-0002-0170-3838 FU GlaxoSmithKline; National Institute on Aging, National Institutes of Health, and Department of Health and Human Services [1 Z01 AG000965-02]; British Heart Foundation [SP/04/002] FX The CoLaus study was sponsored in part by GlaxoSmithKline, a pharmaceutical company. X.Y., D.W., N.L., K.S., H.S., L.C., and V.M. are full-time employees of GlaxoSmithKhne. The InCHIANTI study was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, and Department of Health and Human Services, project number 1 Z01 AG000965-02. LOLIPOP was supported by the British Heart Foundation Grant SP/04/002. We thank the individuals who volunteered to participate in the CoLaus Study, as well as the staff at Lausanne University Hospital and within GlaxoSmithKline who made this collection possible. The computations for CoLaus imputation were performed in part at the Vital-IT center for high performance computing of the Swiss Institute of Bioinformatics. We thank Jacques Beckmann for his comments. NR 44 TC 219 Z9 227 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 10 PY 2008 VL 83 IS 4 BP 520 EP 528 DI 10.1016/j.ajhg.2008.09.012 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 363AV UT WOS:000260239200010 PM 18940312 ER PT J AU Carlson, BA Lee, BJ Hatfield, DL AF Carlson, Bradley A. Lee, Byeong Jae Hatfield, Dolph L. TI Ribosomal frameshifting in response to hypomodified tRNAs in Xenopus oocytes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE asparagine tRNA; phenylalanine tRNA; queuosine base; ribosomal frameshifting; wyebutoxine base; Xenopus oocytes ID ESCHERICHIA-COLI; Q-BASE; TRANSLATION; EXPRESSION; CODON; GENE; MAINTENANCE; EUKARYOTES; SIGNAL AB We used Xenopus oocytes as an intracellular system to Study ribosomal frameshifting. Microinjection of oocytes with a construct encoding the naturally Occurring UUU or AAC cordon at the frameshift site demonstrated that the level of frameshifting was similar or lower than found normally in retroviral frameshifting in mammalian cells, suggesting that oocytes are a reliable system to study this event. Phenylalanine (Phe) or asparagine (Asn) tRNAs with and without the highly modified wyebutoxine (Y) or queuosine (Q) base, respectively, were microinjected to assess their ability to promote frameshifting. tRNA(.y)(Phe) inhibited the level of frameshifting, while tRNA(Phe)-(Y) promoted frameshifting providing evidence that the hypomodified form does not act only to enhance frameshifting, but is an essential requirement. Both tRNA(+Q)(ASn) and tRNA(-Q)(Asn) were used indiscriminately in frameshifting, whether the frameshift site contained the wild-type AAC, or the mutant AAU codon, Suggesting that Q base modification status does not influence this process. (C) 2008 Published by Elsevier Inc. C1 [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Lee, Byeong Jae] Seoul Natl Univ, Inst Mol Biol & Genet, Mol Genet Lab, Seoul 151742, South Korea. RP Carlson, BA (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, 9000 Rockville Pike,Bldg 37,Room 6032, Bethesda, MD 20892 USA. EM carlsonb@mail.nih.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This research was supported by the intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 27 TC 3 Z9 3 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 10 PY 2008 VL 375 IS 1 BP 86 EP 90 DI 10.1016/j.bbrc.2008.07.118 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 349BM UT WOS:000259253800017 PM 18675785 ER PT J AU Scott, I Norris, KL AF Scott, Iain Norris, Kristi L. TI The mitochondrial antiviral signaling protein, MAVS, is cleaved during apoptosis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE MAVS; IPS-1; cardif; apoptosis innate immunity; mitochondria; cleavage proteasome; caspase ID HEPATITIS-C-VIRUS; INNATE IMMUNITY; ADAPTER PROTEIN; 2-5A SYSTEM; ACTIVATION; CELLS; IDENTIFICATION; INDUCTION; PATHWAY AB Apoptosis of virus-infected cells is one important host strategy used to limit viral infection. Recently a member of the innate immune signaling pathway, MAVS, was localized to mitochondria, an organelle important for apoptosis regulation. Here we investigate what role MAVS may play in apoptosis. Induction of cell death led to the rapid cleavage of MAVS, resulting in its release from the outer mitochondrial membrane. This cleavage is blocked in cells incubated with proteasome or caspase inhibitors. Transfection of synthetic viral dsRNA and dsDNA also led to cleavage of MAVS, indicating that this process may be important during infection. Preventing apoptosis by over-expression of anti-apoptotic Bcl-xL blocks MAVS cleavage, placing this process downstream of caspase activation in the apoptotic program. Published by Elsevier Inc. C1 [Scott, Iain; Norris, Kristi L.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Scott, I (reprint author), Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Room 2C-1014,Bldg 35,9000 Rockville Pike, Bethesda, MD 20892 USA. EM scotti@ninds.nih.gov FU ntramural Research Program of the National Institute of Neurological Disorders and Stroke; National Institutes of Health FX This research was performed in the laboratory of Richard J. Youle (NINDS, NIH) and the authors thank him for his Support. The authors thank Kui Li (University of Texas Medical Branch, Galveston, TX) for the GFP-MAVS plasmid and Albert Neutzner (NINDS, NIH) for helpful discussions. This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 26 TC 22 Z9 22 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 10 PY 2008 VL 375 IS 1 BP 101 EP 106 DI 10.1016/j.bbrc.2008.07.147 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 349BM UT WOS:000259253800020 PM 18692023 ER PT J AU Cheng, TF Hu, XP Gnatt, A Brooks, PJ AF Cheng, Tsu-Fan Hu, Xiaopeng Gnatt, Averell Brooks, Philip J. TI Differential blocking effects of the acetaldehyde-derived DNA lesion N(2)-ethyl-2 '-deoxyguanosine on transcription by multisubunit and single subunit RNA polymerases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRUCTURAL BASIS; NUCLEOSIDE TRIPHOSPHATES; TRANSLESION SYNTHESIS; ELONGATION COMPLEXES; ALLOSTERIC BINDING; ADDUCTS; MECHANISM; BACTERIAL; CLEAVAGE; BYPASS AB Acetaldehyde, the first metabolite of ethanol, reacts with DNA to form adducts, including N(2)-ethyl-2'-deoxyguanosine (N(2)-Et-dG). Although the effects of N(2)-Et-dG on DNA polymerases have been well studied, nothing is known about possible effects of this lesion on transcription by RNA polymerases (RNAPs). Using primer extension assays in vitro, we found that a single N(2)-Et-dG lesion is a strong block to both mammalian RNAPII and two other multisubunit RNAPs, (yeast RNAPII and Escherichia coli RNAP), as well as to T7 RNAP. However, the mechanism of transcription blockage appears to differ between the multisubunit RNAPs and T7 RNAP. Specifically, all three of the multisubunit RNAPs can incorporate a single rNTP residue opposite the lesion, whereas T7 RNAP is essentially unable to do so. Using the mammalian RNAPII, we found that CMP is exclusively incorporated opposite the N(2)-Et-dG lesion. In addition, we also show that the accessory transcription factor TFIIS does not act as a lesion bypass factor, as it does for other nonbulky DNA lesions; instead, it stimulates the polymerase to remove the CMP incorporated opposite the lesion by mammalian RNAPII. We also include models of the N(2)-Et-dG within the active site of yeast RNAPII, which are compatible with our observations. C1 [Cheng, Tsu-Fan; Brooks, Philip J.] NIAAA, Mol Neurobiol Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Hu, Xiaopeng; Gnatt, Averell] Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. RP Brooks, PJ (reprint author), NIAAA, Mol Neurobiol Sect, Neurogenet Lab, 5625 Fishers Ln,Rm 3S-32, Rockville, MD 20852 USA. EM pjbrooks@mail.nih.gov FU Division of Clinical and Intramural Research; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the Division of Clinical and Intramural Research, National Institute on Alcohol Abuse and Alcoholism. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 52 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 10 PY 2008 VL 283 IS 41 BP 27820 EP 27828 DI 10.1074/jbc.M804086200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 355OW UT WOS:000259719200053 PM 18669632 ER PT J AU Nascimento, AS Krauchenco, S Golubev, AM Gustchina, A Wlodawer, A Polikarpov, I AF Nascimento, Alessandro S. Krauchenco, Sandra Golubev, Alexander M. Gustchina, Alla Wlodawer, Alexander Polikarpov, Igor TI Statistical coupling analysis of aspartic proteinases based on crystal structures of the Trichoderma reesei enzyme and its complex with pepstatin A SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Trichoderma reesei; aspartic proteinase; crystal structure; pepsin-like fold; statistical coupling analysis ID ASPERGILLUS-ORYZAE; DISULFIDE BOND; ACTIVE-SITES; CIS-PROLINE; RESIDUES; PROTEASE; BINDING; PEPSIN; CRYSTALLOGRAPHY; THERMOSTABILITY AB The crystal structures of an aspartic proteinase from Trichoderma reesei (TrAsP) and of its complex with a competitive inhibitor, pepstatin A, were solved and refined to crystallographic R-factors of 17.9% (R(free)=21.2%) at 1.70 angstrom resolution and 15.81% (R(free) = 19.2%) at 1.85 angstrom resolution, respectively. The three-dimensional structure of TrAsP is similar to structures of other members of the pepsin-like family of aspartic proteinases. Each molecule is folded in a predominantly beta-sheet bilobal structure with the N-terminal and C-terminal domains of about the same size. Structural comparison of the native structure and the TrAsP-pepstatin complex reveals that the enzyme undergoes an induced-fit, rigid-body movement upon inhibitor binding, with the N-terminal and C-terminal lobes tightly enclosing the inhibitor. Upon recognition and binding of pepstatin A, amino acid residues of the enzyme active site form a number of short hydrogen bonds to the inhibitor that may play an important role in the mechanism of catalysis and inhibition. The structures of TrAsP were used as a template for performing statistical coupling analysis of the aspartic protease family. This approach permitted, for the first time, the identification of a network of structurally linked residues putatively mediating conformational changes relevant to the function of this family of enzymes. Statistical coupling analysis reveals coevolved continuous clusters of amino acid residues that extend from the active site into the hydrophobic cores of each of the two domains and include amino acid residues from the flap regions, highlighting the importance of these parts of the protein for its enzymatic activity. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Nascimento, Alessandro S.; Krauchenco, Sandra; Polikarpov, Igor] Univ Sao Paulo, Grp Cristalog, Dept Fis & Informat, Inst Fis Sao Carlos, BR-13560970 Sao Paulo, Brazil. [Golubev, Alexander M.] Petersburg Nucl Phys Inst, St Petersburg 188300, Russia. [Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Polikarpov, I (reprint author), Univ Sao Paulo, Grp Cristalog, Dept Fis & Informat, Inst Fis Sao Carlos, Av Trabalhador Saocarlense 400, BR-13560970 Sao Paulo, Brazil. EM ipolikarpov@if.sc.usp.br RI Nascimento, Alessandro/G-9547-2012; 2, INCT/G-6506-2013; Bioetanol, Inct/I-1068-2013; Polikarpov, Igor/D-2575-2012; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016 OI Nascimento, Alessandro/0000-0001-6656-5379; FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [99/03387-4, 04/08070-9]; National Cancer Institute Center for Cancer Research; National Institutes of Health FX This work was supported in part by grants 99/03387-4 and 04/08070-9 from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and in part by the Intramural Research Program of the National Cancer Institute Center for Cancer Research of the National Institutes of Health. We thank Jose Ribeiro Brandao Neto for his scientific assistance during diffraction data collection and processing. We also thank Lucas Bleicher for the development and implementation of the SCA codes and for the helpful discussions. NR 51 TC 5 Z9 5 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 10 PY 2008 VL 382 IS 3 BP 763 EP 778 DI 10.1016/j.jmb.2008.07.043 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 357ZR UT WOS:000259886400017 PM 18675276 ER PT J AU Chen, WZ Zhu, ZG Feng, Y Xiao, XD Dimitrov, DS AF Chen, Weizao Zhu, Zhongyu Feng, Yang Xiao, Xiaodong Dimitrov, Dirniter S. TI Construction of a large phage-displayed human antibody domain library with a scaffold based on a newly identified highly soluble, stable heavy chain variable domain SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE antibody library; phage display; human; V(H); framework scaffold ID ESCHERICHIA-COLI; FRAMEWORK AB Currently, almost all U.S. Food and Drug Administration-approved therapeutic antibodies and the vast majority of those in clinical trials are full-size antibodies mostly in an immunoglobulin G1 format of about 150 kDa in size. Two fundamental problems for such large molecules are their poor penetration into tissues (e.g., solid tumors) and poor or absent binding to regions on the surface of some molecules [e.g., on the human immunodeficiency virus envelope glycoprotein (Env)] that are accessible by molecules of smaller size. We have identified a phage-displayed heavy chain-only antibody by panning of a large (size, similar to 1.5 x 10(10)) human naive Fab (antigen-binding fragment) library against an Env and found that the heavy chain variable domain (V(H)) of this antibody, designated as m0, was independently folded, stable, highly soluble, monomeric, and expressed at high levels in bacteria. m0 was used as a scaffold to construct a large (size, similar to 2.5x10(10)), highly diversified phage-displayed human V(H) library by grafting naturally occurring complementarity-determining regions (CDRs) 2 and 3 of heavy chains from five human antibody Fab libraries and by randomly mutating four putative solvent-accessible residues in CDR1 to A, D, S, or Y. The sequence diversity of all CDRs was determined from 143 randomly selected clones. Most of these V(H)s were with different CDR2 origins (six of seven groups of V(H) germlines) or CDR3 lengths (ranging from 7 to 24 residues) and could be purified directly from the soluble fraction of the Escherichia coli periplasm. The quality of the library was also validated by successful selection of high-affinity V(H)s against viral and cancer-related antigens; all selected VHS were monomeric, easily expressed, and purified with high solubility and yield. This library could be a valuable source of antibodies targeting size-restricted epitopes and antigens in obstructed locations where efficient penetration could be critical for successful treatment. Published by Elsevier Ltd. C1 [Chen, Weizao; Zhu, Zhongyu; Feng, Yang; Xiao, Xiaodong; Dimitrov, Dirniter S.] NCI Frederick, Prot Interact Grp, Ctr Canc Res, Nanobiol Program,NIH, Frederick, MD 21702 USA. [Zhu, Zhongyu] NCI Frederick, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI Frederick, Prot Interact Grp, Ctr Canc Res, Nanobiol Program,NIH, Frederick, MD 21702 USA. EM dimitrov@ncifcrf.gov FU NIH; National Institute of Allergy and Infectious Diseases; Gates Foundation; NIH NCT Center for Cancer Research Intramural Research Program; NIH NCI [N01-CO-12400] FX This work was supported by the NIH Intramural AIDS Targeted Antiviral Program, by the NIH National Institute of Allergy and Infectious Diseases Intramural Biodefense Program, and by the Gates Foundation (D.S.D.); by the NIH NCT Center for Cancer Research Intramural Research Program; and by federal funds from the NIH NCI under contract N01-CO-12400. NR 13 TC 33 Z9 35 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 10 PY 2008 VL 382 IS 3 BP 779 EP 789 DI 10.1016/j.jmb.2008.07.054 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 357ZR UT WOS:000259886400018 PM 18687338 ER PT J AU Wang, RH Zheng, Y Kim, HS Xu, XL Cao, L Luhasen, T Lee, MH Xiao, CY Vassilopoulos, A Chen, WP Gardner, K Man, YG Hung, MC Finkel, T Deng, CX AF Wang, Rui-Hong Zheng, Yin Kim, Hyun-Seok Xu, Xiaoling Cao, Liu Luhasen, Tyler Lee, Mi-Hye Xiao, Cuiying Vassilopoulos, Athanassios Chen, Weiping Gardner, Kevin Man, Yan-Gao Hung, Mien-Chie Finkel, Toren Deng, Chu-Xia TI Interplay among BRCA1, SIRT1, and Survivin during BRCA1-Associated Tumorigenesis SO MOLECULAR CELL LA English DT Article ID NF-KAPPA-B; BREAST-CANCER; CELL-CYCLE; CHEMOPREVENTIVE AGENT; TRANSCRIPTION FACTORS; CALORIE RESTRICTION; SPINDLE CHECKPOINT; REGULATES SIRT1; RESVERATROL; ACTIVATION AB Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from Brca1 mutant mice have low levels of Sirt1 and high levels of Survivin, which is reversed by induced expression of Brca1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of Sirt1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on Brca1 mutant cancer cells than on Brca1-wild-type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer. C1 [Wang, Rui-Hong; Zheng, Yin; Kim, Hyun-Seok; Xu, Xiaoling; Cao, Liu; Luhasen, Tyler; Lee, Mi-Hye; Xiao, Cuiying; Vassilopoulos, Athanassios; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Chen, Weiping] NIDDK, Microarray Core Facil, NIH, Bethesda, MD 20892 USA. [Gardner, Kevin] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Finkel, Toren] NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. [Man, Yan-Gao] Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, Washington, DC 20306 USA. [Hung, Mien-Chie] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA. FX We thank Dr. Zhi-Ming Zheng for critical reading of the manuscript, Dr. Stina Oredsson for the L56Br-C1 cell line, and Dr. Junjie Chen for the HCC1937 and HCC1937-BRCA1-WT cell lines. This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA. NR 55 TC 177 Z9 189 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 10 PY 2008 VL 32 IS 1 BP 11 EP 20 DI 10.1016/j.molcel.2008.09.011 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 363BF UT WOS:000260240200002 PM 18851829 ER PT J AU Queck, SY Jameson-Lee, M Villaruz, AE Bach, THL Khan, BA Sturdevant, DE Ricklefs, SM Li, M Otto, M AF Queck, Shu Y. Jameson-Lee, Max Villaruz, Amer E. Bach, Thanh-Huy L. Khan, Burhan A. Sturdevant, Daniel E. Ricklefs, Stacey M. Li, Min Otto, Michael TI RNAIII-Independent Target Gene Control by the agr Quorum-Sensing System: Insight into the Evolution of Virulence Regulation in Staphylococcus aureus SO MOLECULAR CELL LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; COMMUNITY-ASSOCIATED MRSA; SIGNAL-TRANSDUCTION; PROTEIN-A; EXPRESSION; IDENTIFICATION; DETERMINANTS; SARA; RNAS; ROT AB Cell-density-dependent gene regulation by quorum-sensing systems has a crucial function in bacterial physiology and pathogenesis. We demonstrate here that the Staphylococcus aureus agr quorum-sensing regulon is divided into (1) control of metabolism and PSM cytolysin genes, which occurs independently of the small regulatory RNA RNAIII, and (2) RNAIIII-dependent control of additional virulence genes. Remarkably, PSM expression was regulated by direct binding of the AgrA response regulator. Our findings suggest that quorum-sensing regulation of PSMs was established before wide-ranging control of virulence was added to the agr regulon, which likely occurred by development of the RNAIII-encoding region around the gene encoding the PSM delta-toxin. Moreover, the agr regulon in the community-associated methicillin-resistant S. aureus MW2 considerably differed from that previously determined using laboratory strains. By establishing a two-level model of quorum-sensing target gene regulation in S. aureus, our study gives important insight into the evolution of virulence control in this leading human pathogen. C1 [Sturdevant, Daniel E.; Ricklefs, Stacey M.] NIAID, Res Technol Branch, Genom Unit, Rocky Mt Labs,Natl Inst Hlth, Hamilton, MT 59840 USA. [Queck, Shu Y.; Jameson-Lee, Max; Villaruz, Amer E.; Bach, Thanh-Huy L.; Khan, Burhan A.; Li, Min; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors thank Larye Parkins for genome pattern searches, Frank Gherardini and Julie Boylan for helpful advice, and Frank DeLeo for critically reading the manuscript. This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, NR 43 TC 191 Z9 196 U1 6 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 10 PY 2008 VL 32 IS 1 BP 150 EP 158 DI 10.1016/j.molcel.2008.08.005 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 363BF UT WOS:000260240200014 PM 18851841 ER PT J AU Le Foll, B Wertheim, CE Goldberg, SR AF Le Foll, Bernard Wertheim, Carrie E. Goldberg, Steven R. TI Effects of baclofen on conditioned rewarding and discriminative stimulus effects of nicotine in rats SO NEUROSCIENCE LETTERS LA English DT Article DE conditioned place preferences; discrimination; reward; nicotine; rats; GABA ID GABA(B) RECEPTOR AGONISTS; NUCLEUS-ACCUMBENS; PLACE PREFERENCES; DOPAMINE RELEASE; SMOKING-CESSATION; COCAINE; ADDICTION; BLOCKS; DRUGS; ACID AB Neurochemical studies suggest that baclofen, an agonist at GABA(B) receptors, maybe useful for treatment of nicotine dependence. However, its ability to selectively reduce nicotine's abuse-related behavioral effects remains in question. We assessed effects of baclofen doses ranging from 0.1 to 3 mg/kg on nicotine-induced conditioned place preferences (CPPs), nicotine discrimination, locomotor activity and food-reinforced behavior in male Sprague-Dawley rats. The high dose of baclofen (3 mg/kg) totally eliminated food-reinforced responding and significantly decreased locomotor activity. Lower doses of baclofen did not have nicotine-like discriminative effects in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio 10 schedule of food delivery. Lower doses of baclofen also did not reduce discriminative stimulus effects of the training dose of nicotine and did not significantly shift the dose-response curve for nicotine discrimination. Rats treated with the high 3 mg/kg dose of baclofen did not express nicotine-induced CPP. These experiments, along with previous reports that baclofen can reduce intravenous nicotine self-administration behavior, confirm the potential utility of baclofen as a tool for smoking cessation. (C) 2008 Published by Elsevier Ireland Ltd. C1 [Le Foll, Bernard] Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. [Le Foll, Bernard; Wertheim, Carrie E.; Goldberg, Steven R.] Natl Inst Drug Abuse, Preclin Pharmcol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Le Foll, B (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM bernard_lefoll@camh.net RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU NIDA-IRP, DHHS; CIHR-TUSP FX This study was supported by NIDA-IRP, DHHS. BLF has received the support of the CIHR-TUSP training program. NR 47 TC 23 Z9 23 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 10 PY 2008 VL 443 IS 3 BP 236 EP 240 DI 10.1016/j.neulet.2008.07.074 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 357ML UT WOS:000259849800026 PM 18682277 ER PT J AU Notkins, AL AF Notkins, Abner L. TI Neutralizing the impact factor culture SO SCIENCE LA English DT Letter C1 [Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, NIH, Bethesda, MD USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, NIH, Bethesda, MD USA. EM anotkins@mail.nih.gov NR 0 TC 6 Z9 8 U1 1 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 10 PY 2008 VL 322 IS 5899 BP 191 EP 191 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358FK UT WOS:000259902300017 PM 18845731 ER PT J AU Shevach, EM AF Shevach, Ethan M. TI Regulating suppression SO SCIENCE LA English DT Editorial Material ID DENDRITIC CELLS; ANTIGEN 4; CTLA-4; INHIBITION; BLOCKADE; CD28 C1 [Shevach, Ethan M.] NIAID, Immunol Lab, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov NR 15 TC 11 Z9 12 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 10 PY 2008 VL 322 IS 5899 BP 202 EP 203 DI 10.1126/science.1164872 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 358FK UT WOS:000259902300026 PM 18845735 ER PT J AU Paladugu, SR Zhao, S Ray, A Raval, A AF Paladugu, Sri R. Zhao, Shan Ray, Animesh Raval, Alpan TI Mining protein networks for synthetic genetic interactions SO BMC BIOINFORMATICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; METABOLIC NETWORKS; YEAST; CENTRALITY; ESSENTIALITY; BETWEENNESS; PREDICTION; MODULARITY; REDUNDANCY; GENOME AB Background: The local connectivity and global position of a protein in a protein interaction network are known to correlate with some of its functional properties, including its essentiality or dispensability. It is therefore of interest to extend this observation and examine whether network properties of two proteins considered simultaneously can determine their joint dispensability, i.e., their propensity for synthetic sick/lethal interaction. Accordingly, we examine the predictive power of protein interaction networks for synthetic genetic interaction in Saccharomyces cerevisiae, an organism in which high confidence protein interaction networks are available and synthetic sick/ lethal gene pairs have been extensively identified. Results: We design a support vector machine system that uses graph-theoretic properties of two proteins in a protein interaction network as input features for prediction of synthetic sick/lethal interactions. The system is trained on interacting and non-interacting gene pairs culled from large scale genetic screens as well as literature-curated data. We find that the method is capable of predicting synthetic genetic interactions with sensitivity and specificity both exceeding 85%. We further find that the prediction performance is reasonably robust with respect to errors in the protein interaction network and with respect to changes in the features of test datasets. Using the prediction system, we carried out novel predictions of synthetic sick/ lethal gene pairs at a genome-wide scale. These pairs appear to have functional properties that are similar to those that characterize the known synthetic lethal gene pairs. Conclusion: Our analysis shows that protein interaction networks can be used to predict synthetic lethal interactions with accuracies on par with or exceeding that of other computational methods that use a variety of input features, including functional annotations. This indicates that protein interaction networks could plausibly be rich sources of information about epistatic effects among genes. C1 [Paladugu, Sri R.; Ray, Animesh; Raval, Alpan] Keck Grad Inst Appl Life Sci, Claremont, CA 91711 USA. [Zhao, Shan] NIH, Virtual Endoscopy & Comp Aided Diag Lab, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Paladugu, Sri R.; Raval, Alpan] Claremont Grad Univ, Sch Math Sci, Claremont, CA 91711 USA. RP Raval, A (reprint author), Keck Grad Inst Appl Life Sci, 535 Watson Dr, Claremont, CA 91711 USA. EM spaladug@kgi.edu; zhaosha@mail.nih.gov; aray@kgi.edu; araval@kgi.edu OI Ray, Animesh/0000-0002-0120-5820 FU National Science Foundation [REU 0243910, EIA 0205061, CCF 0523643, FIBR 0527023] FX This work was supported by grants from the National Science Foundation (REU 0243910; EIA 0205061, CCF 0523643 and FIBR 0527023 to A. Ray; CCF 0523643 and FIBR 0527023 to A. Raval). NR 41 TC 23 Z9 25 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 9 PY 2008 VL 9 AR 426 DI 10.1186/1471-2105-9-426 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 372GO UT WOS:000260890300001 PM 18844977 ER PT J AU Hoogewijs, D De Henau, S Dewilde, S Moens, L Couvreur, M Borgonie, G Vinogradov, SN Roy, SW Vanfleteren, JR AF Hoogewijs, David De Henau, Sasha Dewilde, Sylvia Moens, Luc Couvreur, Marjolein Borgonie, Gaetan Vinogradov, Serge N. Roy, Scott W. Vanfleteren, Jacques R. TI The Caenorhabditis globin gene family reveals extensive nematode-specific radiation and diversification SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID CARBON-DIOXIDE AVOIDANCE; C-ELEGANS; INTRON LOSS; CHEMORECEPTOR GENES; ADAPTIVE EVOLUTION; PROTEIN FAMILY; AMBIENT OXYGEN; EXPRESSION; BRIGGSAE; BEHAVIOR AB Background: Globin isoforms with variant properties and functions have been found in the pseudocoel, body wall and cuticle of various nematode species and even in the eyespots of the insect-parasite Mermis nigrescens. In fact, much higher levels of complexity exist, as shown by recent whole genome analysis studies. In silico analysis of the genome of Caenorhabditis elegans revealed an unexpectedly high number of globin genes featuring a remarkable diversity in gene structure, amino acid sequence and expression profiles. Results: In the present study we have analyzed whole genomic data from C. briggsae, C. remanei, Pristionchus pacificus and Brugia malayi and EST data from several other nematode species to study the evolutionary history of the nematode globin gene family. We find a high level of conservation of the C. elegans globin complement, with even distantly related nematodes harboring orthologs to many Caenorhabditis globins. Bayesian phylogenetic analysis resolves all nematode globins into two distinct globin classes. Analysis of the globin intron-exon structures suggests extensive loss of ancestral introns and gain of new positions in deep nematode ancestors, and mainly loss in the Caenorhabditis lineage. We also show that the Caenorhabditis globin genes are expressed in distinct, mostly non-overlapping, sets of cells and that they are all under strong purifying selection. Conclusion: Our results enable reconstruction of the evolutionary history of the globin gene family in the nematode phylum. A duplication of an ancestral globin gene occurred before the divergence of the Platyhelminthes and the Nematoda and one of the duplicated genes radiated further in the nematode phylum before the split of the Spirurina and Rhabditina and was followed by further radiation in the lineage leading to Caenorhabditis. The resulting globin genes were subject to processes of subfunctionalization C1 [Hoogewijs, David; De Henau, Sasha; Vanfleteren, Jacques R.] Univ Ghent, Dept Biol, B-9000 Ghent, Belgium. [Hoogewijs, David; De Henau, Sasha; Vanfleteren, Jacques R.] Univ Ghent, Ctr Mol Phylogeny & Evolut, B-9000 Ghent, Belgium. [Dewilde, Sylvia; Moens, Luc] Univ Antwerp, Dept Biomed Sci, B-2610 Antwerp, Belgium. [Couvreur, Marjolein; Borgonie, Gaetan] Univ Ghent, Nematol Sect, Dept Biol, B-9000 Ghent, Belgium. [Vinogradov, Serge N.] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. [Roy, Scott W.] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20814 USA. RP Vanfleteren, JR (reprint author), Univ Ghent, Dept Biol, B-9000 Ghent, Belgium. EM David.Hoogewijs@UGent.be; Sasha.DeHenau@UGent.be; Sylvia.Dewilde@ua.ac.be; Luc.Moens@ua.ac.be; Marjolein.Couvreur@UGent.be; Gaetan.Borgonie@UGent.be; svinogra@med.wayne.edu; scottwroy@gmail.com; Jacques.Vanfleteren@UGent.be RI Hoogewijs, David/L-5144-2016 FU Fund for Scientific Research Flanders [G.0331.04] FX We thank Yves Van de Peer for critical reading of the manuscript and Guy Haegeman for use of the fluorescence microscope. This work was supported by grants from the Fund for Scientific Research Flanders (G.0331.04). SD is a postdoctoral fellow of the Fund for Scientific Research Flanders (FWO). NR 51 TC 20 Z9 45 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD OCT 9 PY 2008 VL 8 AR 279 DI 10.1186/1471-2148-8-279 PG 13 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 368XF UT WOS:000260655600001 PM 18844991 ER PT J AU Robinson, GW AF Robinson, Gertraud W. TI Using Notches to Track Mammary Epithelial Cell Homeostasis SO CELL STEM CELL LA English DT Editorial Material ID FATE DETERMINATION; BREAST-CANCER; STEM-CELLS AB Notch signals mediate a wide range of activities in development and cancer. A report in this issue of Cell Stem Cell (Bouras et al., 2008) demonstrates that Notch serves as a switch that controls cell fate and tissue homeostasis in mammary epithelium. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Robinson, GW (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM gertraur@bdg10.niddk.nih.gov RI Robinson, Gertraud/I-2136-2012 FU Intramural NIH HHS NR 10 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 9 PY 2008 VL 3 IS 4 BP 359 EP 360 DI 10.1016/j.stem.2008.09.014 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 361TK UT WOS:000260149800003 PM 18940725 ER PT J AU Anchoori, RK Kortenhorst, MSQ Hidalgo, M Sarkar, T Hallur, G Bai, RL Van Diest, PJ Hamel, E Khan, SR AF Anchoori, Ravi Kumar Kortenhorst, Madeleine Susanne Quirine Hidalgo, Manuel Sarkar, Taradas Hallur, Gurulingappa Bai, Ruoli Van Diest, Paul J. Hamel, Ernest Khan, Saeed R. TI Novel microtubule-interacting phenoxy pyridine and phenyl sulfanyl pyridine analogues for cancer therapy SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BENZOYLPHENYLUREA SULFUR ANALOGS; ANTITUMOR ACTIVITIES AB Current microtubule inhibitory agents used in the clinic to treat cancer have severe side effects, and development of resistance is frequent. We have evaluated the antitumor effect of a novel 30-compound library of phenoxy pyridine and phenyl sulfanyl pyridine derivatives. MTT assays revealed that, of all 30 compounds tested, compounds 2 and 3 showed the largest decrease in proliferation (low mu M range) against Panel and HS766T human pancreatic cancer cells. Flow cytometry experiments with MCF7 breast cancer cells showed a G2/M arrest comparable to that of colcemid. Immunofluorescence staining demonstrated complete disappearance of intracellular microtubules. Tubulin assembly assays, however, showed a dose-dependent decrease in tubulin assembly with compound 3 that seemed limited to about 50% of the control reaction. With compound 2 treatment, there was only a delay in the onset of assembly, with no effect on the extent of the reaction. Taken together, our results show that these novel microtubule inhibitors have promising anticancer activity and can be potentially used to overcome paclitaxel resistance in the clinical setting. C1 [Anchoori, Ravi Kumar; Kortenhorst, Madeleine Susanne Quirine; Hallur, Gurulingappa; Khan, Saeed R.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Div Chem Therapeut, Baltimore, MD 21231 USA. [Kortenhorst, Madeleine Susanne Quirine; Van Diest, Paul J.] Univ Med Ctr Utrecht, Dept Pathol, NL-3584 CX Utrecht, Netherlands. [Hidalgo, Manuel] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Gastrointestinal Canc Program, Baltimore, MD 21231 USA. [Sarkar, Taradas; Bai, Ruoli; Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Khan, SR (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Div Chem Therapeut, 1650 Orleans St,CRB I,162 C, Baltimore, MD 21231 USA. EM khansa@jhmi.edu RI HIDALGO, MANUEL/I-4995-2015 OI HIDALGO, MANUEL/0000-0002-3765-3318 FU FAMRI; NIH FX We gratefully acknowledge the financial support of grants from FAMRI and NIH. We thank the Medicinal Chemistry Center of the SKCCC at Johns Hopkins for conducting the NMR and LC-MS studies. In addition, we thank Susan Dalrymple and Dr. Antonio Jimeno, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, for help in cell culture analysis. NR 8 TC 15 Z9 15 U1 3 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 9 PY 2008 VL 51 IS 19 BP 5953 EP 5957 DI 10.1021/jm800203e PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 356EC UT WOS:000259760500012 PM 18778046 ER PT J AU Kaczmarek, P Keay, SK Tocci, GM Koch, KR Zhang, CO Barchi, JJ Grkovic, D Guo, L Michejda, CJ AF Kaczmarek, Piotr Keay, Susan K. Tocci, Gillian M. Koch, Kristopher R. Zhang, Chen-Ou Barchi, Joseph J., Jr. Grkovic, David Guo, Li Michejda, Christopher J. TI Structure-activity relationship studies for the peptide portion of the bladder epithelial cell antiproliferative factor from interstitial cystitis patients SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOTIFS; THREONINE; PROTEINS; SERINE; GENE AB We performed comprehensive structure-activity relationship (SAR) studies on the peptide portion of antiproliferative factor (APF), a sialylated frizzled-8 related glycopeptide that inhibits normal bladder epithelia] and urothelial carcinoma cell proliferation. Glycopeptide derivatives were synthesized by solid-phase methods using standard Fmoc chemistry and purified by RP-HPLC; all intermediate and final products were verified by HPLC-MS and NMR analyses. Antiproliferative activity of each derivative was determined by inhibition of (3)H-thymidine incorporation in primary normal human bladder epithelial cells. Structural components of the peptide segment of APF that proved to be important for biological activity included the presence of at least eight of the nine N-terminal amino acids, a negative charge in the C-terminal amino acid, a free amino group at the N-terminus, maintenance of a specific amino acid sequence in the C-terminal tail, and trans conformation for the peptide bonds. These data provide critical guidelines for optimization of structure in design of APF analogues as potential therapeutic agents. C1 [Kaczmarek, Piotr; Tocci, Gillian M.; Michejda, Christopher J.] NCI, Mol Aspects Drug Design Sect, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Keay, Susan K.; Koch, Kristopher R.; Zhang, Chen-Ou; Grkovic, David; Guo, Li] Univ Maryland, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA. [Keay, Susan K.] Vet Adm Maryland Hlth Care Syst, Res Serv, Baltimore, MD 21201 USA. [Barchi, Joseph J., Jr.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Keay, SK (reprint author), Baltimore Vet Affairs Med Ctr, Div Res, Room 3B-184,10 N Greene St, Baltimore, MD 21201 USA. EM skeay@medicine.umaryland.edu RI Barchi Jr., Joseph/N-3784-2014; OI Tocci, Giuliano/0000-0002-0635-4921 FU National Institutes of Health [R01 DK52596]; National Cancer Institute FX The authors thank Toby Chai (University of Maryland School of Medicine) for providing bladder biopsy specimens from which the explanted bladder epithelial cells were propagated and R. Andrew Byrd (National Cancer Institute, National Institutes of Health) for helpful discussions. This work was supported by funding from the National Institutes of Health (NIDDK Grant R01 DK52596), as well as in part by funding from the Intramural Research Program of the National Cancer Institute, National Institutes of Health. We also gratefully acknowledge the assistance of the Biophysics Resource, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute. NR 18 TC 10 Z9 10 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 9 PY 2008 VL 51 IS 19 BP 5974 EP 5983 DI 10.1021/jm8002763 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 356EC UT WOS:000259760500015 PM 18788730 ER PT J AU Ghosh, AK Gemma, S Baldridge, A Wang, YF Kovalevsky, AY Koh, Y Weber, IT Mitsuya, H AF Ghosh, Arun K. Gemma, Sandra Baldridge, Abigail Wang, Yuan-Fang Kovalevsky, Andrey Yu. Koh, Yashiro Weber, Irene T. Mitsuya, Hiroaki TI Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: Design, synthesis, biological evaluation, and protein-ligand X-ray studies SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RESOLUTION CRYSTAL-STRUCTURES; DRUG-RESISTANT MUTANTS; ANTIRETROVIRAL THERAPY; TYPE-1 PROTEASE; IN-VITRO; POTENT; DERIVATIVES; SUBSTRATE; SELECTION AB We report the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors. The inhibitors incorporate stereochemically defined flexible cyclic ethers/polyethers as high affinity P2-ligands. Inhibitors containing small ring 1,3-dioxacycloalkanes have shown potent enzyme inhibitory and antiviral activity. Inhibitors 3d and A are the most active inhibitors. Inhibitor 3d maintains excellent potency against a variety of multi-PI-resistant clinical strains. Our structure-activity studies indicate that the ring size, stereochemistry, and position of oxygens are important for the observed activity. Optically active synthesis of 1,3-dioxepan-5-ol along with the syntheses of various cyclic ether and polyether ligands have been described. A protein-ligand X-ray crystal structure of 3d-bound HIV-1 protease was determined. The structure revealed that the P2-ligand makes extensive interactions including hydrogen bonding with the protease backbone in the S2-site. In addition, the P2-ligand in 3d forms a unique water-mediated interaction with the NH of Gly-48. C1 [Ghosh, Arun K.; Gemma, Sandra; Baldridge, Abigail] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Gemma, Sandra; Baldridge, Abigail] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Wang, Yuan-Fang; Kovalevsky, Andrey Yu.; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Koh, Yashiro; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Dept Hematol & Infect Dis, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, 560 Oval Dr, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Gemma, Sandra/D-3568-2009; OI Gemma, Sandra/0000-0002-8313-2417; Kovalevsky, Andrey/0000-0003-4459-9142 FU Intramural NIH HHS; NIGMS NIH HHS [GM53386, GM62920, R01 GM053386, R01 GM053386-14, R01 GM062920, R01 GM062920-09, R01 GM062920-10, R37 GM053386, U01 GM062920] NR 44 TC 30 Z9 30 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 9 PY 2008 VL 51 IS 19 BP 6021 EP 6033 DI 10.1021/jm8004543 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 356EC UT WOS:000259760500020 PM 18783203 ER PT J AU Lazarova, N Zoghbi, SS Hong, J Seneca, N Tuan, E Gladding, RL Liow, JS Taku, A Innis, RB Pike, VW AF Lazarova, Neva Zoghbi, Sami S. Hong, Jinsoo Seneca, Nicholas Tuan, Ed Gladding, Robert L. Liow, Jeih-San Taku, Andrew Innis, Robert B. Pike, Victor W. TI Synthesis and evaluation of [N-methyl-C-11]N-desmethyl-loperamide as a new and improved PET radiotracer for imaging P-gp function SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BLOOD-BRAIN-BARRIER; RECEPTORS IN-VIVO; MULTIDRUG-RESISTANCE; GLYCOPROTEIN FUNCTION; OPIOID RECEPTORS; DRUG-RESISTANCE; LOPERAMIDE; EXPRESSION; RADIOMETABOLITE; TRANSPORTER AB [C-11]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-C-11]N-desmethyl-loperamide ([C-11]dLop; [C-11]3) precludes quantification. We considered that [C-11]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [C-11]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [C-11]iodomethane to give [C-11]3. After administration of [C-11]3 to wild-type mice, brain radioactivity uptake was very low. In P-gp (mdr-la(-/-)) knockout mice, brain uptake of radioactivity at 30 min increased about 3.5-fold by PET measures, and over 7-fold by ex vivo measures. In knockout mice, brain radioactivity was predominantly (90%) unchanged radiotracer. In monkey PET experiments, brain radioactivity uptake was also very low but after P-gp blockade increased more than 7-fold. [C-11]3 is an effective new radiotracer for imaging brain P-gp function and, in favor of future successful quantification, appears free of extensive brain-penetrant radiometabolites. C1 [Lazarova, Neva; Zoghbi, Sami S.; Hong, Jinsoo; Seneca, Nicholas; Tuan, Ed; Gladding, Robert L.; Liow, Jeih-San; Taku, Andrew; 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 National Institute of Mental Health [Z01-MH-002795-04] FX This research was supported by Intramural Research Program of the National Institute of Mental Health (project no. Z01-MH-002795-04). We are grateful to the NIH Clinical Research Center PET Group for radionuclide production and for assistance on PET Imaging, to PMOD Technologies for providing the image analysis software and the NIMH Psychoactive Drug Screening Program (PDSP) for performing assays; the PDSP is directed by Bryan L. Roth, MD, Ph.D. (Urliversity of North Carolina at Chapel Hill) with project officer Jamie Driscol (NIMH) (contract no. NO1MH32004). We are also grateful to GlaxoSmithKline for a gift of reference 3 and to Eli Lilly for DCPQ. NR 49 TC 58 Z9 59 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 9 PY 2008 VL 51 IS 19 BP 6034 EP 6043 DI 10.1021/jm800510m PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 356EC UT WOS:000259760500021 PM 18783208 ER PT J AU Paul, NM Taylor, M Kumar, R Deschamps, JR Luedtke, RR Newman, AH AF Paul, Noel M. Taylor, Michelle Kumar, Rakesh Deschamps, Jeffrey R. Luedtke, Robert R. Newman, Amy Hauck TI Structure-activity relationships for a novel series of dopamine D2-like receptor ligands based on N-substituted 3-aryl-8-azabicyclo[3.2.1]octan-3-ol SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POTENTIAL ANTIPSYCHOTIC AGENT; PROTEIN-COUPLED RECEPTORS; ABUSE THERAPEUTIC AGENTS; D3 RECEPTOR; DRUG-ABUSE; NEW-GENERATION; ANIMAL-MODELS; COCAINE ABUSE; HIGH-AFFINITY; IN-VIVO AB Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K(i)(D2R/MR) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2(L)R- or hD3R-transfected HEK 293 cells (31, K(i)(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, K(i)(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes. C1 [Paul, Noel M.; Newman, Amy Hauck] Natl Inst Drug Abuse, Intramural Res Program, Med Chem Sect, NIH, Baltimore, MD 21224 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Washington, DC 20375 USA. [Taylor, Michelle; Kumar, Rakesh; Luedtke, Robert R.] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA. RP Newman, AH (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Med Chem Sect, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010; Paul, Noel/0000-0002-4980-9383 FU NIDA-IRP; NIH [DA13584-03S1, DA13584-01]; NIH Postdoctoral Intramural Research Training Award (IRTA); NIDA [Y1-DA6002] FX This work was supported by the NIDA-IRP, NIH Grant DA13584-03S1, and NIH Grant DA13584-01. N.M.P. was supported by a NIH Postdoctoral Intramural Research Training Award (IRTA) Fellowship. Crystallographic studies were supported by NIDA Contract Y1-DA6002. NR 54 TC 13 Z9 13 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 9 PY 2008 VL 51 IS 19 BP 6095 EP 6109 DI 10.1021/jm800532x PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 356EC UT WOS:000259760500027 PM 18774793 ER PT J AU Sostaric, JZ Miyoshi, N Cheng, JY Riesz, P AF Sostaric, Joe Z. Miyoshi, Norio Cheng, Jason Y. Riesz, Peter TI Dynamic adsorption properties of n-alkyl glucopyranosides determine their ability to inhibit cytolysis mediated by acoustic cavitation SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID LOW-FREQUENCY SONOPHORESIS; RADICAL-INDUCED OXIDATION; SURFACE-ACTIVE SOLUTES; RADIATION-CHEMISTRY; AQUEOUS-SOLUTIONS; GAS/SOLUTION INTERFACE; PULSED ULTRASOUND; D-GLUCOSE; BUBBLES; SONOCHEMISTRY AB Suspensions of human leukemia (HL-60) cells readily undergo cytolysis when exposed to ultrasound above the acoustic cavitation threshold. However, n-alkyl glucopyranosides (hexyl, heptyl, and octyl) completely inhibit ultrasound-induced (1057 kHz) cytolysis (Sostaric, et al. Free Radical Biol. Med. 2005, 39, 1539-1548). The efficacy of protection from ultrasound-induced cytolysis was determined by the n-alkyl chain length of the glucopyranosides, indicating that protection efficacy depended on adsorption of n-alkyl glucopyranosides to the gas/solution interface of cavitation bubbles and/or the lipid membrane of cells. The current study tests the hypothesis that "sonoprotection" (i.e., protection of cells from ultrasound-induced cytolysis) in vitro depends on the adsorption of glucopyranosides at the gas/solution interface of cavitation bubbles. To test this hypothesis, the effect of ultrasound frequency (from 42 kHz to 1 MHz) on the ability of a homologous series of n-alkyl glucopyranosides to protect cells from ultrasound-induced cytolysis was investigated. It is expected that ultrasound frequency will affect sonoprotection ability since the nature of the cavitation bubble field will change. This will affect the relative importance of the possible mechanisms for ultrasound-induced cytolysis. Additionally, ultrasound frequency will affect the lifetime and rate of change of the surface area of cavitation bubbles, hence the dynamically controlled adsorption of glucopyrano sides to their surface. The data support the hypothesis that sonoprotection efficiency depends on the ability of glucopyrano sides to adsorb at the gas/solution interface of cavitation bubbles. C1 [Cheng, Jason Y.; Riesz, Peter] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Miyoshi, Norio] Univ Fukui, Fac Med, Dept Pathol Sci, Div Tumor Pathol, Matsuoka, Fukui 9101193, Japan. RP Sostaric, JZ (reprint author), Ohio State Univ, Dept Civil & Environm Engn & Geodet Sci, 470 Hitchcock Hall,2070 Neil Ave, Columbus, OH 43210 USA. EM sostaric.2@osu.edu RI Sostaric, Joe/A-6033-2008 FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. J.Z.S. thanks Dr. Eri Miyagi of LMM, NIAID, National Institutes of Health, Bethesda, MD, for useful discussions. NR 52 TC 3 Z9 3 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 9 PY 2008 VL 112 IS 40 BP 12703 EP 12709 DI 10.1021/jp805380e PG 7 WC Chemistry, Physical SC Chemistry GA 356LR UT WOS:000259780200022 PM 18793018 ER PT J AU Qi, H Cannons, JL Klauschen, F Schwartzberg, PL Germain, RN AF Qi, Hai Cannons, Jennifer L. Klauschen, Frederick Schwartzberg, Pamela L. Germain, Ronald N. TI SAP-controlled T-B cell interactions underlie germinal centre formation SO NATURE LA English DT Article ID LINKED LYMPHOPROLIFERATIVE-DISEASE; HUMORAL IMMUNITY; DENDRITIC CELLS; IN-VIVO; LYMPH-NODES; CYTOKINE REGULATION; ANTIBODY-RESPONSES; GENE-PRODUCT; ACTIVATION; INFECTION AB Generation of long- term antibody- mediated immunity depends on the germinal centre reaction, which requires cooperation between antigen- specific T and B lymphocytes. In human X- linked lymphoproliferative disease and its gene- targeted mouse model, loss- of- function mutations in signalling lymphocyte activation molecule- associated protein ( SAP, encoded by SH2D1a) cause a profound defect in germinal centre formation by an as yet unknown mechanism. Here, using two- photon intravital imaging, we show that SAP deficiency selectively impairs the ability of CD4(+) T cells to stably interact with cognate B cells but not antigen- presenting dendritic cells. This selective defect results in a failure of antigen- specific B cells to receive adequate levels of contact- dependent T- cell help to expand normally, despite Sap(-/-) T cells exhibiting the known characteristics of otherwise competent helper T cells. Furthermore, the lack of stable interactions with B cells renders Sap(-/-) T cells unable to be efficiently recruited to and retained in a nascent germinal centre to sustain the germinal centre reaction. These results offer an explanation for the germinal centre defect due to SAP deficiency and provide new insights into the bi- directional communication between cognate T and B cells in vivo. C1 [Qi, Hai; Klauschen, Frederick; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Cannons, Jennifer L.; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pams@nhgri.nih.gov; rgermain@niaid.nih.gov RI Qi, Hai/A-3955-2009; Klauschen, Frederick/C-5637-2015 FU National Institute of Allergy and Infectious Disease; National Human Genome Research Institute; National Institutes of Health, USA. FX H. Q. is in debt to Y. Hong for support, encouragement and inspiration. This work was funded by the intramural research programs of the National Institute of Allergy and Infectious Disease and National Human Genome Research Institute, National Institutes of Health, USA. NR 44 TC 302 Z9 318 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 9 PY 2008 VL 455 IS 7214 BP 764 EP U2 DI 10.1038/nature07345 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 357OB UT WOS:000259854900039 PM 18843362 ER PT J AU Qiu, Q Wang, RYH Jiao, XM Jin, B Sugauchi, F Grandinetti, T Alter, HJ Shih, JWK AF Qiu, Qi Wang, Richard Yuan-Hu Jiao, Xuanmao Jin, Bo Sugauchi, Fuminaka Grandinetti, Teresa Alter, Harvey J. Shih, J. Wai-Kuo TI Induction of multispecific Th-1 type immune response against HCV in mice by protein immunization using CpG and Montanide ISA 720 as adjuvants SO VACCINE LA English DT Article DE Hepatitis C virus; Th1-type immune response; Humoral immune response ID HEPATITIS-C VIRUS; T-LYMPHOCYTE RESPONSE; NONSTRUCTURAL PROTEIN-3; IN-VITRO; NEUTRALIZING ANTIBODY; DNA IMMUNIZATION; VIRAL CLEARANCE; DENDRITIC CELLS; PLUS RIBAVIRIN; CORE PROTEIN AB Recent studies demonstrate that Th1-type immune responses against a broad spectrum of hepatitis C virus (HCV) gene products are crucial to the resolution of acute HCV infection. We investigated new vaccine approaches to augment the strength of HCV-specific Th1-type immune responses. ELISPOT assay revealed that single or multiple protein immunization using both CpG ODN and Montanide ISA 720 as adjuvants induced Much stronger IFN-gamma-producing Th1 responses against core, NS3 and NS5b targets than did the formulation without these adjuvants. Protein vaccination using CpG ODN and Montanide ISA 720 as adjuvants also greatly enhanced humoral responses to HCV core, E1/E2 and NS3. When specific IgG isotypes were assayed, protein immunization using CpG ODN and Montanide ISA 720 as adjuvants produced higher titers of IgG2a dominant antibodies than did protein immunization alone, indicating a more Th1-biased pathway. This increase in IgG2a is consistent with the induction of Th1 cells secreting IFN-gamma demonstrated by ELISPOT assay. In conclusion, protein immunization using CpG CDN and Montanicle ISA 720 as adjuvants greatly enhanced cellular (Th1 type) as well as humoral immune responses against HCV in Balb/c mice. The use of adjuvants appears critical to the induction of Th1 immune responses during HCV vaccination with recombinant proteins. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Qiu, Qi; Wang, Richard Yuan-Hu; Jiao, Xuanmao; Jin, Bo; Sugauchi, Fuminaka; Grandinetti, Teresa; Alter, Harvey J.; Shih, J. Wai-Kuo] NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Shih, JWK (reprint author), Xiamen Univ, Natl Inst Diagnost & Vaccine Dev, Xiamen 361005, Fujian, Peoples R China. EM jwshih@xmu.edu.cn NR 43 TC 13 Z9 16 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 9 PY 2008 VL 26 IS 43 BP 5527 EP 5534 DI 10.1016/j.vaccine.2008.07.034 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 371SX UT WOS:000260852700014 PM 18675871 ER PT J AU Yellaboina, S Dudekula, DB Ko, MSH AF Yellaboina, Sailu Dudekula, Dawood B. Ko, Minoru S. H. TI Prediction of evolutionarily conserved interologs in Mus musculus SO BMC GENOMICS LA English DT Article ID PROTEIN-PROTEIN INTERACTION; PHYLOGENETIC PROFILES; INTERACTION MAP; FUNCTIONAL-RELATIONSHIPS; INTERACTION NETWORKS; ESCHERICHIA-COLI; DATABASE; SYSTEM; IDENTIFICATION; REDUCTION AB Background: Identification of protein-protein interactions is an important first step to understand living systems. High-throughput experimental approaches have accumulated large amount of information on protein-protein interactions in human and other model organisms. Such interaction information has been successfully transferred to other species, in which the experimental data are limited. However, the annotation transfer method could yield false positive interologs due to the lack of conservation of interactions when applied to phylogenetically distant organisms. Results: To address this issue, we used phylogenetic profile method to filter false positives in interologs based on the notion that evolutionary conserved interactions show similar patterns of occurrence along the genomes. The approach was applied to Mus musculus, in which the experimentally identified interactions are limited. We first inferred the protein-protein interactions in Mus musculus by using two approaches: i) identifying mouse orthologs of interacting proteins (interologs) based on the experimental protein-protein interaction data from other organisms; and ii) analyzing frequency of mouse ortholog co-occurrence in predicted operons of bacteria. We then filtered possible false-positives in the predicted interactions using the phylogenetic profiles. We found that this filtering method significantly increased the frequency of interacting protein-pairs coexpressed in the same cells/tissues in gene expression omnibus (GEO) database as well as the frequency of interacting protein-pairs shared the similar Gene Ontology (GO) terms for biological processes and cellular localizations. The data supports the notion that phylogenetic profile helps to reduce the number of false positives in interologs. Conclusion: We have developed protein-protein interaction database in mouse, which contains 41109 interologs. We have also developed a web interface to facilitate the use of database http://lgsun.grc.nia.nih.gov/mppi/. C1 [Yellaboina, Sailu; Dudekula, Dawood B.; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. EM yellaboinas@mail.nih.gov; dudekuladb@mail.nih.gov; kom@mail.nih.gov RI Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Dudekula, Dawood/0000-0002-4054-1827 FU Intramural Research Program of National Institute on Aging, NIH [Z01 AG000656] FX We are grateful to the high-performance computational capabilities of the Biowulf PC/Linux cluster at the NIH http://biowulf.nih.gov for providing computational facilities. We thank Alexei Sharov for his suggestions on the Manuscript. This work was supported by the Intramural Research Program of National Institute on Aging, NIH (Z01 AG000656). NR 45 TC 14 Z9 15 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 8 PY 2008 VL 9 AR 465 DI 10.1186/1471-2164-9-465 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 369FD UT WOS:000260678800001 PM 18842131 ER PT J AU Milner, JA AF Milner, J. A. TI Nutrition and cancer: Essential elements for a roadmap SO CANCER LETTERS LA English DT Review DE Preemption; Roadmap; Phenotype; Nutrigenomics; Molecular targets; Nutrients ID COPY-NUMBER VARIATION; BREAST-CANCER; VITAMIN-D; CARDIOVASCULAR-DISEASE; ORGANOSULFUR COMPOUNDS; HISTONE DEACETYLASES; PREVENTION RESEARCH; MEDITERRANEAN DIET; DIALLYL DISULFIDE; PROSTATE-CANCER AB Personalizing nutrition for cancer prevention and therapy will require a comprehensive understanding of "genotypes/phenotypes" in order to identify, evaluate, and prioritize appropriate points for dietary intervention. This nutritional preemption roadmap must begin with accurately assessing intakes/exposures of which bioactive food component(s) is needed to bring about a desired response in critical cellular processes (carcinogen metabolism, DNA repair, cell proliferation, apoptosis, inflammation, immunity, differentiation, angiogenesis, hormonal regulation and cellular energetic) within an individual. Understanding this "individuality" through a better understanding of the "omics" is fundamental to arriving at the correct destination and thus interpreting biological variables which establish the magnitude or direction of a response to bioactive food components. Published by Elsevier Ltd. C1 NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH,HHS, Rockville, MD 20852 USA. RP Milner, JA (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH,HHS, 6130 Execut Blvd,Execut Plaza N,Suite 3164, Rockville, MD 20852 USA. EM milnerj@mail.nih.gov NR 66 TC 28 Z9 28 U1 2 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD OCT 8 PY 2008 VL 269 IS 2 SI SI BP 189 EP 198 DI 10.1016/j.canlet.2008.05.030 PG 10 WC Oncology SC Oncology GA 361QZ UT WOS:000260143500003 PM 18599198 ER PT J AU Mattera, R Bonifacino, JS AF Mattera, Rafael Bonifacino, Juan S. TI Ubiquitin binding and conjugation regulate the recruitment of Rabex-5 to early endosomes SO EMBO JOURNAL LA English DT Article DE endosomes; Rabaptin-5; Rabex-5; RabGEF1; ubiquitin ID SMALL GTPASE RAB5; ENDOCYTIC MEMBRANE-FUSION; EXCHANGE FACTOR RABEX-5; MEDIATED ENDOCYTOSIS; NUCLEOTIDE EXCHANGE; INTERACTING MOTIF; STRUCTURAL BASIS; PROTEIN; ACTIVATION; RECEPTOR AB Rab GTPases and ubiquitination are critical regulators of transmembrane cargo sorting in endocytic and lysosomal targeting pathways. The endosomal protein Rabex-5 intersects these two layers of regulation by being both a guanine nucleotide exchange factor (GEF) for Rab5 and a substrate for ubiquitin (Ub) binding and conjugation. The ability of trafficking machinery components to bind ubiquitinated proteins is known to have a function in cargo sorting. Here, we demonstrate that Ub binding is essential for the recruitment of Rabex-5 from the cytosol to endosomes, independently of its GEF activity and of Rab5. We also show that monoubiquitinated Rabex-5 is enriched in the cytosol. These observations are consistent with a model whereby a cycle of Ub binding and monoubiquitination regulates the association of Rabex-5 with endosomes. C1 [Mattera, Rafael; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU National Institute of Child Health and Human Development, National Institutes of Health FX We thank P Burgos, G Mardones and R Rojas for helpful discussions and advice, and H Tsai for expert technical assistance. This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 38 TC 39 Z9 40 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 8 PY 2008 VL 27 IS 19 BP 2484 EP 2494 DI 10.1038/emboj.2008.177 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 358BL UT WOS:000259891300003 PM 18772883 ER PT J AU Tadeu, AMB Ribeiro, S Johnston, J Goldberg, I Gerloff, D Earnshaw, WC AF Tadeu, Ana Mafalda Baptista Ribeiro, Susana Johnston, Josiah Goldberg, Ilya Gerloff, Dietlind Earnshaw, William C. TI CENP-V is required for centromere organization, chromosome alignment and cytokinesis SO EMBO JOURNAL LA English DT Article DE chromosome passenger complex; kinetochore; mitosis; pericentromeric heterochromatin; primary constriction ID KINETOCHORE-MICROTUBULE INTERFACE; SPINDLE-ASSEMBLY CHECKPOINT; SISTER-CHROMATID COHESION; AURORA-B; HISTONE MODIFICATIONS; MITOTIC CHROMOSOMES; PROTEOMIC ANALYSIS; INNER CENTROMERE; HETEROCHROMATIN; CELLS AB The mechanism of mitotic chromosome condensation is poorly understood, but even less is known about the mechanism of formation of the primary constriction, or centromere. A proteomic analysis of mitotic chromosome scaffolds led to the identification of CENP-V, a novel kinetochore protein related to a bacterial enzyme that detoxifies formaldehyde, a by-product of histone demethylation in eukaryotic cells. Overexpression of CENP-V leads to hypercondensation of pericentromeric heterochromatin, a phenotype that is abolished by mutations in the putative catalytic site. CENP-V depletion in HeLa cells leads to abnormal expansion of the primary constriction of mitotic chromosomes, mislocalization and destabilization of the chromosomal passenger complex (CPC) and alterations in the distribution of H3K9me3 in interphase nucleoplasm. CENP-V-depleted cells suffer defects in chromosome alignment in metaphase, lagging chromosomes in anaphase, failure of cytokinesis and rapid cell death. CENP-V provides a novel link between centromeric chromatin, the primary constriction and the CPC. C1 [Tadeu, Ana Mafalda Baptista; Ribeiro, Susana; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Sch Biol Sci, Edinburgh EH9 3JR, Midlothian, Scotland. [Tadeu, Ana Mafalda Baptista] Univ Coimbra, Ctr Neurosci & Cell Biol, PDBEB, Dept Biochem, Coimbra, Portugal. [Johnston, Josiah; Goldberg, Ilya] NIA, Image Informat & Computat Biol Unit, NIH, Baltimore, MD 21224 USA. [Gerloff, Dietlind] Univ Calif Santa Cruz, Baskin Sch Engn, Dept Cellular & Mol Pharmacol, Santa Cruz, CA 95064 USA. RP Earnshaw, WC (reprint author), Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Sch Biol Sci, Mayfield Rd, Edinburgh EH9 3JR, Midlothian, Scotland. EM bill.earnshaw@ed.ac.uk RI Goldberg, Ilya/H-5307-2011 OI Goldberg, Ilya/0000-0001-8514-6110 FU FCT-Fundacao para a Ciencia e Tecnologia of Portugal; Wellcome Trust FX We thank R Klose (Oxford, UK) for performing histone de-methylase assays, H Masumoto (Nagoya, Japan) for anti-CENP-A. In Edinburgh, we thank D Kelly for help with image analysis, P Vagnarelli for advice and all members of the Earnshaw laboratory for comments on the paper. AMB Tadeu is a PhD student at the Programa Doutoral em Biologia Experimental e Biomedicina of the Universidade de Coimbra supported by a PhD fellowship from FCT-Fundacao para a Ciencia e Tecnologia of Portugal. The laboratory of WC Earnshaw is funded by the Wellcome Trust, of which he is a Principal Research Fellow. NR 58 TC 13 Z9 14 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 8 PY 2008 VL 27 IS 19 BP 2510 EP 2522 DI 10.1038/emboj.2008.175 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 358BL UT WOS:000259891300005 PM 18772885 ER PT J AU Bushlin, I Petralia, RS Wu, FB Harel, A Mughal, MR Mattson, MP Yao, PJ AF Bushlin, Ittai Petralia, Ronald S. Wu, Fangbai Harel, Asaff Mughal, Mohamed R. Mattson, Mark P. Yao, Pamela J. TI Clathrin Assembly Protein AP180 and CALM Differentially Control Axogenesis and Dendrite Outgrowth in Embryonic Hippocampal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE AP180; CALM; trafficking; neuron; polarity; development ID SYNAPTIC VESICLE ENDOCYTOSIS; VESICULAR STOMATITIS-VIRUS; COATED VESICLES; MONOCLONAL-ANTIBODIES; MEMBRANE-PROTEINS; LIVING CELLS; LOCALIZATION; TRAFFICKING; EXPRESSION; POLARITY AB Emerging data suggest that, much like epithelial cells, the polarized growth of neurons requires both the secretory and endocytic pathways. The clathrin assembly proteins AP180 and CALM ( clathrin assembly lymphoid myeloid protein) are known to be involved in clathrin-mediated endocytosis, but their roles in mammalian neurons and, in particular, in developmental processes before synaptogenesis are unknown. Here we provide evidence that AP180 and CALM play critical roles in establishing the polarity and controlling the growth of axons and dendrites in embryonic hippocampal neurons. Knockdown of AP180 primarily impairs axonal development, whereas reducing CALM levels results in dendritic dystrophy. Conversely, neurons that overexpress AP180 or CALM generate multiple axons. Ultrastructural analysis shows that CALM affiliates with a wider range of intracellular trafficking organelles than does AP180. Functional analysis shows that endocytosis is reduced in both AP180-deficient and CALM-deficient neurons. Additionally, CALM-deficient neurons show disrupted secretory transport. Our data demonstrate previously unknown functions for AP180 and CALM in intracellular trafficking that are essential in the growth of neurons. C1 [Yao, Pamela J.] NIA, Neurosci Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS [Z99 AG999999, Z01 AG000317-07] NR 53 TC 42 Z9 44 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 8 PY 2008 VL 28 IS 41 BP 10257 EP 10271 DI 10.1523/JNEUROSCI.2471-08.2008 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 358JG UT WOS:000259912400008 PM 18842885 ER PT J AU Beck, S Richardson, SP Shamim, EA Dang, N Schubert, M Hallett, M AF Beck, Sandra Richardson, Sarah Pirio Shamim, Ejaz A. Dang, Nguyet Schubert, Martin Hallett, Mark TI Short Intracortical and Surround Inhibition Are Selectively Reduced during Movement Initiation in Focal Hand Dystonia SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dystonia; motor control; motor cortex; inhibition; human; coordination ID HUMAN MOTOR CORTEX; RECIPROCAL INHIBITION; MUSCLE ACTIVATION; WRITERS CRAMP; MODULATION; MECHANISMS; FACILITATION; CIRCUITS; HUMANS; REFLEX AB In patients with focal hand dystonia (FHD), pathological overflow activation occurs in muscles not involved in the movement. Surround inhibition is a neural mechanism that can sharpen desired movement by inhibiting unwanted movement in adjacent muscles. To further establish the phenomenon of surround inhibition and to determine whether short intracortical inhibition (SICI) reflecting inhibition from the local interneurons in primary motor cortex (M1), might play a role in its genesis, single-and paired-pulse transcranial magnetic stimulation (TMS), and Hoffmann reflex testing were applied to evaluate the excitability of the relaxed abductor pollicis brevis muscle (APB) at various intervals during a movement of the index finger in 16 patients with FHD and 20 controls. Whereas controls showed inhibition of APB motor-evoked potential (MEP) size during movement initiation and facilitation of APB MEP size during the maintenance phase, FHD patients did not modulate APB MEP size. In contrast, SICI remained constant in controls, but FHD patients showed reduced SICI during movement initiation. The H-max/M-max ratio in control subjects increased during movement initiation. The results provide additional evidence for the presence of surround inhibition in M1, where it occurs only during movement initiation, indicating that different mechanisms underlie movement initiation and maintenance. Thus, surround inhibition is sculpted both in time and space and may be an important neural mechanism during movement initiation to counteract increased spinal excitability. SICI may contribute to its generation, because in patients with FHD, the lack of depression of APB MEP size is accompanied by a reduction in SICI. C1 [Beck, Sandra; Richardson, Sarah Pirio; Shamim, Ejaz A.; Dang, Nguyet; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Beck, Sandra] Univ Freiburg, Dept Clin Neurol & Neurophysiol, D-70196 Freiburg, Germany. [Richardson, Sarah Pirio] Univ New Mexico, Dept Neurol, Albuquerque, NM 87106 USA. [Schubert, Martin] Univ Hosp Balgrist, Spinal Cord Injury Ctr, CH-8008 Zurich, Switzerland. RP Beck, S (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bldg 10-5N240,10 Ctr Dr, Bethesda, MD 20892 USA. EM becksa@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003031-08] NR 45 TC 66 Z9 67 U1 1 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 8 PY 2008 VL 28 IS 41 BP 10363 EP 10369 DI 10.1523/JNEUROSCI.3564-08.2008 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 358JG UT WOS:000259912400018 PM 18842895 ER PT J AU Lee, KK Gan, L Tsuruta, H Moyer, C Conway, JF Duda, RL Hendrix, RW Steven, AC Johnson, JE AF Lee, Kelly K. Gan, Lu Tsuruta, Hiro Moyer, Crystal Conway, James F. Duda, Robert L. Hendrix, Roger W. Steven, Alasdair C. Johnson, John E. TI Virus Capsid Expansion Driven by the Capture of Mobile Surface Loops SO STRUCTURE LA English DT Article ID X-RAY CRYSTALLOGRAPHY; STRUCTURAL TRANSITIONS; CRYOELECTRON MICROSCOPY; CONFORMATIONAL-CHANGES; BACTERIOPHAGE HK97; COMMON ANCESTRY; NMR SYSTEM; CRYO-EM; MATURATION; PROTEIN AB The capsids of tailed-DNA bacteriophages first assemble as procapsids, which mature by converting into a new form that is strong enough to contain a densely packed viral chromosome. We demonstrate that the intersubunit crosslinking that occurs during maturation of HK97 capsids actually promotes the structural transformation. Small-angle X-ray scattering and crosslinking assays reveal that a shift in the crosslink pattern accompanies conversion of a semimature particle, Expansion Intermediate-I/II, to a more mature state, Balloon. This transition occurs in a switch-like fashion. We find that crosslink formation shifts the global conformational balance to favor the balloon state. A pseudoatomic model of EI-I/II derived from cryo-EM provides insight into the relationship between crosslink formation and conformational switching. C1 [Lee, Kelly K.; Gan, Lu; Johnson, John E.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Tsuruta, Hiro] Stanford Univ, Stanford Synchrotron Radiat Lab, Menlo Pk, CA 94025 USA. [Moyer, Crystal; Duda, Robert L.; Hendrix, Roger W.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Conway, James F.] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RP Johnson, JE (reprint author), Scripps Res Inst, Dept Mol Biol, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM jackj@scripps.edu RI Gan, Lu/F-8317-2011; Conway, James/A-2296-2010 OI Gan, Lu/0000-0002-8685-4896; Conway, James/0000-0002-6581-4748 FU National Institutes of Health [R01AI040101, R01GM047795, F32GM65013]; Intramural Research Program of NIAMS; DoE, Office of Biological and Environmental Research FX We thank Ilya Gertsman (TSRI) for providing the Prohead-II PDB coordinates used in our analysis. We thank Jeff Speir for his valuable computational assistance. This work was supported by National Institutes of Health funding R01AI040101 (J.E.J.), R01GM047795 (R.W.H.), F32GM65013 (K.K.L.), and supported in part (A.C.S.) by the Intramural Research Program of NIAMS. SAXS experiments were carried out at SSRL BL4-2, a national facility operated by Stanford University on behalf of the U.S. Dept. of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the DoE, Office of Biological and Environmental Research, and by the NIH, National Center for Research Resources, Biomedical Technology Program. The content is solely the responsibility of the authors and does not necessarily reflect the official views of NCRR or NIH. NR 41 TC 24 Z9 26 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT 8 PY 2008 VL 16 IS 10 BP 1491 EP 1502 DI 10.1016/j.str.2008.06.014 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 358PU UT WOS:000259930800008 PM 18940605 ER PT J AU Zuniga, JE Schmidt, JJ Fenn, T Burnett, JC Arac, D Gussio, R Stafford, RG Badie, SS Bavari, S Brunger, AT AF Zuniga, Jorge E. Schmidt, James J. Fenn, Timothy Burnett, James C. Arac, Demet Gussio, Rick Stafford, Robert G. Badie, Shirin S. Bavari, Sina Brunger, Axel T. TI A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A Has a Very Different Conformation than SNAP-25 Substrate SO STRUCTURE LA English DT Article ID LIGHT-CHAIN; NEUROTRANSMITTER RELEASE; RESOLUTION AB Botulinum neurotoxin serotype A is the most lethal of all known toxins. Here, we report the crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNT/A bound to a potent peptidomimetic inhibitor (K-i = 41 nM) that resembles the local sequence of the SNAP-25 substrate. Surprisingly, the inhibitor adopts a helical conformation around the cleavage site, in contrast to the extended conformation of the native substrate. The backbone of the inhibitor's P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the "proton shuttle" E224. This mechanism of inhibition is aided by residue contacts in the conserved S1' pocket of the substrate binding cleft and by the induction of new hydrophobic pockets, which are not present in the apo form, especially for the P2' residue of the inhibitor. Our inhibitor is specific for BoNT/A as it does not inhibit other BoNT serotypes orthermolysin. C1 [Zuniga, Jorge E.; Fenn, Timothy; Arac, Demet; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Fenn, Timothy; Arac, Demet; Brunger, Axel T.] Stanford Univ, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Fenn, Timothy; Arac, Demet; Brunger, Axel T.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Fenn, Timothy; Arac, Demet; Brunger, Axel T.] Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA. [Zuniga, Jorge E.; Fenn, Timothy; Arac, Demet; Brunger, Axel T.] Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA. [Schmidt, James J.; Stafford, Robert G.; Badie, Shirin S.; Bavari, Sina] USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Burnett, James C.] SAIC Frederick Inc, Target Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. [Gussio, Rick] NCI, Dev Therapeut Program, Frederick, MD 21702 USA. RP Brunger, AT (reprint author), Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. EM brunger@stanford.edu OI Brunger, Axel/0000-0001-5121-2036 FU Department of Energy; National Institutes of Health [N01-CO-12400]; National Institute of General Medical Sciences; Department of Defense [3.1002406RDB]; Defense Threat Reduction Agency [3.1002307RDB]; National Cancer Institute; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX SSRL is a national userfacility operated by Stanford University on behalf ofthe US Department of Energy (Office of Basic Energy Sciences). The SSRL Structural Molecular Biology Program is supported by the Department of Energy (Office of Biological and Environmental Research), and by the National Institutes of Health (National Center for Research Resources, Biomedical Technology Program), and the National Institute of General Medical Sciences. This work was supported by the Department of Defense (proposal number 3.1002406RDB to A.T.B.) and by the Defense Threat Reduction Agency (proposal number 3.1002307RDB to J.J.S.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the US Army. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 24 TC 42 Z9 42 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT 8 PY 2008 VL 16 IS 10 BP 1588 EP 1597 DI 10.1016/j.str.2008.07.011 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 358PU UT WOS:000259930800017 PM 18940613 ER PT J AU Roddam, AW Allen, NE Appleby, P Key, TJ Ferrucci, L Carter, HB Metter, EJ Chen, C Weiss, NS Fitzpatrick, A Hsing, AW Lacey, JV Helzlsouer, K Rinaldi, S Riboli, E Kaaks, R Janssen, JAMJL Wildhagen, MF Schroder, FH Platz, EA Pollak, M Giovannucci, E Schaefer, C Quesenberry, CP Vogelman, JH Severi, G English, DR Giles, GG Stattin, P Hallmans, G Johansson, M Chan, JM Gann, P Oliver, SE Holly, JM Donovan, J Meyer, F Bairati, I Galan, P AF Roddam, Andrew W. Allen, Naomi E. Appleby, Paul Key, Timothy J. Ferrucci, Luigi Carter, H. Ballentine Metter, E. Jeffrey Chen, Chu Weiss, Noel S. Fitzpatrick, Annette Hsing, Ann W. Lacey, James V., Jr. Helzlsouer, Kathy Rinaldi, Sabina Riboli, Elio Kaaks, Rudolf Janssen, Joop A. M. J. L. Wildhagen, Mark F. Schroeder, Fritz H. Platz, Elizabeth A. Pollak, Michael Giovannucci, Edward Schaefer, Catherine Quesenberry, Charles P., Jr. Vogelman, Joseph H. Severi, Gianluca English, Dallas R. Giles, Graham G. Stattin, Paer Hallmans, Goeran Johansson, Mattias Chan, June M. Gann, Peter Oliver, Steven E. Holly, Jeff M. Donovan, Jenny Meyer, Francois Bairati, Isabelle Galan, Pilar TI Insulin-like growth factors, their binding proteins, and prostate cancer risk: Analysis of individual patient data from 12 prospective studies SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID I IGF-I; FACTOR (IGF)-I; FACTOR AXIS; PSA ERA; MEN; PREDICTORS; METAANALYSIS; ASSOCIATION; ANDROGENS; ANTIGEN AB Background: Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer. Purpose: To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer. Data Sources: Studies identified in PubMed, Web of Science, and CancerLit. Study Selection: The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate. Data Extraction: Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom. Data Synthesis: The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake. Limitations: Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies. Conclusion: High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer. C1 [Roddam, Andrew W.] Univ Oxford, Canc Epidemiol Unit, Oxford OX3 7LF, England. Johns Hopkins Univ, NIA, Harbor Hosp, Baltimore, MD USA. St Johns Mercy Med Ctr, Baltimore, MD USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Collaborat Hlth Studies Coordinating Ctr, Seattle, WA USA. NCI, Bethesda, MD 20892 USA. Int Agcy Res Canc, F-69372 Lyon, France. German Natl Canc Ctr, Heidelberg, Germany. Univ London Imperial Coll Sci Technol & Med, London, England. Erasmus MC, Rotterdam, Netherlands. McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Canc Prevent Res Unit, Montreal, PQ H3T 1E2, Canada. Univ Laval, Ctr Rech Cancerol, Quebec City, PQ, Canada. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Kaiser Div Res, Oakland, CA USA. Orentreich Fdn Advancement Sci, Cold Spring on Hudson, NY USA. Canc Epidemiol Ctr, Canc Council Victoria, Carlton, Vic, Australia. Umea Univ, Umea, Sweden. Univ Calif San Francisco, San Francisco, CA 94143 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Univ York, Hull York Med Sch, York YO10 5DD, N Yorkshire, England. Univ Bristol, Paul OGorman Lifeline Ctr, Southmead Hosp, Bristol, Avon, England. UMR SMBH Univ, Bobigny, France. RP Roddam, AW (reprint author), Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg,Roosevelt Dr, Oxford OX3 7LF, England. EM andrew.roddam@ceu.ox.ac.uk RI Pollak, Michael/G-9094-2011; OI Pollak, Michael/0000-0003-3047-0604; Janssen, Joseph A.M.J.L./0000-0002-9363-6408; Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188 FU Cancer Research UK, London, United Kingdom FX The central pooling and analysis of these data were supported by Cancer Research UK, London, United Kingdom. NR 40 TC 182 Z9 188 U1 0 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 7 PY 2008 VL 149 IS 7 BP 461 EP W88 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA 359QY UT WOS:000260004400003 PM 18838726 ER PT J AU Smedley, JG Sharp, JS Kuhn, JF Tomer, KB AF Smedley, James G., III Sharp, Joshua S. Kuhn, Jeffrey F. Tomer, Kenneth B. TI Probing the pH-dependent prepore to pore transition of Bacillus anthracis protective antigen with differential oxidative protein footprinting SO BIOCHEMISTRY LA English DT Article ID HYDROXYL RADICAL PROBE; X-RAY RADIOLYSIS; MASS-SPECTROMETRY; LETHAL FACTOR; STRUCTURAL REORGANIZATION; SYNCHROTRON RADIOLYSIS; ADENYLATE-CYCLASE; EUKARYOTIC CELLS; TOXIN RECEPTOR; EDEMA FACTOR AB The protective antigen (PA) component of the anthrax toxin (ATx) plays an essential role in the pathogenesis of the bioterrorism bacterium Bacillus anthracis. After oligomerization on the cell surface and docking of lethal factor and/or edema factor, PA is internalized and undergoes a conformational change when exposed to the low pH of the endosome to form a membrane-penetrating pore. While the structure of the PA prepore has been determined, precise structural information regarding the pore state remains lacking. Oxidative protein footprinting (OPF) can provide dynamic structural information about a protein complex through analysis of amino acid oxidation both before and after a conformational change. In this study, PA at pH 7.5 and 5.5 was exposed to hydroxyl radicals generated by ionizing radiation. Mass spectrometry was then used to both identify and quantitate the extent of oxidation of differentially modified residues. Several residues were found to be more readily oxidized at pH 7.5, most of which clustered toward the bottom plane of the prepore heptamer. Two amino acids had greater oxidation rates at pH 5.5, both found on the outer periphery of the prepore. When the OPF results were mapped to a current computational model of the pore, the accessibilities of some residues were consistent with their modeled positions in the pore (i.e., Y688 and V619/I620), while data for other residues (W346 and M350) appeared to conflict with the model. The results from this study illustrate the utility of OPF in generating empirical structural information for yet undetermined structures and offering opportunities for refinement for models thereof. C1 [Smedley, James G., III; Sharp, Joshua S.; Kuhn, Jeffrey F.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Tomer, KB (reprint author), NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM tomer@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 47 TC 16 Z9 16 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 7 PY 2008 VL 47 IS 40 BP 10694 EP 10704 DI 10.1021/bi800533t PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 353XW UT WOS:000259603600019 PM 18785752 ER PT J AU Wolf, MY Wolf, YI Koonin, EV AF Wolf, Maxim Y. Wolf, Yuri I. Koonin, Eugene V. TI Comparable contributions of structural-functional constraints and expression level to the rate of protein sequence evolution SO BIOLOGY DIRECT LA English DT Article ID ESSENTIAL GENES; DATABASE; NETWORK; NUMBER; YEAST; CLASSIFICATION; DISPENSABILITY; BACTERIA; GENOMES; MODEL AB Background: Proteins show a broad range of evolutionary rates. Understanding the factors that are responsible for the characteristic rate of evolution of a given protein arguably is one of the major goals of evolutionary biology. A long-standing general assumption used to be that the evolution rate is, primarily, determined by the specific functional constraints that affect the given protein. These constrains were traditionally thought to depend both on the specific features of the protein's structure and its biological role. The advent of systems biology brought about new types of data, such as expression level and protein-protein interactions, and unexpectedly, a variety of correlations between protein evolution rate and these variables have been observed. The strongest connections by far were repeatedly seen between protein sequence evolution rate and the expression level of the respective gene. It has been hypothesized that this link is due to the selection for the robustness of the protein structure to mistranslation-induced misfolding that is particularly important for highly expressed proteins and is the dominant determinant of the sequence evolution rate. Results: This work is an attempt to assess the relative contributions of protein domain structure and function, on the one hand, and expression level on the other hand, to the rate of sequence evolution. To this end, we performed a genome-wide analysis of the effect of the fusion of a pair of domains in multidomain proteins on the difference in the domain-specific evolutionary rates. The mistranslation-induced misfolding hypothesis would predict that, within multidomain proteins, fused domains, on average, should evolve at substantially closer rates than the same domains in different proteins because, within a mutlidomain protein, all domains are translated at the same rate. We performed a comprehensive comparison of the evolutionary rates of mammalian and plant protein domains that are either joined in multidomain proteins or contained in distinct proteins. Substantial homogenization of evolutionary rates in multidomain proteins was, indeed, observed in both animals and plants, although highly significant differences between domain-specific rates remained. The contributions of the translation rate, as determined by the effect of the fusion of a pair of domains within a multidomain protein, and intrinsic, domain-specific structural-functional constraints appear to be comparable in magnitude. Conclusion: Fusion of domains in a multidomain protein results in substantial homogenization of the domain-specific evolutionary rates but significant differences between domain-specific evolution rates remain. Thus, the rate of translation and intrinsic structural-functional constraints both exert sizable and comparable effects on sequence evolution. Reviewers: This article was reviewed by Sergei Maslov, Dennis Vitkup, Claus Wilke (nominated by Orly Alter), and Allan Drummond (nominated by Joel Bader). For the full reviews, please go to the Reviewers' Reports section. C1 [Wolf, Maxim Y.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM nskwolf@gmail.com; wolf@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov FU Department of Health and Human Services intramural program (NIH, National Library of Medicine) FX We thank Liran Carmel, Sergei Maslov, Claus Wilke and, especially, Allan Drummond, for helpful discussions and advice, David Lipman for critical reading of the manuscript, Malay Kumar Basu for providing the data on the Arabidopsis-cottonwood gene orthology, and Kira Makarova for help with the figure preparation. The authors' research is supported by the Department of Health and Human Services intramural program (NIH, National Library of Medicine). We are grateful to the Aspen Center for Physics for providing the venue for fruitful discussions during the workshop on "Evolution: From Atom to Organism" (August 10-31, 2008). NR 46 TC 31 Z9 31 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD OCT 7 PY 2008 VL 3 AR 40 DI 10.1186/1745-6150-3-40 PG 15 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 365UQ UT WOS:000260434800001 PM 18840284 ER PT J AU Wang, RH Sengupta, K Li, CL Kim, HS Cao, L Xiao, CY Kim, SS Xu, XL Zheng, Y Chilton, B Jia, R Zheng, ZM Appella, E Wang, XW Ried, T Deng, CX AF Wang, Rui-Hong Sengupta, Kundan Li, Cuiling Kim, Hyun-Seok Cao, Liu Xiao, Cuiying Kim, Sangsoo Xu, Xiaoling Zheng, Yin Chilton, Beverly Jia, Rong Zheng, Zhi-Ming Appella, Ettore Wang, Xin Wei Ried, Thomas Deng, Chu-Xia TI Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice SO CANCER CELL LA English DT Article ID DOUBLE-STRAND BREAKS; GENETIC INSTABILITY; CELL-CYCLE; IN-VIVO; SACCHAROMYCES-CEREVISIAE; NEGATIVE REGULATOR; PROSTATE-CANCER; HISTONE H2AX; RESVERATROL; BRCA1 AB In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity, and genome stability. Here we mutated the Sirt1 gene, a homolog of yeast Sir2, in mice to study its function. We show that a majority of SIRT1 null embryos die between E9.5 and E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrate that Sirt1(+/-),p53(+/-)mice develop tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduces tumorigenesis. Finally, we show that many human cancers exhibit reduced levels of SIRT1 compared to normal controls. Thus, SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity. C1 [Wang, Rui-Hong; Li, Cuiling; Kim, Hyun-Seok; Cao, Liu; Xiao, Cuiying; Kim, Sangsoo; Xu, Xiaoling; Zheng, Yin; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Sengupta, Kundan; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Jia, Rong; Zheng, Zhi-Ming] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Chilton, Beverly] Texas Tech Univ, Hlth Sci Ctr, Dept Biochem & Cell Biol, Lubbock, TX 79430 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI Wang, Xin/B-6162-2009; deng, chuxia/N-6713-2016 FU Intramural Research Program; NIH National Institute of Diabetes; Digestive and Kidney Diseases FX We thank members of the Deng laboratory for critical discussions of this work. We gratefully acknowledge H.M. Padilla-Nash and N. McNeil for assistance with SKY analyses. This research was supported by the Intramural Research Program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases. NR 52 TC 388 Z9 413 U1 3 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 7 PY 2008 VL 14 IS 4 BP 312 EP 323 DI 10.1016/j.ccr.2008.09.001 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 358DI UT WOS:000259896500006 PM 18835033 ER PT J AU Tisherman, SA Powell, JL Schmidt, TA Aufderheide, TP Kudenchuk, PJ Spence, J Climer, D Kelly, D Marcantonio, A Brown, T Sopko, G Kerber, R Sugarman, J Hoyt, D AF Tisherman, Samuel A. Powell, Judy L. Schmidt, Terri A. Aufderheide, Tom P. Kudenchuk, Peter J. Spence, Julie Climer, Dixie Kelly, Donna Marcantonio, Angela Brown, Todd Sopko, George Kerber, Richard Sugarman, Jeremy Hoyt, David CA Resuscitation Outcomes Consortium TI Regulatory challenges for the Resuscitation Outcomes Consortium SO CIRCULATION LA English DT Article ID HOSPITAL CARDIAC-ARREST; HEALTH-SERVICES RESEARCH; INFORMED-CONSENT; COMMUNITY CONSULTATION; EMERGENCY EXCEPTION; LIFE-SUPPORT; FINAL RULE; WAIVER; TRIAL; ATTITUDES C1 [Tisherman, Samuel A.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15261 USA. [Powell, Judy L.; Kudenchuk, Peter J.] Univ Washington, Seattle, WA 98195 USA. [Schmidt, Terri A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Aufderheide, Tom P.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Spence, Julie] Univ Toronto, Toronto, ON, Canada. [Climer, Dixie] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Kelly, Donna] Univ Calif San Diego, San Diego, CA 92103 USA. [Marcantonio, Angela] Univ Ottawa, Ottawa, ON, Canada. [Brown, Todd] Univ Alabama, Birmingham, AL USA. [Sopko, George] NHLBI, Bethesda, MD 20892 USA. [Kerber, Richard] Univ Iowa, Iowa City, IA USA. [Sugarman, Jeremy] Johns Hopkins Univ, Baltimore, MD USA. [Hoyt, David] Univ Calif Irvine, Irvine, CA USA. RP Tisherman, SA (reprint author), Univ Pittsburgh, Dept Surg, 638 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM tishermansa@upmc.edu FU National Heart, Lung and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke [5U01 HL077863, HL077881, HL077871 HL077872, HL077866, HL077908, HL077867, HL077885, HL077863]; US Army Research and Materiel Command; Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health; Defense Research and Development Canada; American Heart Association; Heart and Stroke Foundation of Canada FX This study was supported by a series of cooperative agreements to 10 regional centers and 1 data coordinating center (5U01 HL077863, HL077881, HL077871 HL077872, HL077866, HL077908, HL077867, HL077885, HL077885, HL077863) with the National Heart, Lung and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke, US Army Research and Materiel Command, the Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health, Defense Research and Development Canada, American Heart Association, and the Heart and Stroke Foundation of Canada. NR 39 TC 21 Z9 21 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 7 PY 2008 VL 118 IS 15 BP 1585 EP 1592 DI 10.1161/CIRCULATIONAHA.107.764084 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 357BT UT WOS:000259822000010 PM 18838574 ER PT J AU Westermann, D Lettau, O Schultheiss, HP Tschope, C Mersmann, J Melchior, A Freudenberger, T Fischer, JW Petrik, C Unger, T Schaefer, L Lullmann-Rauch, R Jacoby, C Schrader, J Brand-Herrman, SM Young, MF Levkau, B Baba, HA Zacharowski, K AF Westermann, D. Lettau, O. Schultheiss, H. P. Tschoepe, C. Mersmann, J. Melchior, A. Freudenberger, T. Fischer, J. W. Petrik, C. Unger, T. Schaefer, L. Luellmann-Rauch, R. Jacoby, C. Schrader, J. Brand-Herrman, S. M. Young, M. F. Levkau, B. Baba, H. A. Zacharowski, K. TI Response to letter regarding article, "Biglycan Is Required for Adaptive Remodeling After Myocardial Infarction - Reply SO CIRCULATION LA English DT Letter ID DECORIN C1 [Westermann, D.; Lettau, O.; Schultheiss, H. P.; Tschoepe, C.] Charite Univ Klinikum Berlin, Abt Kardiol & Pneumol, Berlin, Germany. [Mersmann, J.] Univ Klinikum Dusseldorf, Anasthesiol Klin, Mol Cardioprotect & Inflammat Grp, Dusseldorf, Germany. [Melchior, A.; Freudenberger, T.; Fischer, J. W.] Univ Klinikum Dusseldorf, Inst Pharmakol & Klin Pharmakol, Dusseldorf, Germany. [Zacharowski, K.] Univ Hosp Bristol, Bristol Royal Infirm, Dept Anaesthesia, Mol Cardioprotect & Inflammat Grp, Bristol, Avon, England. [Baba, H. A.] Univ Klinikum Essen, Inst Pathol, Essen, Germany. [Levkau, B.] Univ Klinikum Essen, Inst Pathophysiol, Essen, Germany. [Young, M. F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Natl Inst Hlth, Bethesda, MD USA. [Brand-Herrman, S. M.] Univ Munster, Dept Mol Genet Cardiovasc Dis, Leibniz Inst Arteriosclerosis Res, Munster, Germany. [Jacoby, C.; Schrader, J.] Univ Dusseldorf, Inst Herzkreislauf Physiol, Dusseldorf, Germany. [Luellmann-Rauch, R.] Univ Kiel, Inst Anat, D-2300 Kiel, Germany. [Schaefer, L.] Univ Frankfurt, Allgemeine Pharmakol & Toxikol Klinikum, Frankfurt, Germany. [Petrik, C.; Unger, T.] Charite Univ Med Berlin, Campus Charite Mitte, Inst Pharmakol & Toxikol, Cardiovasc Res Ctr, Berlin, Germany. RP Westermann, D (reprint author), Charite Univ Klinikum Berlin, Abt Kardiol & Pneumol, Campus Benjamin Franklin, Berlin, Germany. NR 4 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 7 PY 2008 VL 118 IS 15 BP E522 EP E522 DI 10.1161/CIRCULATIONAHA.108.796920 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 357BT UT WOS:000259822000017 ER PT J AU Philosof-Mazor, L Volinsky, R Comin, MJ Lewin, NE Kedei, N Blumberg, PM Marquez, VE Jelinek, R AF Philosof-Mazor, Liron Volinsky, Roman Comin, Maria J. Lewin, Nancy E. Kedei, Noemi Blumberg, Peter M. Marquez, Victor E. Jelinek, Raz TI Self-assembly and lipid interactions of diacylglycerol lactone derivatives studied at the air/water interface SO LANGMUIR LA English DT Article ID PROTEIN-KINASE-C; BREWSTER-ANGLE MICROSCOPY; AIR-WATER-INTERFACE; DAG-LACTONES; MONOLAYERS; MEMBRANES; PHOSPHOLIPIDS; MORPHOLOGY; PEPTIDES; ALPHA AB Synthetic diacylglycerol lactones (DAG-lactones) have been shown to be effective modulators of critical cellular signaling pathways. The biological activity of these amphiphilic molecules depends in part upon their lipid interactions within the cellular plasma membrane. This study explores the thermodynamic and structural features of DAG-lactone derivatives and their lipid interactions at the air/water interface. Surface-pressure/area isotherms and Brewster angle microscopy revealed the significance of specific side-groups attached to the terminus of a very rigid 4-(2-phenylethynyl)benzoyl chain of the DAG-lactones, which affected both the self-assembly of the molecules and their interactions with phospholipids. The experimental data highlight the formation of different phases within mixed DAG-lactone/phospholipid monolayers and underscore the relationship between the two components in binary mixtures of different mole ratios. Importantly, the results suggest that DAG-lactones are predominantly incorporated within fluid phospholipid phases rather than in the condensed phases that form, for example, by cholesterol. Moreover, the size and charge of the phospholipid headgroups do not seem to affect DAG-lactone interactions with lipids. C1 [Comin, Maria J.; Marquez, Victor E.] NCI, Ctr Canc Res, Med Chem Lab, NIH, Frederick, MD 21702 USA. [Philosof-Mazor, Liron; Volinsky, Roman; Jelinek, Raz] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Philosof-Mazor, Liron; Volinsky, Roman; Jelinek, Raz] Ben Gurion Univ Negev, Ilse Katz Inst Nanotechnol, IL-84105 Beer Sheva, Israel. [Lewin, Nancy E.; Kedei, Noemi; Blumberg, Peter M.] NCI, Ctr Canc Res, Lab Canc Biol & Genet, NIH, Frederick, MD 21702 USA. RP Marquez, VE (reprint author), NCI, Ctr Canc Res, Med Chem Lab, NIH, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov; razj@bgu.ac.il RI Volinsky, Roman/B-8443-2011; JELINEK, RAZ/F-2023-2012; OI jelinek, raz/0000-0002-0336-1384 FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 32 TC 4 Z9 4 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD OCT 7 PY 2008 VL 24 IS 19 BP 11043 EP 11052 DI 10.1021/la802204n PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 354XP UT WOS:000259673500077 PM 18788772 ER PT J AU Copenhaver, BR Hsia, AW Merino, JG Burgess, RE Fifi, JT Davis, L Warach, S Kidwell, CS AF Copenhaver, B. R. Hsia, A. W. Merino, J. G. Burgess, R. E. Fifi, J. T. Davis, L. Warach, S. Kidwell, C. S. TI Racial differences in microbleed prevalence in primary intracerebral hemorrhage SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; RISK-FACTORS; LOBAR HEMORRHAGE; ISCHEMIC-STROKE; MRI; POPULATION; LOCATION; LESIONS; WHITES AB Background: Primary intracerebral hemorrhage is two to three times more common in many racial populations, including black patients. Previous studies have shown that microbleeds, identified on gradient echo MRI (GRE), are present in 50 - 80% of patients with primary ICH. The objective of this study was to compare, by race, the rates, risk factors, and topography of microbleeds in patients hospitalized for primary ICH. Methods: Patients diagnosed with primary ICH at two metropolitan stroke centers were included. Clinical and neuroimaging data were recorded for each patient. Analyses were performed to compare baseline characteristics as well as imaging findings by race. Results: A total of 87 patients met inclusion criteria ( 42 black subjects, 45 white subjects). The black cohort was younger (p < 0.001), and had a greater rate of hypertension (p < 0.001), but not other vascular risk factors. Microbleeds were more prevalent in the black population, with 74% of blacks having one or more microbleeds compared to 42% of whites (p < 0.005). The black population also tended to have a greater frequency of microbleeds in multiple territories than the white population (38% vs 22%, p = 0.106). When adjusting for age, hypertension, and alcohol use, race was an independent predictor of microbleeds (OR 3.308, 95% CI 1.144 - 9.571, p = 0.027). Conclusions: These pilot data suggest that significant racial differences exist in the frequency and topography of microbleeds in patients with primary ICH. Microbleeds may be an important emerging imaging biomarker with the potential to provide insights into ICH pathophysiology, prognosis, and disease progression, as well as possible therapeutic strategies, particularly in medically underserved populations. C1 [Hsia, A. W.; Fifi, J. T.; Kidwell, C. S.] Washington Hosp Ctr, Stroke Ctr, Washington, DC 20010 USA. [Copenhaver, B. R.; Hsia, A. W.; Burgess, R. E.; Kidwell, C. S.] Georgetown Univ, Dept Neurol, Washington, DC USA. [Merino, J. G.] Suburban Hosp Stroke Program, Bethesda, MD USA. [Davis, L.; Warach, S.] NINDS, NIH, Bethesda, MD 20892 USA. RP Kidwell, CS (reprint author), Washington Hosp Ctr, Stroke Ctr, 110 Irving St NW,E Bldg Room 6126, Washington, DC 20010 USA. EM ck256@georgetown.edu OI Merino, Jose/0000-0002-6676-0008 FU NIH [U54NS057405, P50 NS44378] FX Supported by the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke (NINDS), NIH. C. S. K. receives funding from the NINDS, grants U54NS057405 and P50 NS44378. NR 24 TC 27 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 7 PY 2008 VL 71 IS 15 BP 1176 EP 1182 DI 10.1212/01.wnl.0000327524.16575.ca PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 356XE UT WOS:000259810100009 PM 18838665 ER PT J AU Yano, A Tsutsumi, S Soga, S Lee, MJ Trepel, J Osada, H Neckers, L AF Yano, Akihiro Tsutsumi, Shinji Soga, Shiro Lee, Min-Jung Trepel, Jane Osada, Hiroyuki Neckers, Len TI Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; geldanamycin; heat shock protein 90; osteoclastogenesis ID COLONY-STIMULATING FACTOR; LUNG-CANCER CELLS; HEAT-SHOCK-PROTEIN-90 INHIBITOR; TUMOR-GROWTH; TARGETED DISRUPTION; ANDROGEN RECEPTOR; LEUKEMIA-CELLS; BREAST-CANCER; IN-VITRO; KINASE AB Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Src-dependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy. C1 [Yano, Akihiro; Tsutsumi, Shinji; Soga, Shiro; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lee, Min-Jung; Trepel, Jane] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Osada, Hiroyuki] RIKEN, Discovery Res Inst, Antibiot Lab, Wako, Saitama 3510198, Japan. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM neckersl@mail.nih.gov RI Osada, Hiroyuki/N-4305-2014 FU National Institutes of Health, National Cancer Institute FX Grant support was provided by funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 47 TC 59 Z9 59 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 7 PY 2008 VL 105 IS 40 BP 15541 EP 15546 DI 10.1073/pnas.0805354105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 364UI UT WOS:000260360500059 PM 18840695 ER PT J AU Bin Kwon, O Paredes, D Gonzalez, CM Neddens, J Hernandez, L Vullhorst, D Buonanno, A AF Bin Kwon, Oh Paredes, Daniel Gonzalez, Carmen M. Neddens, Joerg Hernandez, Luis Vullhorst, Detlef Buonanno, Andres TI Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE depotentiation; ErbB receptor; plasticity; schizophrenia; clozapine ID LONG-TERM POTENTIATION; NICOTINIC ACETYLCHOLINE-RECEPTORS; PREFRONTAL CORTEX NEURONS; TYROSINE KINASE; NERVOUS-SYSTEM; MUTANT MICE; ADULT-RAT; NRG1 GENE; SCHIZOPHRENIA; EXPRESSION AB Neuregulin-1 (NRG-1) is genetically linked with schizophrenia, a neurodevelopmental cognitive disorder characterized by imbalances in glutamatergic and dopaminergic function. NRG-1 regulates numerous neurodevelopmental processes and, in the adult, suppresses or reverses long-term potentiation (LTP) at hippocampal glutamatergic synapses. Here we show that NRG-1 stimulates dopamine release in the hippocampus and reverses early-phase LTP via activation of D4 dopamine receptors (D4R). NRG-1 fails to depotentiate LTP in hippocampal slices treated with the antipsychotic clozapine and other more selective D4R antagonists. Moreover, LTP is not depotentiated in D4R null mice by either NRG-1 or theta-pulse stimuli. Conversely, direct D4R activation mimics NRG-1 and reduces AMPA receptor currents and surface expression. These findings demonstrate that NRG-1 mediates its unique role in counteracting LTP via dopamine signaling and opens future directions to study new aspects of NRG function. The novel functional link between NRG-1, dopamine, and glutamate has important implications for understanding how imbalances in Neuregulin-ErbB signaling can impinge on dopaminergic and glutamatergic function, neurotransmitter pathways associated with schizophrenia. C1 [Bin Kwon, Oh; Paredes, Daniel; Gonzalez, Carmen M.; Neddens, Joerg; Vullhorst, Detlef; Buonanno, Andres] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Hernandez, Luis] Univ Los Andes, Lab Behav Physiol, Merida, Venezuela. RP Buonanno, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, NIH, Bldg 35,Room 2C-1000, Bethesda, MD 20892 USA. EM buonanno@mail.nih.gov RI yu, yan/C-2322-2012; Paredes , Daniel/L-6610-2013 FU NICHD Intramural Research Program FX The authors thank D. Abebe and Dr. I. Karavanova for animal husbandry and genotyping, Drs, L. Dye and V. Schram from the National Institute of Child Health and Human Development (NICHD) imaging core, and Dr. D. Grandy (Oregon University, Portland, OR) for D4R mice. This work was supported by the NICHD Intramural Research Program. NR 51 TC 1 Z9 1 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 7 PY 2008 VL 105 IS 40 BP 15587 EP 15592 DI 10.1073/pnas.0805722105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 364UI UT WOS:000260360500067 ER PT J AU Satheshkumar, PS Moss, B AF Satheshkumar, P. S. Moss, Bernard TI Poxvirus transcriptome analysis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID HINDIII-D FRAGMENT; VACCINIA; GENES; RNA; MAP C1 [Satheshkumar, P. S.; 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 Intramural NIH HHS NR 5 TC 3 Z9 3 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 7 PY 2008 VL 105 IS 40 BP E62 EP E62 DI 10.1073/pnas.0804594105 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 364UI UT WOS:000260360500001 PM 18832142 ER PT J AU Stewart, TJ Abrams, SI AF Stewart, T. J. Abrams, S. I. TI How tumours escape mass destruction SO ONCOGENE LA English DT Review DE tumour immunity; tumour escape; tumour microenvironment; immunosuppression; immunosurveillance ID REGULATORY T-CELLS; MYELOID SUPPRESSOR-CELLS; FAS-MEDIATED APOPTOSIS; COLON-CARCINOMA CELLS; GROWTH-FACTOR-BETA; ANTIGEN-PROCESSING MACHINERY; IMMUNE-RESPONSES; PERIPHERAL-BLOOD; CANCER-IMMUNOTHERAPY; BREAST-CANCER AB It is now well established that the immune system can control neoplastic development and growth in a process termed immunosurveillance. A link between host immunosurveillance and neoplastic progression is revealed in cases where the immune response becomes compromised due to genetic or other pathological conditions, resulting in a substantially increased incidence and rate of spontaneous tumour formation in both preclinical animal models and patients. It has also been demonstrated in tumour-bearing hosts that the tumorigenic process itself can promote a state of immunosuppression that, in turn, facilitates neoplastic progression. The ability of neoplastic populations to induce a hostile microenvironment through both cell contact-dependent and -independent immunosuppressive networks is a significant barrier to effective cellmediated immunity and immunotherapy. Thus, a competent immune system is integral for the control of neoplastic disease, and dissecting the plethora of tumour escape mechanisms that disrupt this essential host defense capability is integral for the development of effective immunotherapeutic paradigms. C1 [Stewart, T. J.; Abrams, S. I.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), Roswell Pk Canc Inst, Dept Immunol, Elm & Carlton St, Buffalo, NY 14263 USA. EM scott.abrams@roswellpark.org RI Stewart, Trina/F-5967-2012 OI Stewart, Trina/0000-0003-3220-9231 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 109 TC 97 Z9 104 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 6 PY 2008 VL 27 IS 45 BP 5894 EP 5903 DI 10.1038/onc.2008.268 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 355QE UT WOS:000259722600004 PM 18836470 ER PT J AU Nelson, JK Twamley, B Villalobos, TJ Natale, NR AF Nelson, Jared K. Twamley, Brendan Villalobos, Trinidad J. Natale, Nicholas R. TI The catalytic asymmetric addition of alkyl- and aryl-zinc reagents to an isoxazole aldehyde SO TETRAHEDRON LETTERS LA English DT Article ID HIGHLY ENANTIOSELECTIVE ADDITION; LATERAL METALATION; LIGANDS; ISOXAZOLYLOXAZOLINES; MECHANISM; TITANIUM; AGONIST; UTILITY; ROUTE; ACIDS AB Nucleophilic addition of alkyl- and aryl-zinc reagents to a C(4) functionalized isoxazolyl aldehyde proceeded effectively with high enantioselectivity (85-94% ee). The amino alcohol catalyst (S)-2-piperidinyl-1,1,2-triphenyl ethanol (10) afforded the (R)-product 2b. as established by X-ray crystallography. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Nelson, Jared K.; Twamley, Brendan; Villalobos, Trinidad J.; Natale, Nicholas R.] Univ Idaho, Dept Chem, Moscow, ID 83844 USA. [Natale, Nicholas R.] Univ Montana, COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. RP Natale, NR (reprint author), Univ Idaho, Dept Chem, Moscow, ID 83844 USA. EM Nicholas.natale@umontana.edu FU NIH [NS038444, P20RR015583, P20RR16454]; Fraternal Order of Eagles Alzheimer's Fund; Malcolm and Carol Renfrew Scholarship; NSF-EPSCoR program FX The authors thank NIH for grants NS038444(NN), P20RR015583(NN), P20RR16454(JKN), the Fraternal Order of Eagles Alzheimer's Fund (NN), and the Malcolm and Carol Renfrew Scholarship (JKN). The Bruker (Siemens) SMART APEX diffraction facility was established at the University of Idaho with the assistance of the NSF-EPSCoR program and the M. J. Murdock Charitable Trust, Vancouver, WA, USA. We thank Rakesh Kumar and Shikha Sharma for technical assistance. NR 37 TC 7 Z9 7 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD OCT 6 PY 2008 VL 49 IS 41 BP 5957 EP 5960 DI 10.1016/j.tetlet.2008.07.169 PG 4 WC Chemistry, Organic SC Chemistry GA 353UX UT WOS:000259595100033 PM 19812681 ER PT J AU Shi, JJ Wittke-Thompson, JK Badner, JA Hattori, E Potash, JB Willour, VL McMahon, FJ Gershon, ES Liu, CY AF Shi, Jiajun Wittke-Thompson, Jacqueline K. Badner, Judith A. Hattori, Eiji Potash, James B. Willour, Virginia L. McMahon, Francis J. Gershon, Elliot S. Liu, Chunyu TI Clock Genes May Influence Bipolar Disorder Susceptibility and Dysfunctional Circadian Rhythm SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE single nucleotide polymorphism; linkage disequilibrium; haplotype; bipolar disorder; circadian rhythm ID SINGLE NUCLEOTIDE POLYMORPHISM; SLEEP-PHASE SYNDROME; GLYCOGEN-SYNTHASE KINASE-3-BETA; SEASONAL AFFECTIVE-DISORDER; MULTIPLE RARE VARIANTS; MOOD DISORDERS; DROSOPHILA-MELANOGASTER; LENGTH POLYMORPHISM; DIURNAL PREFERENCE; NATURAL-SELECTION AB Several previous studies suggest that dysfunction of cireadian rhythms may increase susceptibility to bipolar disorder (BP). We conducted an association study of five cireadian genes (CRY2, PER1-3, and TIMELESS) in a family collection of 36 trios and 79 quads (Sample I), and 10 circadian genes (ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CSNK1D, CSNK1E, DBP, and NR1D1) in an extended family collection of 70 trios and 237 quads (Sample 11), which includes the same 114 families but not necessarily the same individuals as Sample I. In Sample II, the Sibling-Transmission Disequilibrium. Test (sib-tdt) analysis showed nominally significant association of BP with three SNPs within or near the CLOCK gene (rs534654, P = 0.0097; rs6850524, P = 0.012; rs4340844, P = 0.015). In addition, SNPs in the ARNTL2, CLOCK, DBP, and TIMELESS genes and haplotypes in the ARNTL, CLOCK, CSNK1E, and TIMELESS genes showed suggestive evidence of association with several circadian phenotypes identified in BP patients. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. A multi-locus interaction between rs6442925 in the 5' upstream of BHLHB2, rs1534891 in CSNK1E, and rs534654 near the 3' end of the CLOCK gene, however, is significantly associated with BP (P = 0.00000172). It remains significant after correcting for multiple testing using the False Discovery Rate method. Our results indicate an interaction between three circadian genes in susceptibility to bipolar disorder. (C) 2008 Wiley-Liss, Inc. C1 [Liu, Chunyu] Univ Chicago, Dept Psychiat, Knapp Ctr, Chicago, IL 60637 USA. [Hattori, Eiji] RIKEN, Brain Sci Inst, Lab Mol Psychiat, Saitama, Japan. [Potash, James B.; Willour, Virginia L.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [McMahon, Francis J.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Mood & Anxiety Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gershon, Elliot S.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Liu, CY (reprint author), Univ Chicago, Dept Psychiat, Knapp Ctr, 924 E 57th St,R012, Chicago, IL 60637 USA. EM cliu@yoda.bsd.uchicago.edu RI Liu, Chunyu/G-7561-2012; OI Liu, Chunyu/0000-0002-5986-4415; McMahon, Francis/0000-0002-9469-305X FU NARSAD Young Investigator Awards; Brain Research Foundation; NIH [MH065560-02, MH61613-05A1, MH200065]; NIMH Intramural Research Program; Wellcome Trust [076113] FX The authors thank all the families participated in this study. We are grateful to the members of the NIMH Genetics Initiative for Bipolar Disorder consortium and the Chicago-Hopkins-Intramural Project (CHIP) for their efforts in family ascertainment, DNA sample collection and clinical diagnosis. We appreciate that the Stanley Medical Research Institute and its Collaborators, and Dr. Michael Elashoff and Dr. Fuller Torrey generously gave permission to publish circadian gene expression data. This work was supported by NARSAD Young Investigator Awards (to E.H., C.L., and J.S.), the Brain Research Foundation at the University of Chicago (to C.L.), NIH MH065560-02, MH61613-05A1 (to E.S.G.), and the NIMH Intramural Research Program (to F.J.M.). Dr. Jacqueline K. Wittke-Thompson is a postdoctoral fellow in an NIH supported Multidisciplinary Psychiatric Genetics Training Program (T32 MH200065 to E.S.G.). Support from the Geraldi Norton Foundation and the Eklund Family are also gratefully acknowledged. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. NR 96 TC 100 Z9 102 U1 1 U2 18 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT 5 PY 2008 VL 147B IS 7 BP 1047 EP 1055 DI 10.1002/ajmg.b.30714 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 359IK UT WOS:000259979500007 PM 18228528 ER PT J AU Ishiguro, H Gong, JP Hall, FS Arinami, T Uhl, GR AF Ishiguro, Hiroki Gong, Jian-Ping Hall, F. Scott Arinami, Tadao Uhl, George R. TI Association of PTPRB Gene Polymorphism With Drug Addiction SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE substance abuse; association; protein tyrosine phosphatase ID POLYSUBSTANCE ABUSERS; GLOBUS-PALLIDUS; VULNERABILITY; EXPRESSION; DOPAMINE; RECEPTOR; MICE AB Several lines of evidence support the involvement of protein tyrosine phosphatase receptor type beta (PTPRB) in addiction. Generally, PTPs interact with both neuronal receptors and cell adhesion molecules, and appear to play roles in neurite growth and neuronal differentiation. We previously identified a role of the cell adhesion molecule NrCAM in polysubstance abuse vulnerability in humans, as well as in the rewarding effects of abused drugs in animals. Furthermore, we have identified genomic regions containing several cell adhesion molecules as polysubstance abuse vulnerability loci by whole-genome association study. The present study of human chromosome 12 loci revealed that the Ser127Gly polymorphism in PTPRB is associated with substance abuse vulnerability in three independent case-control samples (European-American from COGA families, USA, n = 177, P = 0.047; European-American from Maryland, USA, n = 650, P = 0.018; and African-American from Maryland, USA, n = 331, P = 0.009). However, this polymorphism was not associated with alcoholism in Japanese subjects (n = 1,599, P = 0.37). To confirm the importance of PTPRB in responses to drugs of abuse the expression of Ptprb in mouse brain was examined after chronic morphine treatment and found to be up-regulated in some brain regions. Thus, PTPRB is an addiction-associated and drug-regulated gene whose variants may affect substance abuse vulnerability. (C) 2008 Wiley-Liss, Inc. C1 [Ishiguro, Hiroki; Arinami, Tadao] Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Med Genet, Tsukuba, Ibaraki, Japan. [Ishiguro, Hiroki; Gong, Jian-Ping; Hall, F. Scott; Uhl, George R.] NIDA IRP, Mol Neurobiol Branch, NIH, Baltimore, MD USA. RP Ishiguro, H (reprint author), 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058577, Japan. EM hishigur@md.tsukuba.ac.jp RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU National Institute on Drug Abuse; NIH; DHSS; KAKENHI [18790823]; Japan Society for the Promotion of Science (JSPS); Ministry of Health, Labor and Welfare of Japan FX Grant sponsor: National Institute on Drug Abuse; Grant sponsor: NIH; Grant sponsor: DHSS; Grant sponsor: KAKENHI; Grant number: #18790823; Grant sponsor: Japan Society for the Promotion of Science (JSPS); Grant sponsor: Ministry of Health, Labor and Welfare of Japan. NR 17 TC 9 Z9 9 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT 5 PY 2008 VL 147B IS 7 BP 1167 EP 1172 DI 10.1002/ajmg.b.30742 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 359IK UT WOS:000259979500022 PM 18361428 ER PT J AU Shi, JJ Badner, JA Hattori, E Potash, JB Willour, VL McMahon, FJ Gershon, ES Liu, CY AF Shi, Jiajun Badner, Judith A. Hattori, Eiji Potash, James B. Willour, Virginia L. McMahon, Francis J. Gershon, Elliot S. Liu, Chunyu TI Neurotransmission and Bipolar Disorder: A Systematic Family-Based Association Study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Review DE bipolar disorder; neurotransmitter; single nucleotide polymorphism; monoamine; amino acid ID DOPAMINE TRANSPORTER GENE; TRYPTOPHAN-HYDROXYLASE GENE; MAJOR DEPRESSIVE DISORDER; GENOME-WIDE ASSOCIATION; LINKAGE ANALYSIS; MOOD DISORDERS; II DISORDER; PSYCHIATRIC-DISORDERS; SYNAPTIC PLASTICITY; CANDIDATE GENES AB Neurotransmission pathways/systems have been proposed to be involved in the pathophysiology and treatment of bipolar disorder for over 40 years. In order to test the hypothesis that common variants of genes in one or more of five neurotransmission systems confer risk for bipolar disorder, we analyzed 1,005 tag single nucleotide polymorphisms in 90 genes from dopaminergic, serotonergic, noradrenergic, GABAergic, and glutamatergic neurotransmitter systems in 101 trios and 203 quads from Caucasian bipolar families. Our sample has 80% power to detect ORs >= 1.82 and >= 1.57 for minor allele frequencies of 0.1 and 0.5, respectively. Nominally significant allelic and haplotypic associations were found for genes from each neurotransmission system, with several reaching gene-wide significance (allelic: GRIA1, GRIN2D, and QDPR; haplotypic: GRIN2C, QDPR, and SLC6A3). However, none of these associations survived correction for multiple testing in an individual system, or in all systems considered together. Significant single nucleotide polymorphism associations were not found with sub-phenotypes (alcoholism, psychosis, substance abuse, and suicide attempts) or significant gene-gene interactions. These results suggest that, within the detectable odds ratios of this study, common variants of the selected genes in the five neurotransmission systems do not play major roles in influencing the risk for bipolar disorder or comorbid sub-phenotypes. (C) 2008 Wiley-Liss, Inc. C1 [Shi, Jiajun; Badner, Judith A.; Gershon, Elliot S.; Liu, Chunyu] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Hattori, Eiji] RIKEN Brain Sci Inst, Lab Mol Psychiat, Saitama, Japan. [Potash, James B.; Willour, Virginia L.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [McMahon, Francis J.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Mood & Anxiety Program, NIH,US Dept HHS, Bethesda, MD USA. [Gershon, Elliot S.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. RP Liu, CY (reprint author), Univ Chicago, Dept Psychiat, 924 E 57th St,Knapp Ctr,R012, Chicago, IL 60637 USA. EM cliu@yoda.bsd.uchicago.edu RI Liu, Chunyu/G-7561-2012; OI Liu, Chunyu/0000-0002-5986-4415; McMahon, Francis/0000-0002-9469-305X FU NARSAD; Brain Research Foundation at the University of Chicago; NIH [MH065560-02, MH61613-05A1, 5R01MH080425-1]; NIMH; Wellcome Trust [076113] FX Grant sponsor: NARSAD Young Investigator Awards; Grant sponsor: Brain Research Foundation at the University of Chicago; Grant sponsor: NIH; Grant numbers: MH065560-02, MH61613-05A1, 5R01MH080425-1 Grant sponsor: NIMH Intramural Research Program; Grant sponsor: Wellcome Trust; Grant number: 076113. NR 116 TC 12 Z9 12 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT 5 PY 2008 VL 147B IS 7 BP 1270 EP 1277 DI 10.1002/ajmg.b.30769 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 359IK UT WOS:000259979500035 PM 18444252 ER PT J AU Georgiadis, P Makedonopouloul, P Kaila, S Poirier, MC Kyrtopoulos, SA AF Georgiadis, Panagiotis Makedonopouloul, Paraskevi Kaila, Stella Poirier, Miriam C. Kyrtopoulos, Soterios A. TI Development and application of high sensitivity, high-throughput immunochemical assays for DNA adducts for use in molecular epidemiology SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 45th Congress of the European-Societies-of-Toxicology CY OCT 05-08, 2008 CL Rhodes, GREECE SP European Soc Toxicol C1 [Georgiadis, Panagiotis; Makedonopouloul, Paraskevi; Kaila, Stella; Poirier, Miriam C.; Kyrtopoulos, Soterios A.] Natl Hellen Res Fdn, Athens, Greece. [Georgiadis, Panagiotis; Makedonopouloul, Paraskevi; Kaila, Stella; Poirier, Miriam C.; Kyrtopoulos, Soterios A.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 5 PY 2008 VL 180 SU 1 BP S85 EP S85 DI 10.1016/j.toxlet.2008.06.524 PG 1 WC Toxicology SC Toxicology GA 349AV UT WOS:000259252100270 ER PT J AU Goshorn, J Chang, F AF Goshorn, Jeanne Chang, Florence TI Drug information portal on the web SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 45th Congress of the European-Societies-of-Toxicology CY OCT 05-08, 2008 CL Rhodes, GREECE SP European Soc Toxicol C1 [Goshorn, Jeanne; Chang, Florence] Natl Lib Med, NIH, US Dept HHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 5 PY 2008 VL 180 SU 1 BP S131 EP S131 DI 10.1016/j.toxlet.2008.06.756 PG 1 WC Toxicology SC Toxicology GA 349AV UT WOS:000259252100422 ER PT J AU Negishi, M AF Negishi, Masahiko TI Nuclear receptor CAR-mediated signals responsible for hepatocellular carcinoma SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 45th Congress of the European-Societies-of-Toxicology CY OCT 05-08, 2008 CL Rhodes, GREECE SP European Soc Toxicol C1 [Negishi, Masahiko] NIEHS, Res Triangle Pk, NC 27709 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 5 PY 2008 VL 180 SU 1 BP S15 EP S15 DI 10.1016/j.toxlet.2008.06.803 PG 1 WC Toxicology SC Toxicology GA 349AV UT WOS:000259252100050 ER PT J AU Ramot, Y Nyska, A Lieuallen, W Maly, A Zlotogorski, A Flake, G Kissling, G Brix, A Malarkey, D Hooth, M AF Ramot, Yuval Nyska, Abraham Lieuallen, Warren Maly, Alex Zlotogorski, Abraham Flake, Gordon Kissling, Grace Brix, Amy Malarkey, David Hooth, Michelle TI Exposure to tetrachloroazobenzene (TCAB) for 2 years in B6C3F1 mice is associated with inflammatory and chloracne-like skin lesions SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 45th Congress of the European-Societies-of-Toxicology CY OCT 05-08, 2008 CL Rhodes, GREECE SP European Soc Toxicol C1 [Ramot, Yuval; Zlotogorski, Abraham; Hooth, Michelle] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Nyska, Abraham] Tel Aviv Univ & Timrat, Tel Aviv, Israel. [Lieuallen, Warren] Charles River Labs Pathol Associates, Durham, NC USA. [Flake, Gordon; Kissling, Grace; Brix, Amy; Malarkey, David] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 5 PY 2008 VL 180 SU 1 BP S54 EP S54 DI 10.1016/j.toxlet.2008.06.627 PG 1 WC Toxicology SC Toxicology GA 349AV UT WOS:000259252100170 ER PT J AU Iyer, LM Abhiman, S Aravind, L AF Iyer, Lakshminarayan M. Abhiman, Saraswathi Aravind, L. TI A new family of polymerases related to superfamily A DNA polymerases and T7-like DNA-dependent RNA polymerases SO BIOLOGY DIRECT LA English DT Article ID CASSETTE CHROMOSOME MEC; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; RECOMBINASE; EVOLUTION; TRANSCRIPTION; INITIATION; PROTEINS; SEQUENCE; INSIGHTS AB Using sequence profile methods and structural comparisons we characterize a previously unknown family of nucleic acid polymerases in a group of mobile elements from genomes of diverse bacteria, an algal plastid and certain DNA viruses, including the recently reported Sputnik virus. Using contextual information from domain architectures and gene-neighborhoods we present evidence that they are likely to possess both primase and DNA polymerase activity, comparable to the previously reported prim-pol proteins. These newly identified polymerases help in defining the minimal functional core of superfamily A DNA polymerases and related RNA polymerases. Thus, they provide a framework to understand the emergence of both DNA and RNA polymerization activity in this class of enzymes. They also provide evidence that enigmatic DNA viruses, such as Sputnik, might have emerged from mobile elements coding these polymerases. C1 [Iyer, Lakshminarayan M.; Abhiman, Saraswathi; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM lakshmin@ncbi.nlm.nih.gov; saraswaa@mail.nih.gov; aravind@ncbi.nlm.nih.gov FU intramural funds of the National Library of Medicine at the National Institutes of Health, USA FX Work by the authors is supported by the intramural funds of the National Library of Medicine at the National Institutes of Health, USA. NR 20 TC 12 Z9 12 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD OCT 4 PY 2008 VL 3 AR 39 DI 10.1186/1745-6150-3-39 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 372KP UT WOS:000260900800001 PM 18834537 ER PT J AU Jakupciak, JP Maragh, S Markowitz, ME Greenberg, AK Hoque, MO Maitra, A Barker, PE Wagner, PD Rom, WN Srivastava, S Sidransky, D O'Connell, CD AF Jakupciak, John P. Maragh, Samantha Markowitz, Maura E. Greenberg, Alissa K. Hoque, Mohammad O. Maitra, Anirban Barker, Peter E. Wagner, Paul D. Rom, William N. Srivastava, Sudhir Sidransky, David O'Connell, Catherine D. TI Performance of mitochondrial DNA mutations detecting early stage cancer SO BMC CANCER LA English DT Article ID NIPPLE ASPIRATE FLUID; PROSTATE-CANCER; HEPATOCELLULAR-CARCINOMA; MONONUCLEOTIDE REPEAT; PRIMARY TUMORS; BREAST-CANCER; GENOME; MTDNA; REARRANGEMENTS; MARKERS AB Background: Mutations in the mitochondrial genome (mtgenome) have been associated with cancer and many other disorders. These mutations can be point mutations or deletions, or admixtures (heteroplasmy). The detection of mtDNA mutations in body fluids using resequencing microarrays, which are more sensitive than other sequencing methods, could provide a strategy to measure mutation loads in remote anatomical sites. Methods: We determined the mtDNA mutation load in the entire mitochondrial genome of 26 individuals with different early stage cancers (lung, bladder, kidney) and 12 heavy smokers without cancer. MtDNA was sequenced from three matched specimens (blood, tumor and body fluid) from each cancer patient and two matched specimens (blood and sputum) from smokers without cancer. The inherited wildtype sequence in the blood was compared to the sequences present in the tumor and body fluid, detected using the Affymetrix Genechip (R) Human Mitochondrial Resequencing Array 1.0 and supplemented by capillary sequencing for noncoding region. Results: Using this high-throughput method, 75% of the tumors were found to contain mtDNA mutations, higher than in our previous studies, and 36% of the body fluids from these cancer patients contained mtDNA mutations. Most of the mutations detected were heteroplasmic. A statistically significantly higher heteroplasmy rate occurred in tumor specimens when compared to both body fluid of cancer patients and sputum of controls, and in patient blood compared to blood of controls. Only 2 of the 12 sputum specimens from heavy smokers without cancer (17%) contained mtDNA mutations. Although patient mutations were spread throughout the mtDNA genome in the lung, bladder and kidney series, a statistically significant elevation of tRNA and ND complex mutations was detected in tumors. Conclusion: Our findings indicate comprehensive mtDNA resequencing can be a high-throughput tool for detecting mutations in clinical samples with potential applications for cancer detection, but it is unclear the biological relevance of these detected mitochondrial mutations. Whether the detection of tumor-specific mtDNA mutations in body fluidsy this method will be useful for diagnosis and monitoring applications requires further investigation. C1 [Jakupciak, John P.; Maragh, Samantha; Barker, Peter E.] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Markowitz, Maura E.] Geocenters Inc, Newton, MA USA. [Hoque, Mohammad O.; Maitra, Anirban; Sidransky, David] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Wagner, Paul D.; Srivastava, Sudhir] NCI, Canc Biomarkers Res Grp, Rockville, MD USA. [Greenberg, Alissa K.; Rom, William N.] NYU, Sch Med, Div Pulm & Crit Care Med, New York, NY USA. [O'Connell, Catherine D.] Tetracore Inc, Rockville, MD USA. RP Maragh, S (reprint author), NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. EM johnjakupciak@verizon.net; samantha.maragh@nist.gov; mauraeve@yahoo.com; alissa.greenberg@med.nyu.edu; mhoque1@jhmi.edu; amaitra1@jhmi.edu; peter.barker@nist.gov; wagnerp@mail.nih.gov; william.rom@med.nyu.edu; srivasts@mail.nih.gov; dsidrans@jhmi.edu; coconnell@tetracore.com FU NCI-EDRN [Y1CN2020, Y1CN5001-01, UO1 CA86137] FX This study was funded by the NCI-EDRN interagency agreements Y1CN2020, Y1CN5001-01 and UO1 CA86137. This study was a collaborative effort between the National Institute of Standards and Technology (NIST) and the National Cancer Institute's Early Detection Research Network (EDRN). NR 60 TC 36 Z9 37 U1 3 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 3 PY 2008 VL 8 AR 285 DI 10.1186/1471-2407-8-285 PG 11 WC Oncology SC Oncology GA 368OC UT WOS:000260630500003 PM 18834532 ER PT J AU Takizawa, T Meaburn, KJ Misteli, T AF Takizawa, Takumi Meaburn, Karen J. Misteli, Tom TI The meaning of gene positioning SO CELL LA English DT Article ID NUCLEAR LAMINA; TRANSCRIPTIONAL REGULATION; DROSOPHILA-MELANOGASTER; CHROMOSOME TERRITORIES; SPATIAL-ORGANIZATION; GENOME FUNCTION; LOCUS; REORGANIZATION; EXPRESSION; LOCALIZATION AB There is no doubt that genomes are organized nonrandomly in the nucleus of higher eukaryotes. But what is the functional relevance of this nonrandomness? In this Essay, we explore the biological meaning of spatial gene positioning by examining the functional link between the activity of a gene and its radial position in the nucleus. C1 [Takizawa, Takumi; Meaburn, Karen J.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Meaburn, Karen/0000-0002-1327-5957 FU Intramural NIH HHS [Z01 BC010309-09] NR 38 TC 122 Z9 125 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 3 PY 2008 VL 135 IS 1 BP 9 EP 13 DI 10.1016/j.cell.2008.09.026 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 355SH UT WOS:000259728100001 PM 18854147 ER PT J AU dos Santos, CO Dore, LC Valentine, E Shelat, SG Hardison, RC Ghosh, M Wang, W Eisenstein, RS Costa, FF Weiss, MJ AF dos Santos, Camila O. Dore, Louis C. Valentine, Eric Shelat, Suresh G. Hardison, Ross C. Ghosh, Manik Wang, Wei Eisenstein, Richard S. Costa, Fernando F. Weiss, Mitchell J. TI An iron responsive element-like stem-loop regulates alpha-hemoglobin-stabilizing protein mRNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LOCUS-CONTROL REGION; BINDING-PROTEIN; BETA-THALASSEMIA; HIGH-AFFINITY; HAIRPIN LOOP; ERYTHROID-DIFFERENTIATION; TRANSLATIONAL REGULATION; 5'-UNTRANSLATED REGION; 3'-UNTRANSLATED REGION; DEPENDENT REGULATION AB Hemoglobin production during erythropoiesis is mechanistically coupled to the acquisition and metabolism of iron. We discovered that iron regulates the expression of alpha-hemoglobin-stabilizing protein (AHSP), a molecular chaperone that binds and stabilizes free alpha-globin during hemoglobin synthesis. In primates, the 3 '-untranslated region (UTR) of AHSP mRNA contains a nucleotide sequence resembling iron responsive elements (IREs), stem-loop structures that regulate gene expression post-transcriptionally by binding iron regulatory proteins (IRPs). The AHSP IRE-like stem-loop deviates from classical consensus sequences and binds IRPs poorly in electrophoretic mobility shift assays. However, in cytoplasmic extracts, AHSP mRNA co-immunoprecipitates with IRPs in a fashion that is dependent on the stem-loop structure and inhibited by iron. Moreover, this interaction enhances AHSP mRNA stability in erythroid and heterologous cells. Our findings demonstrate that IRPs can regulate mRNA expression through non-canonical IREs and extend the repertoire of known iron-regulated genes. In addition, we illustrate a new mechanism through which hemoglobin may be modulated according to iron status. C1 [dos Santos, Camila O.; Dore, Louis C.; Valentine, Eric; Weiss, Mitchell J.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Shelat, Suresh G.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hardison, Ross C.] Penn State Univ, Dept Biochem & Mol Biol, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. [Ghosh, Manik] NICHD, NIH, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. [Wang, Wei] Wake Forest Univ Hlth Sci, Dept Biochem, Winston Salem, NC 27157 USA. [Eisenstein, Richard S.] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. [Costa, Fernando F.] Univ Estadual Campinas, Ctr Hemotherapy & Hematol, Sao Paulo, Brazil. RP Weiss, MJ (reprint author), Childrens Hosp Philadelphia, Div Hematol, 3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM weissmi@email.chop.edu RI Hardison, Ross/G-1142-2010; Costa, Fernando/D-1566-2012; Weiss, Mitchell/A-1245-2013; Sangue, Inct/I-1919-2013; Dore, Louis/A-5689-2009 OI Hardison, Ross/0000-0003-4084-7516; Dore, Louis/0000-0002-7837-5887 FU National Institutes of Health [R01 DK61692, R01 HL087427, R01 DK65806, R01 DK66600]; American Heart Association Postdoctoral Fellowship Award [4247620608]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [02/13801-7] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 DK61692 and R01 HL087427 (to M.J.W.), R01 DK65806 (to R. C. H.), and R01 DK66600 (to R. S. E.). This work was also supported by an American Heart Association Postdoctoral Fellowship Award (Grant 4247620608) (to C.O.S.), by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (Grant 02/13801-7) (to F. F. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 69 TC 28 Z9 28 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 3 PY 2008 VL 283 IS 40 BP 26956 EP 26964 DI 10.1074/jbc.M802421200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 353RT UT WOS:000259586600016 PM 18676996 ER PT J AU Saad, JS Ablan, SD Ghanam, RH Kim, A Andrews, K Nagashima, K Soheilian, F Freed, EO Summers, MF AF Saad, Jamil S. Ablan, Sherimay D. Ghanam, Ruba H. Kim, Andrew Andrews, Kalola Nagashima, Kunio Soheilian, Ferri Freed, Eric O. Summers, Michael F. TI Structure of the myristylated human immunodeficiency virus type 2 matrix protein and the role of phosphatidylinositol-(4,5)-bisphosphate in membrane targeting SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; HIV-2; Gag; myristyl; myr; matrix; MA; phosphatidylinositol-45-bisphosphate; PI(4,5)P-2 ID TERM AVIREMIC INDIVIDUALS; HIV-1 GAG PROTEINS; PLASMA-MEMBRANE; MYRISTOYL SWITCH; WEST-AFRICA; FYVE DOMAIN; LIFE-CYCLE; BINDING; MECHANISM; PRECURSOR AB During the late phase of retroviral replication, newly synthesized Gag proteins are targeted to the plasma membrane (PM), where they assemble and bud to form immature virus particles. Membrane targeting by human immunodeficiency viurs type 1 (HIV-1) Gag is mediated by the PM marker molecule phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P-2], which is capable of binding to the matrix (MA) domain of Gag in an extended lipid conformation and of triggering myristate exposure. Here, we show that, as observed previously for HIV-1 MA, the myristyl group of HIV-2 MA is partially sequestered within a narrow hydrophobic tunnel formed by side chains of helices 1, 2, 3, and 5. However, the myristate of HIV-2 MA is more tightly sequestered than that of the HIV-1 protein and does not exhibit concentration-dependent exposure. Soluble PI(4,5)P-2 analogs containing truncated acyl chains bind HIV-2 MA and induce minor long-range structural changes but do not trigger myristate exposure. Despite these differences, the site of HIV-2 assembly in vivo can be manipulated by enzymes that regulate PI(4,5)P-2 localization. Our findings indicate that HIV-1 and HIV-2 are both targeted to the PM for assembly via a PI(4,5)P-2-dependent mechanism, despite differences in the sensitivity of the MA myristyl switch, and suggest a potential mechanism that may contribute to the poor replication kinetics of HIV-2. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Saad, Jamil S.; Ghanam, Ruba H.; Kim, Andrew; Andrews, Kalola; Summers, Michael F.] Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. [Saad, Jamil S.; Ghanam, Ruba H.; Kim, Andrew; Andrews, Kalola; Summers, Michael F.] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Nagashima, Kunio; Soheilian, Ferri] NCI, Image Anal Lab, Adv Technol Program, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM efreed@mail.nih.gov; summers@hhmi.umbc.edu FU NIH [A130917]; Intramural Research Program of the Center for Cancer Research; National Cancer Institute, NIH [N0-1-CO-12400]; Intramural AIDS Targeted Antiviral Program FX This work was supported by the NIH through grant A130917 (M.F.S.); the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH (E.O.F.), the Intramural AIDS Targeted Antiviral Program (E.O.F.); and federal funds from the National Cancer Institute, NIH, under contract N0-1-CO-12400 (K.N.). We thank Rob Edwards and Chen Yu (University of Maryland Baltimore County Howard Hughes Medical Institute staff), Dr. Dorothy Beckett (University of Maryland, College Park, MD), and David King (University of California, Berkeley, Howard Hughes Medical Institute, Berkley, CA) for technical support; Dr. Bechet, A. M. L. Lever, and the Centralized Facility, for AIDS Reagents (UK) for providing the HIV-2 cDNA (pROD10) plasmid, J. Donaldson and P. Majerus for providing Arf6/Q67L and 5ptaseIV expression vectors, respectively; J. Kappes for the anti-p27gag monoclonal antibody R1C7; and the AIDS Research and Reference Reagent Program for HIV-1g. NR 71 TC 62 Z9 63 U1 0 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 3 PY 2008 VL 382 IS 2 BP 434 EP 447 DI 10.1016/j.jmb.2008.07.027 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354RS UT WOS:000259657300014 PM 18657545 ER PT J AU Stricher, F Huang, CC Descours, A Duquesnoy, S Combes, O Decker, JM Do Kwon, Y Lusso, P Shaw, GM Vita, C Kwong, PD Martin, L AF Stricher, Francois Huang, Chih-Chin Descours, Anne Duquesnoy, Sophie Combes, Olivier Decker, Julie M. Do Kwon, Young Lusso, Paolo Shaw, George M. Vita, Claudio Kwong, Peter D. Martin, Loic TI Combinatorial optimization of a CD4-mimetic miniprotein and cocrystal structures with HIV-1 gp120 envelope glycoprotein SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; neutralization; induced CCR5 affinity; macromolecular interface transplantation; molecular mimicry; scorpion-toxin scaffold ID PROTEIN-PROTEIN INTERACTIONS; IMMUNODEFICIENCY-VIRUS GP120; PHASE PEPTIDE-SYNTHESIS; DRUG DISCOVERY; BINDING-SITE; CD4; RECEPTOR; EXPRESSION; LIBRARIES; ENTRY AB Miniproteins provide a bridge between proteins and small molecules. Here we adapt methods from combinatorial chemistry to optimize CD4M33, a synthetic miniprotein into which we had previously transplanted the HIV-1 gp120 binding surface of the CD4 receptor. Iterative deconvolution of generated libraries produced CD4M47, a derivative of CD4M33 that had been optimized at four positions. Surface plasmon resonance demonstrated fourfold to sixfold improvement in CD4M47 affinity for gp120 to a level about threefold tighter than that of CD4 itself. Assessment of the neutralization properties of CD4M47 againsta diverse range of isolates spanning from HIV-1 to SIVcpz showed that CD4M47 retained the extraordinary breadth of the parent CD4M33, but yielded only limited improvements in neutralization potencies. Crystal structures of CD4M47 and a phenylalanine variant ([Phe23]M47) were dertermined at resolutions of 2.4 and 2.6 angstrom, in ternary complexes with HIV-1 gp120 and the 17b antibody. Analysis of these structures revealed a correlation between mimetic affinity for gp120 and overall mimetic-gp120 interactive surface. A correlation was also observed between CD4- and mimetic-induced gp120 structural similarity and CD4- and mimetic-induced gp120 affinity for the CCR5 coreceptor. Despite mimetic substitutions, including a glycine-to-(D)-proline change, the gp120 conformation induced by CD4M47 was an close or closer to the conformation induced by CD4 as the one induced by the parent CD4M33. Our results demonstrate the ability of combinatorial chemistry to optimize a disulfide-containing miniprotein, and of structural biology to decipher the resultant interplay between binding affinity, neutralization breadth, molecular mimicry, and induced affinity for CCR5. Published by Elsevier Ltd. C1 [Huang, Chih-Chin; Do Kwon, Young; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Stricher, Francois; Descours, Anne; Duquesnoy, Sophie; Combes, Olivier; Vita, Claudio; Martin, Loic] SIMOPRO, iBiTecS, CEA, F-91191 Gif Sur Yvette, France. [Decker, Julie M.; Shaw, George M.] Univ Alabama, Howard Hughes Med Inst, Dept Med, Dept Microbiol, Birmingham, AL 35294 USA. [Lusso, Paolo] Ist Sci San Raffaele, Unit Human Virol, I-20132 Milan, Italy. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov; loic.martin@cea.fr RI Kwon, Young Do/A-6957-2010 FU European Union program EVA/MRC [QLKZ-CT-1999-00609]; UK Medical Research Council; US Department of Energy, Basic Energy Science, Office of Science [W-31-109-Eng-38] FX We thank Lawrence Shapiro for comments on the Manuscript, Francesca Sironi for assistance with neutralization assays, Indresh Srivastava (Chiron Vaccine Co.) for gp120, and Jonathan Stuckey for assistance with figures. Support was provided by the European Microbicides Project the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health, and a grant from the Bill and Melinda Gates Foundation Grand Challenges in Global Health Initiative. We acknowledge Becton Dickinson and the Center for AIDS Reagents supported by European Union program EVA/MRC (contract no. QLKZ-CT-1999-00609) and the UK Medical Research Council. Use of SER-CAT at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Science, Office of Science, under contract no. W-31-109-Eng-38. NR 62 TC 37 Z9 38 U1 2 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 3 PY 2008 VL 382 IS 2 BP 510 EP 524 DI 10.1016/j.jmb.2008.06.069 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354RS UT WOS:000259657300020 PM 18619974 ER PT J AU Zerhouni, EA Nabel, EG AF Zerhouni, Elias A. Nabel, Elizabeth G. TI Protecting aggregate genomic data SO SCIENCE LA English DT Letter C1 [Zerhouni, Elias A.] NIH, Bethesda, MD 20892 USA. [Nabel, Elizabeth G.] NIH, Sr Oversight Committee, Bethesda, MD 20892 USA. [Nabel, Elizabeth G.] NHLBI, Bethesda, MD 20892 USA. RP Zerhouni, EA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 31 Z9 31 U1 1 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 3 PY 2008 VL 322 IS 5898 BP 44 EP 44 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 355AE UT WOS:000259680200018 PM 18772394 ER PT J AU Zarin, DA Tse, T AF Zarin, Deborah A. Tse, Tony TI Closing a loophole in the FDA Amendments Act SO SCIENCE LA English DT Letter C1 [Zarin, Deborah A.; Tse, Tony] NIH, Natl Lib Med, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Tse, T (reprint author), NIH, Natl Lib Med, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. EM atse@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 3 PY 2008 VL 322 IS 5898 BP 45 EP 46 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 355AE UT WOS:000259680200024 ER PT J AU Rogers, CJ Zaharoff, DA Hance, KW Perkins, SN Hursting, SD Schlom, J Greiner, JW AF Rogers, Connie J. Zaharoff, David A. Hance, Kenneth W. Perkins, Susan N. Hursting, Stephen D. Schlom, Jeffrey Greiner, John W. TI Exercise enhances vaccine-induced antigen-specific T cell responses SO VACCINE LA English DT Article DE adaptive immunity; cytokines; cell proliferation ID IN-HOUSE MICE; RESPIRATORY-TRACT INFECTIONS; SALIVARY IMMUNOGLOBULIN-A; PHYSICAL-ACTIVITY; MODERATE EXERCISE; VOLUNTARY EXERCISE; STRENUOUS EXERCISE; ANTIBODY-RESPONSE; IMMUNE FUNCTION; OXYGEN-CONSUMPTION AB Regular moderate exercise has been proposed to enhance immune function, but its effects on immunity and their consequences have not been well studied. Mice without(AL) or with access (AL+ EX) to voluntary running wheels were vaccinated with a model antigen (ovalbumin (OVA)) via intranasal or subcutaneous routes to target the mucosal and systemic immune compartments, respectively. EX enhanced OVA-specific CD4(+) T cell cytokine production and proliferation in all lymphoid organs examined without changes in cell distribution in any organ. These results suggest that coupling moderate exercise with vaccination may enhance vaccine efficacy for the prevention and/or therapy of numerous diseases. Published by Elsevier Ltd. C1 [Greiner, John W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Rogers, Connie J.; Hance, Kenneth W.] NCI, Canc Prevent Div, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Perkins, Susan N.; Hursting, Stephen D.] Univ Texas Austin, Dept Human Ecol, Div Nutr Sci, Austin, TX 78712 USA. [Hursting, Stephen D.] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX 78712 USA. RP Greiner, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, Natl Inst Hlth, 10 Ctr Dr,Bldg 10,Room 8B04,MSC 1750, Bethesda, MD 20892 USA. EM greinerj@mail.nih.gov OI Zaharoff, David/0000-0001-6885-6727 FU Intramural NIH HHS [ZIA BC010967-02]; NIEHS NIH HHS [P30 ES 007784, P30 ES007784] NR 57 TC 13 Z9 14 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 3 PY 2008 VL 26 IS 42 BP 5407 EP 5415 DI 10.1016/j.vaccine.2008.07.081 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 358SA UT WOS:000259936600013 PM 18706954 ER PT J AU Lee, H Larson, RG AF Lee, Hwankyu Larson, Ronald G. TI Lipid bilayer curvature and pore formation induced by charged linear polymers and dendrimers: The effect of molecular shape SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID NONVIRAL GENE DELIVERY; COARSE-GRAINED MODEL; POLY(AMIDOAMINE) DENDRIMERS; POLYCATIONIC POLYMERS; STARBURST DENDRIMERS; HOLE FORMATION; FORCE-FIELD; NANOPARTICLES; DYNAMICS; CELLS AB We performed molecular dynamics (MD) simulations of multiple copies of poly-L-lysine (PLL) and charged polyamidoamine (PAMAM) dendrimers in dimyristoylphosphatidylcholine (DMPC) bilayers with explicit water using the coarse-grained model developed by Marrink et al. (J. Chem. Theory Comput. 2008, 4, 819). Membrane disruption is enhanced at higher concentrations and charge densities of both spheroidally shaped dendrimers and linear PLL polymers, in qualitatively agreement with experimental studies by Hong et al. (Bioconjugate Chem. 2006, 17, 728). However, larger molecular size enhances membrane disruption and pore formation only for dendrimers and not for the linear PLL. Despite more intimate electrostatic interactions of linear molecules than are possible for spheroidal dendrimers, only the dendrimers were found to perforate membranes, apparently because they cannot spread onto a single leaflet, and so must penetrate the bilayer to get favorable electrostatic interactions with head groups on the opposite leaflet. These results indicate that a relatively rigid spheroidal shape is more efficient than a flexible linear shape in increasing membrane permeability. These results compare favorably with experimental findings. C1 [Lee, Hwankyu] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Larson, Ronald G.] Univ Michigan, Dept Chem Engn Biomed Engn Mech Engn & Macromol S, Ann Arbor, MI 48109 USA. [Larson, Ronald G.] Univ Michigan, Engn Prgrom, Ann Arbor, MI 48109 USA. RP Lee, H (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM leeh3@nhlbi.nih.gov FU Intramural NIH HHS [NIH0013263008]; PHS HHS [NIH0013263008] NR 38 TC 72 Z9 72 U1 3 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 2 PY 2008 VL 112 IS 39 BP 12279 EP 12285 DI 10.1021/jp805026m PG 7 WC Chemistry, Physical SC Chemistry GA 353FR UT WOS:000259552000016 PM 18767788 ER PT J AU Tang, C Louis, JM Aniana, A Suh, JY Clore, GM AF Tang, Chun Louis, John M. Aniana, Annie Suh, Jeong-Yong Clore, G. Marius TI Visualizing transient events in amino-terminal autoprocessing of HIV-1 protease SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PARAMAGNETIC RELAXATION ENHANCEMENT; CHEMICAL-SHIFT DATA; NMR STRUCTURES; PRECURSOR; BINDING; KINETICS; ASSOCIATION; MECHANISM; PROTEINS AB HIV- 1 protease processes the Gag and Gag- Pol polyproteins into mature structural and functional proteins, including itself, and is therefore indispensable for viral maturation(1,2). The mature protease is active only as a dimer(3-5) with each subunit contributing catalytic residues(6). The full- length transframe region protease precursor appears to be monomeric yet undergoes maturation via intramolecular cleavage of a putative precursor dimer(5,7-11), concomitant with the appearance of mature- like catalytic activity(7,9). How such intramolecular cleavage can occur when the amino and carboxy termini of the mature protease are part of an intersubunit beta-sheet located distal from the active site is unclear. Here we visualize the early events in N- terminal autoprocessing using an inactive mini- precursor with a four- residue N- terminal extension that mimics the transframe region protease precursor(5,12). Using paramagnetic relaxation enhancement, a technique that is exquisitely sensitive to the presence of minor species(13-16), we show that the mini- precursor forms highly transient, lowly populated (3-5%) dimeric encounter complexes that involve the mature dimer interface but occupy a wide range of subunit orientations relative to the mature dimer. Furthermore, the occupancy of the mature dimer configuration constitutes a very small fraction of the self- associated species ( accounting for the very low enzymatic activity of the protease precursor), and the N- terminal extension makes transient intra- and intersubunit contacts with the substrate binding site and is therefore available for autocleavage when the correct dimer orientation is sampled within the encounter complex ensemble. C1 [Tang, Chun; Louis, John M.; Aniana, Annie; Suh, Jeong-Yong; Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the NIH; NIDDK; AIDS Targeted Antiviral program FX We thank R. Ishima for providing initial backbone assignments for the SFNFPR(D25N) protease construct; C. Schwieters for many discussions; Y. Sheng for help with the CS-Rosetta calculations; Y. Kim for providing the code for structure clustering and d.r.m.s. calculations; and J. Sayer for MALDI measurements. This work was supported by funds from the Intramural Program of the NIH, NIDDK and the AIDS Targeted Antiviral program of the Office of the Director of the NIH (to G.M.C.). NR 40 TC 78 Z9 80 U1 3 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 2 PY 2008 VL 455 IS 7213 BP 693 EP U92 DI 10.1038/nature07342 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 354KY UT WOS:000259639700053 PM 18833280 ER PT J AU Schutz, B Von Engelhardt, J Gordes, M Schafer, MKH Eiden, LE Monyer, H Weihe, E AF Schuetz, B. Von Engelhardt, J. Goerdes, M. Schaefer, M. K.-H. Eiden, L. E. Monyer, H. Weihe, E. TI Sweat gland innervation is pioneered by sympathetic neurons expressing a cholinergic/noradrenergic co-phenotype in the mouse SO NEUROSCIENCE LA English DT Article DE acetylcholine; development; transgene; vesicular transporter ID VESICULAR ACETYLCHOLINE TRANSPORTER; CHOLINERGIC GENE LOCUS; NERVOUS-SYSTEM; NEUROTRANSMITTER PHENOTYPE; TRANSGENIC MICE; CHEMICAL NEUROANATOMY; STELLATE GANGLION; GDNF FAMILY; IN-VIVO; DIFFERENTIATION AB Classic neurotransmitter phenotypes are generally predetermined and develop as a consequence of target-independent lineage decisions. A unique mode of target-dependent phenotype instruction is the acquisition of the cholinergic phenotype in the peripheral sympathetic nervous system. A body of work suggests that the sweat gland plays an important role to determine the cholinergic phenotype at this target site. A key issue is whether neurons destined to innervate the sweat glands express cholinergic markers before or only after their terminals make target contact. We employed cholinergic-specific over-expression of the vesicular acetylcholine transporter (VAChT) in transgenic mice to overcome sensitivity limits in the detection of initial cholinergic sweat gland innervation. We found that VAChT immunoreactive nerve terminals were present around the sweat gland anlage already from the earliest postnatal stages on, coincident selectively at this sympathetic target with tyrosine hydroxylase-positive fibers. Our results provide a new mechanistic model for sympathetic neuron-target interaction during development, with initial selection by the target of pioneering nerve terminals expressing a cholinergic phenotype, and subsequent stabilization of this phenotype during development. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Schuetz, B.; Goerdes, M.; Schaefer, M. K.-H.; Weihe, E.] Univ Marburg, Dept Mol Neurosci, Inst Anat & Cell Biol, D-35032 Marburg, Germany. [Von Engelhardt, J.; Monyer, H.] Univ Heidelberg, Dept Clin Neurobiol, D-69120 Heidelberg, Germany. [Eiden, L. E.] NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD USA. RP Weihe, E (reprint author), Univ Marburg, Dept Mol Neurosci, Inst Anat & Cell Biol, Robert Koch Str 8, D-35032 Marburg, Germany. EM weihe@staff.uni-marburg.de RI von Engelhardt, Jakob/G-7397-2015; OI von Engelhardt, Jakob/0000-0003-3861-3294; Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [Z01 MH002386-21] NR 38 TC 18 Z9 18 U1 3 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 2 PY 2008 VL 156 IS 2 BP 310 EP 318 DI 10.1016/j.neuroscience.2008.06.074 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 358TD UT WOS:000259939500008 PM 18722510 ER PT J AU Grandjean, P Heindel, JJ AF Grandjean, Philippe Heindel, Jerrold J. TI In utero and early-life conditions and adult health and disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Grandjean, Philippe] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Heindel, Jerrold J.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Grandjean, P (reprint author), Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. EM pgrand@hsph.harvard.edu OI Grandjean, Philippe/0000-0003-4046-9658 NR 2 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 2 PY 2008 VL 359 IS 14 BP 1523 EP 1523 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 354ID UT WOS:000259631700023 PM 18832254 ER PT J AU Reddy, NM Kleeberger, SR Bream, JH Fallon, PG Kensler, TW Yamamoto, M Reddy, SP AF Reddy, N. M. Kleeberger, S. R. Bream, J. H. Fallon, P. G. Kensler, T. W. Yamamoto, M. Reddy, S. P. TI Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling SO ONCOGENE LA English DT Article DE oxidative stress; Nrf2; cell cycle; G(2)/M-checkpoint; Akt ID ANTIOXIDANT RESPONSE ELEMENT; ALVEOLAR EPITHELIAL-CELLS; DNA-DAMAGE; S-GLUTATHIONYLATION; OXIDATIVE STRESS; DEPENDENT PHOSPHORYLATION; BINDING DOMAIN; DIESEL EXHAUST; 14-3-3 PROTEIN; MICE LACKING AB Genetic disruption of Nrf2 greatly enhances susceptibility to prooxidant- and carcinogen-induced experimental models of various human disorders; but the mechanisms by which this transcription factor confers protection are unclear. Using Nrf2-proficient (Nrf2(+/+)) and Nrf2-deficient (Nrf2(-/-)) primary epithelial cultures as a model, we now show that Nrf2 deficiency leads to oxidative stress and DNA lesions, accompanied by impairment of cell-cycle progression, mainly G(2)/M-phase arrest. Both N-acetylcysteine and glutathione (GSH) supplementation ablated the DNA lesions and DNA damage-response pathways in Nrf2(-/-) cells; however only GSH could rescue the impaired colocalization of mitosis-promoting factors and the growth arrest. Akt activation was deregulated in Nrf2(-/-) cells, but GSH supplementation restored it. Inhibition of Akt signaling greatly diminished the GSH-induced Nrf2(-/-) cell proliferation and wild-type cell proliferation. GSH depletion impaired Akt signaling and mitosis-promoting factor colocalization in Nrf2(+/+) cells. Collectively, our findings uncover novel functions for Nrf2 in regulating oxidative stress-induced cell-cycle arrest, especially G(2)/M-checkpoint arrest, and proliferation, and GSH-regulated redox signaling and Akt are required for this process. C1 [Reddy, N. M.; Kensler, T. W.; Reddy, S. P.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Kleeberger, S. R.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. [Bream, J. H.; Fallon, P. G.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Yamamoto, M.] Tohoku Univ, Grad Sch Med, Dept Med Biochem, Sendai, Miyagi 980, Japan. RP Reddy, SP (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Room E7610,615 N Wolfe St, Baltimore, MD 21205 USA. EM sreddy@jhsph.edu RI Yamamoto, Masayuki/A-4873-2010; Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NIH [HL66109, ES11863]; SCCOR [P50 HL073994]; NIEHS [P30 ES 038819] FX This work was supported by NIH grants HL66109, ES11863 and SCCOR P50 HL073994 (to SPR), and NIEHS center grant P30 ES 038819. We acknowledge the help provided for FACS analysis by Becton Dickinson Immune Function Laboratory, Johns Hopkins Bloomberg School of Public Health. NR 71 TC 66 Z9 67 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 2 PY 2008 VL 27 IS 44 BP 5821 EP 5832 DI 10.1038/onc.2008.188 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 355QC UT WOS:000259722400006 PM 18542053 ER PT J AU Wendeler, M Lee, HF Bermingham, A Miller, JT Chertov, O Bona, MK Baichoo, NS Ehteshami, M Beutler, J O'Keefe, BR Gotte, M Kvaratskhelia, M Le Grice, S AF Wendeler, Michaela Lee, Hsiu-Fang Bermingham, Alun Miller, Jennifer T. Chertov, Oleg Bona, Marion K. Baichoo, Noel S. Ehteshami, Maryam Beutler, John O'Keefe, Barry R. Gotte, Matthias Kvaratskhelia, Mamuka Le Grice, Stuart TI Vinylogous Ureas as a Novel Class of Inhibitors of Reverse Transcriptase-Associated Ribonuclease H Activity SO ACS CHEMICAL BIOLOGY LA English DT Article ID UNNATURAL AMINO-ACIDS; HIV RNASE-H; MASS-SPECTROMETRY; CRYSTAL-STRUCTURE; GENETIC-CODE; BINDING-SITE; PRIMER GRIP; COMPLEX; POLYMERASE; MUTATIONS AB High-throughput screening of National Cancer Institute libraries of synthetic and natural compounds identified the vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (NSC727447) and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (NSC727448) as inhibitors of the ribonuclease H (RNase H) activity of HIV-1 and HIV-2 reverse transcriptase (RT). A Yonetani - Theorell analysis demonstrated that NSC727447, and the active-site hydroxytropolone RNase H inhibitor beta-thujaplicinol were mutually exclusive in their interaction with the RNase H domain. Mass spectrometric protein footprinting of the NSC727447 binding site indicated that residues Cys280 and Lys281 in helix I of the thumb subdomain of p51 were affected by ligand binding. Although DNA polymerase and pyrophosphorolysis activities of HIV-1 RT were less sensitive to inhibition by NSC727447, protein footprinting indicated that NSC727447 occupied the equivalent region of the p66 thumb. Site-directed mutagenesis using reconstituted p66/p51 heterodimers; substituted with natural or non-natural amino acids indicates that altering the p66 RNase H primer grip significantly affects inhibitor sensitivity. NSC727447 thus represents a novel class of RNase H antagonists with a mechanism of action differing from active site, divalent metal-chelating inhibitors that have been reported. C1 [Wendeler, Michaela; Miller, Jennifer T.; Baichoo, Noel S.; Le Grice, Stuart] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Lee, Hsiu-Fang; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Retrovirus Res, Coll Pharm, Columbus, OH 43210 USA. [Lee, Hsiu-Fang; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Bermingham, Alun; Beutler, John; O'Keefe, Barry R.] NCI, Mol Targets Dev Program, Frederick, MD 21701 USA. [Chertov, Oleg; Bona, Marion K.] SAIC Frederick, Prot Chem Lab, Adv Technol Program, Frederick, MD USA. [Ehteshami, Maryam; Gotte, Matthias] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Bona, Marion K.] SAIC Frederick, Basic Res Program, Frederick, MD USA. RP Le Grice, S (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM slegrice@ncifcrf.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU National Cancer Institute; National Institutes of Health; Canadian Foundation; NIH [AI062520, N01-CO-12400] FX S. Le G. is supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, M.G. by a grant from the Canadian Foundation for AIDS Research, and M.K. by NIH Grant AI062520. We thank A. Waminu for technical assistance. This project was supported in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. 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 34 TC 40 Z9 42 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD OCT PY 2008 VL 3 IS 10 BP 635 EP 644 DI 10.1021/cb8001039 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362JD UT WOS:000260193100007 PM 18831589 ER PT J AU Prabakaran, P Vu, BK Gan, JH Feng, Y Dimitrov, DS Ji, XH AF Prabakaran, Ponraj Vu, Bang K. Gan, Jianhua Feng, Yang Dimitrov, Dimiter S. Ji, Xinhua TI Structure of an isolated unglycosylated antibody C(H)2 domain SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID INTACT MONOCLONAL-ANTIBODY; CRYSTAL-STRUCTURE; HUMAN-IGG; CANINE LYMPHOMA; FC-RECEPTOR; CH2 DOMAIN; COMPLEX; FRAGMENT; BINDING; MECHANISM AB The C(H)2 (C(H)3 for IgM and IgE) domain of an antibody plays an important role in mediating effector functions and preserving antibody stability. It is the only domain in human immunoglobulins (Igs) which is involved in weak interchain protein-protein interactions with another C(H)2 domain solely through sugar moieties. The N-linked glycosylation at Asn297 is conserved in mammalian IgGs as well as in homologous regions of other antibody isotypes. To examine the structural details of the C(H)2 domain in the absence of glycosylation and other antibody domains, the crystal structure of an isolated unglycosylated antibody gamma 1 C(H)2 domain was determined at 1.7 angstrom resolution and compared with corresponding C(H)2 structures from intact Fc, IgG and Fc receptor complexes. Furthermore, the oligomeric state of the protein in solution was studied using size-exclusion chromatography. The results suggested that the unglycosylated human antibody C(H)2 domain is a monomer and that its structure is similar to that found in the intact Fc, IgG and Fc receptor complex structures. However, certain structural variations were observed in the Fc receptor-binding sites. Owing to its small size, stability and non-immunogenic Ig template, the C(H)2-domain structure could be useful for the development by protein design of antibody domains exerting effector functions and/or antigen specificity and as a robust scaffold in protein-engineering applications. C1 [Prabakaran, Ponraj; Vu, Bang K.; Feng, Yang; Dimitrov, Dimiter S.] NCI, Protein Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. [Gan, Jianhua; Ji, Xinhua] NCI, Biomol Struct Sect, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI, Protein Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. EM dimitrov@ncifcrf.gov; jix@ncifcrf.gov RI Ji, Xinhua/C-9664-2012; Ponraj, Prabakaran/D-6325-2011 OI Ji, Xinhua/0000-0001-6942-1514; FU Intramural AIDS Targeted Antiviral Program (IATAP); National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research FX We thank the Advanced Biomedical Computing Center, NCI-Frederick for computing facilities. X-ray diffraction data were collected on the Southeast Regional Collaborative Access Team 22-ID beamline of the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. This work was supported by the Intramural AIDS Targeted Antiviral Program (IATAP), National Institutes of Health (NIH) to DSD and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 17 Z9 17 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD OCT PY 2008 VL 64 BP 1062 EP 1067 DI 10.1107/S0907444908025274 PN 10 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 355IK UT WOS:000259702400007 PM 18931413 ER PT J AU Wu, MX Wang, SG Yu, KF AF Wu, Mi Xia Wang, Song Gui Yu, Kai Fun TI Simultaneous Optimality of LSE and ANOVA Estimate in General Mixed Models SO ACTA MATHEMATICA SINICA-ENGLISH SERIES LA English DT Article DE Linear mixed model; Least squares estimate; Analysis of variance estimate; Minimum variance unbiased estimate; Uniformly most powerful unbiased test ID VARIANCE-COMPONENTS AB Problems of the simultaneous optimal estimates and the optimal tests in general mixed models are considered. A necessary and sufficient condition is presented for the least squares estimate of the fixed effects and the analysis of variance (Hendreson III's) estimate of variance components being uniformly minimum variance unbiased estimates simultaneously. This result can be applied to the problems of finding uniformly optimal unbiased tests and uniformly most accurate unbiased confidential interval on parameters of interest, and for finding equivalences of several common estimates of variance components. C1 [Wu, Mi Xia; Wang, Song Gui] Beijing Univ Technol, Coll Appl Sci, Beijing 100022, Peoples R China. [Wu, Mi Xia; Yu, Kai Fun] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. RP Wu, MX (reprint author), Beijing Univ Technol, Coll Appl Sci, Beijing 100022, Peoples R China. EM wumixia@bjut.edu.cn; wangsg@bjut.edu.cn; yukf@mail.nih.gov FU Academic Human Resources Development in Institutions of Higher Learning; National Natural Science Foundation of China (NSFC) [10801005]; NSFC [10771010]; National Institute of Child Health and Human Development; National Institute of Health FX The work is supported by Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality PHR (IHLB), National Natural Science Foundation of China (NSFC) (10801005) and (NSFC) (10771010) and the Intramural Research Program of the National Institute of Child Health and Human Development, National Institute of Health NR 20 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1439-8516 J9 ACTA MATH SIN JI Acta. Math. Sin.-English Ser. PD OCT PY 2008 VL 24 IS 10 BP 1637 EP 1650 DI 10.1007/s10114-008-6220-6 PG 14 WC Mathematics, Applied; Mathematics SC Mathematics GA 363ID UT WOS:000260260100005 ER PT J AU Bagic, A Theodore, WH Boudreau, EA Bonwetsch, R Greenfield, J Elkins, W Sato, S AF Bagic, A. Theodore, W. H. Boudreau, E. A. Bonwetsch, R. Greenfield, J. Elkins, W. Sato, S. TI Towards a non-invasive interictal application of hypothermia for treating seizures: a feasibility and pilot study SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE brain; core temperature; cortical excitability; epilepsy; non-invasive hypothermia; interictal cooling; seizures; treatment ID EXPERIMENTAL NEOCORTICAL SEIZURES; TEMPERATURE-MEASUREMENT; FOCAL SEIZURES; TECHNICAL NOTE; CRITICAL-CARE; EPILEPSY; BRAIN; PLACEBO; CORTEX; TERMINATION AB Objectives - To evaluate the feasibility and safety of head-neck cooling in conscious normal volunteers (10) and patients with medically refractory epilepsy (5) without causing shivering. Patients and methods - We used a non-invasive head-neck cooling system (CoolSystems Inc., Lincoln, CA, USA). The tympanic temperature (TT) and intestinal temperature (IT) were measured as two measurements of 'core temperature' (CT), and multi-site external temperatures, several physiologic variables and EEG were monitored. Seizure counts over 4-week precooling, treatment and follow-up phases were compared. Results - All 15 participants completed all the cooling sessions without significant complaints. At the end of 60 min of cooling, scalp temperature fell on average by 12.2 degrees C (P < 0.001), TT by 1.67 degrees C (P < 0.001), and IT by 0.12 degrees C (P = NS). Average weekly seizure frequency decreased from 2.7 to 1.7 events per patient per week (MANOVA: P < 0.05). Conclusions - Non-invasive head-neck cooling is safe and well-tolerated. Initial pilot data in patients suggest that additional therapeutic studies are warranted. C1 [Bagic, A.] Univ Pittsburgh, Sch Med, CABMSI, Pittsburgh, PA 15213 USA. [Bagic, A.; Bonwetsch, R.; Greenfield, J.; Sato, S.] NINDS, NIH, EEG Sect, Bethesda, MD 20892 USA. [Bagic, A.; Theodore, W. H.] NINDS, NIH, Clin Epilepsy Sect, Bethesda, MD 20892 USA. [Boudreau, E. A.] Portland VA Med Ctr, Portland, OR USA. [Elkins, W.] CoolSyst Inc, Lincoln, CA USA. BioCool Technol, Lincoln, CA USA. RP Bagic, A (reprint author), Univ Pittsburgh, Sch Med, CABMSI, Suite 811,Kaufmann Med Bldg,3471 5th Ave, Pittsburgh, PA 15213 USA. EM bagica@upmc.edu FU Intramural NIH HHS [Z01 NS002236-33] NR 38 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD OCT PY 2008 VL 118 IS 4 BP 240 EP 244 DI 10.1111/j.1600-0404.2008.01008.x PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 345BC UT WOS:000258970000005 PM 18355392 ER PT J AU Stranahan, AM Lee, K Mattson, MP AF Stranahan, Alexis M. Lee, Kim Mattson, Mark P. TI Contributions of impaired hippocampal plasticity and neurodegeneration to age-related deficits in hormonal pulsatility SO AGEING RESEARCH REVIEWS LA English DT Review DE Alzheimer's disease; Circadian rhythms; Dendritic spines; Hypothalamus; LTP; Neurogenesis; Oxidative stress ID LONG-TERM POTENTIATION; CIRCADIAN CLOCK GENE; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; SUPRACHIASMATIC NUCLEUS; PARAVENTRICULAR NUCLEUS; SYNAPTIC PLASTICITY; NEUROTROPHIC FACTOR; ADULT NEUROGENESIS; CELL-PROLIFERATION AB Connectivity between. the hippocampus and hypothalamus plays an essential role in circadian rhythmicity and stress responsiveness. Both hippocampal dysfunction and loss of hormonal pulsatility have been demonstrated in aged animals, but the possibility of a functional interaction between these two processes remains unexplored. Correlated hippocampal neuropathology and flattening of the circadian rhythms occur in the elderly, and we propose that these processes are causally linked. In this review, we discuss the anatomical and functional nature of hippocampal interconnections with the hypothalamus. We also discuss the results of studies exploring the relationship between circadian phase and hippocampal plasticity in young animals, with the goal of understanding how these mechanisms might be restored in the aging brain. Published by Elsevier Ireland Ltd. C1 [Stranahan, Alexis M.; Lee, Kim; Mattson, Mark P.] NIA, Intramural Res Program, Neurosci Lab, Cellular & Mol Neurosci Sect, Baltimore, MD 21224 USA. [Stranahan, Alexis M.] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. RP Mattson, MP (reprint author), NIA, Intramural Res Program, Neurosci Lab, Cellular & Mol Neurosci Sect, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; OI Lee, Kim/0000-0002-5675-1896 FU Intramural NIH HHS [Z01 AG000317-07]; NIA NIH HHS [F31 AG024690, F31 AG024690-01, F31 AG024690-02, F31 AG024690-03, F31 AG024690-04] NR 84 TC 10 Z9 10 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD OCT PY 2008 VL 7 IS 3 SI SI BP 164 EP 176 DI 10.1016/j.arr.2007.12.004 PG 13 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 368KY UT WOS:000260621200002 PM 18262476 ER PT J AU Martin, B Golden, E Carlson, OD Egan, JM Mattson, MP Maudsley, S AF Martin, Bronwen Golden, Erin Carlson, Olga D. Egan, Josephine M. Mattson, Mark P. Maudsley, Stuart TI Caloric restriction: Impact upon pituitary function and reproduction SO AGEING RESEARCH REVIEWS LA English DT Review DE Caloric restriction; Neuroendocrine pulsatility; Pituitary ID GONADOTROPIN-RELEASING-HORMONE; GALANIN-LIKE PEPTIDE; PROTEIN-COUPLED RECEPTOR; SHORT-TERM STARVATION; PROOPIOMELANOCORTIN MESSENGER-RNA; HYPOTHALAMIC KISS-1 SYSTEM; FEMALE SEXUAL-BEHAVIOR; GROWTH-FACTOR-I; LUTEINIZING-HORMONE; NEUROPEPTIDE-Y AB Reduced energy intake, or caloric restriction (CR), is known to extend life span and to retard age-related health decline in a number of different species, including worms, flies, fish, mice and rats. CR has been shown to reduce oxidative stress, improve insulin sensitivity, and alter neuroendocrine responses and central nervous system (CNS) function in animals. CR has particularly profound and complex actions upon reproductive health. At the reductionist level the most crucial physiological function of any organism is its capacity to reproduce. For a successful species to thrive, the balance between available energy (food) and the energy expenditure required for reproduction must be tightly linked. An ability to coordinate energy balance and fecundity involves complex interactions of hormones from both the periphery and the CNS and primarily centers upon the master endocrine gland, the anterior pituitary. In this review article we review the effects of CR on pituitary gonadotrope function and on the male and female reproductive axes. A better understanding of how dietary energy intake affects reproductive axis function and endocrine pulsatility could provide novel strategies for the prevention and management of reproductive dysfunction and its associated comorbidities. Published by Elsevier Ireland Ltd. C1 [Martin, Bronwen; Golden, Erin; Mattson, Mark P.; Maudsley, Stuart] NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. [Carlson, Olga D.; Egan, Josephine M.] NIA, Intramural Res Program, Clin Invest Lab, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Martin, B (reprint author), NIA, Intramural Res Program, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM martinbro@grc.nia.nih.gov RI Perez , Claudio Alejandro/F-8310-2010; Mattson, Mark/F-6038-2012 OI Perez , Claudio Alejandro/0000-0001-9688-184X; FU Intramural Research Program of the National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. NR 134 TC 34 Z9 37 U1 2 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD OCT PY 2008 VL 7 IS 3 SI SI BP 209 EP 224 DI 10.1016/j.arr.2008.01.002 PG 16 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 368KY UT WOS:000260621200005 PM 18329344 ER PT J AU McMains, VC Liao, XH Kimmel, AR AF McMains, Vanessa C. Liao, Xin-Hua Kimmel, Alan R. TI Oscillatory signaling and network responses during the development of Dictyostelium discoideum SO AGEING RESEARCH REVIEWS LA English DT Review DE cAMP; Adaptation; Chemotaxis; Protein kinases; PI3K; PTEN; PLA(2); cGMP ID RECEPTOR-MEDIATED ACTIVATION; PLECKSTRIN HOMOLOGY DOMAIN; DIRECTIONAL CELL-MOVEMENT; ALPHA PROTEIN SUBUNITS; CYCLIC-AMP RECEPTORS; ADENYLYL-CYCLASE; PHOSPHOLIPASE-C; CAMP RECEPTOR; LEADING-EDGE; CHEMOATTRACTANT RECEPTOR AB Periodic biological variations reflect interactions among molecules and cells, or even organisms. The Dictyostelium cAMP oscillatory circuit is a highly robust example. cAMP oscillations in Dictyostelium arise intracellularly by a complex interplay of activating and inhibiting pathways, are transmitted extracellularly, and synchronize an entire local population. Once established, cAMP signal-relay persists stably for hours. On a two-dimensional surface, > 100,000 cells may form a single coordinated territory. In suspension culture, > 10(10) cells can oscillate in harmony. This review focuses on molecular mechanisms that cyclically activate and attenuate signal propagation and on chemotactic responses to oscillatory wave progression. Published by Elsevier Ireland Ltd. C1 [McMains, Vanessa C.; Liao, Xin-Hua; Kimmel, Alan R.] NIDDK, Cellular & Dev Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [McMains, Vanessa C.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Kimmel, AR (reprint author), NIDDK, Cellular & Dev Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases. NR 94 TC 25 Z9 27 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD OCT PY 2008 VL 7 IS 3 SI SI BP 234 EP 248 DI 10.1016/j.arr.2008.04.003 PG 15 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 368KY UT WOS:000260621200007 PM 18657484 ER PT J AU Strong, R Miller, RA Astle, CM Floyd, RA Flurkey, K Hensley, KL Javors, MA Leeuwenburgh, C Nelson, JF Ongini, E Nadon, NL Warner, HR Harrison, DE AF Strong, Randy Miller, Richard A. Astle, Clinton M. Floyd, Robert A. Flurkey, Kevin Hensley, Kenneth L. Javors, Martin A. Leeuwenburgh, Christiaan Nelson, James F. Ongini, Ennio Nadon, Nancy L. Warner, Huber R. Harrison, David E. TI Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice SO AGING CELL LA English DT Article DE aging; aspirin; longevity; mice; nordihydroguaiaretic acid ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TERT-BUTYL NITRONE; COLORECTAL-CANCER; BREAST-CANCER; RATS; 5-LIPOXYGENASE; ACTIVATION; GROWTH; CELLS; MODEL AB The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio). Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen, 4-OH-alpha-phenyl-N-tert-butyl nitrone, or nordihydroguaiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in lifespan in either sex, with 80% power, using data from two of the three sites. Pooling data from all three sites, a log-rank test showed that both NDGA (p = 0.0006) and aspirin (p = 0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan; neither NDGA (p = 0.12) nor aspirin (p = 0.16) had a significant effect in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed lack of effects of NDGA or aspirin on lifespan in females could be related to gender differences in drug disposition or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses, might prove to postpone death and various age-related outcomes reproducibly in mice. C1 [Strong, Randy] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Strong, Randy] S Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX 78229 USA. [Miller, Richard A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Miller, Richard A.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Miller, Richard A.] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA. [Miller, Richard A.] Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. [Astle, Clinton M.; Flurkey, Kevin; Harrison, David E.] Jackson Lab, Bar Harbor, ME 04609 USA. [Floyd, Robert A.; Hensley, Kenneth L.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Floyd, Robert A.] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73104 USA. [Javors, Martin A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Leeuwenburgh, Christiaan] Univ Florida, Dept Aging & Geriatr, Gainesville, FL 32610 USA. [Nelson, James F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Nelson, James F.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Ongini, Ennio] Nicox Res Inst, Milan, Italy. [Nadon, Nancy L.] NIA, Biol Aging Program, Bethesda, MD 20892 USA. [Warner, Huber R.] Univ Minnesota, Coll Biol Sci, St Paul, MN 55108 USA. RP Strong, R (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM strong@uthscsa.edu FU National Institute on Aging [AG022303, AG025707, AG022308, AG022307, AG13319]; Department of Veterans Affairs FX This work was supported by National Institute on Aging grants AG022303 (R.A.M.), AG025707 and AG022308 (D.E.H.), and AG022307 and AG13319 (R.S.), and the Department of Veterans Affairs (R.M. and R.S.). We wish to thank Vivian Diaz, Elizabeth Fernandez, Greg Friesenhahn, Melissa Han, Patricia Harrison, Roni Kobrosly, Bill Kohler, Pam Krason, Jessica Sewald, and Maggie Lauderdale for technical support. We thank Scott Pletcher and Andrzej Galecki for assistance in power analysis and study design. NR 51 TC 103 Z9 106 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD OCT PY 2008 VL 7 IS 5 BP 641 EP 650 DI 10.1111/j.1474-9726.2008.00414.x PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 349TU UT WOS:000259307000005 PM 18631321 ER PT J AU Vestergaard, S Kronborg, C Puggaard, L AF Vestergaard, Sonja Kronborg, Christian Puggaard, Lis TI Home-based video exercise intervention for community-dwelling frail older women: a randomized controlled trial SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Activities of daily living; exercise; frail elderly; health-related quality of life; video ID QUALITY-OF-LIFE; PHYSICAL-ACTIVITY; FUNCTIONAL PERFORMANCE; 85-YEAR-OLD WOMEN; PREVENT FALLS; WALKING SPEED; LEG EXTENSION; ELDERLY-WOMEN; PROGRAM; HEALTH AB Background and aims: Home-based exercise is a viable solution for frail elderly individuals with difficulties in reaching exercise facilities outside home. The aim of this study was to determine the effects of a home-based video exercise program on physiological performance, functional capacity and health-related quality of life. Methods: Community-dwelling frail women >= 75 yrs, receiving public home care, were randomized into a training group (n=30) and a control group (n=31). Participants exercised for 26 minutes, three times per week for five months. Both groups received a bi-weekly telephone call. The effect of intervention was evaluated by the physical performance test, mobility-tiredness score, maximal isometric handgrip and biceps strength, lower limb explosive power, repeated chair rise (5 times), 10-m maximal walking-speed, semi-tandem balance, and health-related quality of life, as measured by EQ-5D and self-rated health. Results: Twenty-five participants (83%) in the training group and 28 (90%) in the control group completed the project. Adherence to the training protocol was on average 89.2%. At follow-up, between-group analysis revealed a significant difference only in EQ-5D (valued by time-trade-off tariffs), resulting from a significant decrease observed in the control group and a trend towards an increase in the training group (p=0.082). Significant within-group improvements, ranging from 8-35%, were also observed for the physical performance test, mobility-tiredness score, handgrip, biceps strength, chair rise, and 10-m maximal walking-speed in the training group, and for walking-speed and self-rated health in the control group. Conclusions: These results suggest that home-based training for frail older women using an exercise video induces lasting health-related quality-of-life (EQ-5D). In addition, a tendency towards improvements in physiological performance and functional capacity was observed. (Aging Clin Exp Res 2008,: 20: 479-486) (c) 2008, Editrice Kurtis. C1 [Vestergaard, Sonja; Puggaard, Lis] Univ So Denmark, Inst Sports Sci & Clin Biomech, Ctr Appl & Clin Exercise Sci, Odense, Denmark. [Kronborg, Christian] Univ So Denmark, Inst Publ Hlth, Hlth Econ Res Unit, Odense, Denmark. RP Vestergaard, S (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Suite 3C309, Bethesda, MD 20892 USA. EM vestergaards@mail.nih.gov OI Kronborg, Christian/0000-0001-9627-1419 FU Ministry of Social Affairs, Age Forum; Board of Sports Science of the Danish Ministry of Culture FX This research was supported by grants from Ministry of Social Affairs, Age Forum. and the Board of Sports Science of the Danish Ministry of Culture. No members from any of the organisations participated in any part of the study. We thank the co-operating contact persons, healthcare workers, and participants from the four municipalities, We thank Kirsten Kjaer and Anne Larsen for valuable assistance in data collection. NR 44 TC 14 Z9 14 U1 2 U2 12 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD OCT PY 2008 VL 20 IS 5 BP 479 EP 486 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 381BR UT WOS:000261510300014 PM 19039291 ER PT J AU Boyer, J Hirao, L Yan, J Khan, A Dai, A Draghia-Akli, R Sardesai, NY Hokey, D Wu, L Lewis, M Betts, M Warren, J Miller, N Weiner, D AF Boyer, J. Hirao, L. Yan, J. Khan, A. Dai, A. Draghia-Akli, R. Sardesai, N. Y. Hokey, D. Wu, L. Lewis, M. Betts, M. Warren, J. Miller, N. Weiner, D. TI Induction of Potent T Cell Immunity in Macaques by EP DNA plus Molecular Adjuvants SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Boyer, J.; Hirao, L.; Yan, J.; Khan, A.; Dai, A.; Draghia-Akli, R.; Sardesai, N. Y.; Hokey, D.; Wu, L.; Betts, M.] VGX Pharmaceut Inc, The Woodlands, TX USA. [Lewis, M.] Bioqual Inc, Rockville, MD USA. [Warren, J.; Miller, N.] NIH, DAIDS, Bethesda, MD 20892 USA. [Weiner, D.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 3 EP 4 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800004 ER PT J AU Streeck, H Jolin, JS Yassine-Diab, B Qi, Y Kwon, D Addo, MM Johnson, R Brumme, C Routy, J Little, S Jessen, H Kelleher, A Sekaly, R Rosenberg, ES Walker, BD Carrington, M Altfeld, M AF Streeck, H. Jolin, J. S. Yassine-Diab, B. Qi, Y. Kwon, D. Addo, M. M. Johnson, R. Brumme, C. Routy, J. Little, S. Jessen, H. Kelleher, A. Sekaly, R. Rosenberg, E. S. Walker, B. D. Carrington, M. Altfeld, M. TI Early CD8+T Cell Responses are the Major Contributors to the Later Viral Set Point SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Streeck, H.; Jolin, J. S.; Kwon, D.; Addo, M. M.; Brumme, C.; Rosenberg, E. S.; Walker, B. D.; Altfeld, M.] Partners AIDS Res Ctr, Charlestown, MA USA. [Yassine-Diab, B.; Routy, J.; Sekaly, R.] McGill Univ, Div Hematol & Immunodeficiency Serv, Montreal, PQ, Canada. [Qi, Y.; Johnson, R.] NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. [Little, S.] UCSD, San Diego, CA USA. [Jessen, H.] HIV Clin Berlin, Berlin, Germany. [Kelleher, A.] UNSW, NCHECR, Sydney, NSW, Australia. NR 0 TC 0 Z9 0 U1 1 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 7 EP 7 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800014 ER PT J AU Chen, W Zhu, Z Zhang, M Macagno, A Prabakaran, P Owens, J Longo, NS Markowitz, M Lanzavecchia, A Haynes, BF Dimitrov, DS AF Chen, W. Zhu, Z. Zhang, M. Macagno, A. Prabakaran, P. Owens, J. Longo, N. S. Markowitz, M. Lanzavecchia, A. Haynes, B. F. Dimitrov, D. S. TI All Known Cross-Reactive HIV-1 Neutralizing Antibodies are Highly Divergent from Germline and Their Elicitation May Require Prolonged Periods of Time SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Chen, W.; Zhu, Z.; Zhang, M.; Owens, J.] NCI Frederick, SAIC Frederick, Frederick, ME USA. [Macagno, A.; Lanzavecchia, A.] Biomed Res Inst, Bellinzona, Ticino, Switzerland. [Prabakaran, P.] NCI Frederick, Human Vaccine Inst, Durham, NC USA. [Longo, N. S.] NIAMSD, Bethesda, MD 20892 USA. [Markowitz, M.] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Haynes, B. F.] Duke Human Vaccine Inst, Durham, NC USA. [Dimitrov, D. S.] NCI Frederick, NIH, Frederick, MD USA. RI Ponraj, Prabakaran/D-6325-2011 NR 0 TC 9 Z9 9 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 11 EP 12 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800025 ER PT J AU Davis, D Koornstra, W Mortier, D Fagrouch, Z Verschoor, E Robert-Guroff, M Srivastava, I Barnett, S Heeney, J Bogers, W AF Davis, D. Koornstra, W. Mortier, D. Fagrouch, Z. Verschoor, E. Robert-Guroff, M. Srivastava, I. Barnett, S. Heeney, J. Bogers, W. TI Events during the Absorption Phase of a Neutralization Assay are Predictive of Protection in the SHIV - Rhesus Macaque Model SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Davis, D.; Koornstra, W.; Mortier, D.; Fagrouch, Z.; Verschoor, E.; Heeney, J.; Bogers, W.] Biomed Primate Res Ctr, Rijswijk, Netherlands. [Robert-Guroff, M.] NCI, NIH, Bethesda, MD 20892 USA. [Srivastava, I.; Barnett, S.] Novartis Vaccines & Diagnost Inc, Emeryville, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 13 EP 13 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800029 ER PT J AU Bolton, DL Song, K Rao, S Kozlowski, P Roederer, M AF Bolton, D. L. Song, K. Rao, S. Kozlowski, P. Roederer, M. TI Fine Aerosol Adenovirus Vaccination against SIV in Rhesus Macaque SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Bolton, D. L.; Song, K.; Rao, S.; Roederer, M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kozlowski, P.] LSU Hlth Sci Univ, Tulane, LA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 14 EP 14 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800032 ER PT J AU Kozlowski, PA Oaks, EV Camp, JV Wilson, RL Nabel, GJ Rao, S Aldovini, A Singletary, M Blanchard, J AF Kozlowski, P. A. Oaks, E. V. Camp, J. V. Wilson, R. L. Nabel, G. J. Rao, S. Aldovini, A. Singletary, M. Blanchard, J. TI Invaplex: A Safe Nasal Adjuvant for Enhancing Mucosal and Systemic Antibody Responses to DNA/Protein Vaccines SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Kozlowski, P. A.; Camp, J. V.; Wilson, R. L.] LSU Hlth Sci Ctr, New Orleans, LA USA. [Oaks, E. V.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Nabel, G. J.; Rao, S.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Aldovini, A.] Childrens Hosp, Boston, MA 02115 USA. [Singletary, M.; Blanchard, J.] Tulane Natl Primate Res Ctr, Covington, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 14 EP 15 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800033 ER PT J AU Pavlakis, GN Rosati, M Patel, V Bergamaschi, C Valentin, A Kulkarni, V Jalah, R Alicea, C von Gegerfelt, A Minang, JT Trivett, MT Ohlen, CR Khan, A Draghia-Akli, R Van Rompay, K Felber, BK AF Pavlakis, G. N. Rosati, M. Patel, V. Bergamaschi, C. Valentin, A. Kulkarni, V. Jalah, R. Alicea, C. von Gegerfelt, A. Minang, J. T. Trivett, M. T. Ohlen, C. R. Khan, A. Draghia-Akli, R. Van Rompay, K. Felber, B. K. TI Electroporation of Optimized DNA Vaccines Leads to Greatly Enhanced Responses in Blood and Mucosal Surfaces SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Pavlakis, G. N.; Rosati, M.; Patel, V.; Bergamaschi, C.; Valentin, A.; Kulkarni, V.; Jalah, R.; Alicea, C.; von Gegerfelt, A.; Felber, B. K.] NCI, Frederick, MD 21701 USA. [Minang, J. T.; Trivett, M. T.; Ohlen, C. R.] SAIC Frederick Inc, Frederick, MD USA. [Khan, A.; Draghia-Akli, R.] VGX Pharmaceut, The Woodlands, TX USA. [Van Rompay, K.] Calif Res Primate Res Ctr, Davis, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 15 EP 16 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800035 ER PT J AU De Rosa, SC Thomas, EP Huang, Y Morgan, C Kalams, S Lau, C Graham, B Nabel, GJ McElrath, MJ AF De Rosa, S. C. Thomas, E. P. Huang, Y. Morgan, C. Kalams, S. Lau, C. Graham, B. Nabel, G. J. McElrath, M. J. TI Kinetics of T Cell Responses to Vaccination for HIV with Heterologous DNA Prime-rAd5 Boost Contrasted with Homologous rAd5 Prime-Boost SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [De Rosa, S. C.; Thomas, E. P.; McElrath, M. J.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Huang, Y.] SCHARP, Seattle, WA USA. [Morgan, C.] HIV Vaccine Trials Network, Seattle, WA USA. [Kalams, S.] Vanderbilt Univ, Nashville, TN USA. [Lau, C.] DAIDS NIH, Bethesda, MD USA. [Graham, B.; Nabel, G. J.] Vaccine Res Ctr, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 16 EP 16 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800037 ER PT J AU Bakari, M Mhalu, F Aboud, S Nilsson, C Francis, J Janabi, M Lyamuya, E Aris, EA Mbwana, J Buma, D Mwanyika, L Hejdeman, B Brave, A Robb, M Marovich, M Michael, N Earl, P Wahren, B Biberfeld, G Pallangyo, K Sandstrom, E AF Bakari, M. Mhalu, F. Aboud, S. Nilsson, C. Francis, J. Janabi, M. Lyamuya, E. Aris, E. A. Mbwana, J. Buma, D. Mwanyika, L. Hejdeman, B. Brave, A. Robb, M. Marovich, M. Michael, N. Earl, P. Wahren, B. Biberfeld, G. Pallangyo, K. Sandstrom, E. TI Safety and Immunogenicity of an HIV-1 DNA Plasmid Vaccine Boosted with HIV-1 MVA Among Police Officers (PO's) in Dar es Salaam, Tanzania SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Bakari, M.; Mhalu, F.; Aboud, S.; Lyamuya, E.; Mbwana, J.; Pallangyo, K.] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Nilsson, C.; Brave, A.; Wahren, B.; Biberfeld, G.] Swedish Inst Infect Dis Control, Stockholm, Sweden. [Nilsson, C.; Brave, A.; Wahren, B.; Biberfeld, G.] Karolinska Inst, Stockholm, Sweden. [Francis, J.] Muhimbili Med Ctr, Natl Inst Med Res, Dar Es Salaam, Tanzania. [Janabi, M.; Aris, E. A.; Buma, D.] Muhmbili Natl Hosp, Dar Es Salaam, Tanzania. [Mwanyika, L.] Tanzania Police Force, Dar Es Salaam, Tanzania. [Hejdeman, B.] Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. [Robb, M.; Marovich, M.; Michael, N.] Walter Reed Army Inst Res, Rockville, MD USA. [Earl, P.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 17 EP 17 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800039 ER PT J AU Cuurier, J Ngauy, V Cox, J Earl, P Moss, B Robb, M Michael, N Marovich, M AF Cuurier, J. Ngauy, V. Cox, J. Earl, P. Moss, B. Robb, M. Michael, N. Marovich, M. TI Comprehensive Characterization of Cellular Immune Responses Induced by Modified Vaccinia Ankara (MVA)-HIV-1 in a Phase I Randomized, Controlled Trial SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Cuurier, J.; Ngauy, V.; Cox, J.; Robb, M.; Michael, N.] Int AIDS Vaccine Initiat, Rockville, MD USA. [Earl, P.; Moss, B.] NIH, Viral Dis Lab, Bethesda, MD 20892 USA. [Marovich, M.] US Mil HIV Res Program, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 17 EP 18 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800040 ER PT J AU Churchyard, GJ Morgan, C Keefer, M Adams, E Hural, J Graham, B Moodie, Z Gray, G Vardas, E Bekker, L McElrath, MJ AF Churchyard, G. J. Morgan, C. Keefer, M. Adams, E. Hural, J. Graham, B. Moodie, Z. Gray, G. Vardas, E. Bekker, L. McElrath, M. J. CA NIAID HIV Vaccine Trials Network TI Safety and Immunogenicity of a Multiclade HIV-1 DNA Vaccine Boosted by a Multiclade HIV-1 Ad5 Vaccine in HIV-Uninfected Adult Subjects (HVTN 204) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Churchyard, G. J.; NIAID HIV Vaccine Trials Network] Aurum Inst Hlth Res, Johannesburg, South Africa. [Morgan, C.; Hural, J.; Moodie, Z.; McElrath, M. J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Keefer, M.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Adams, E.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Graham, B.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Gray, G.; Vardas, E.] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Bekker, L.] Univ Cape Town, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, Western Cape, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 18 EP 18 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800041 ER PT J AU Maenetje, PW Casazza, J Ambrozak, D Koup, R Gray, G de Bruyn, G Gray, C AF Maenetje, P. W. Casazza, J. Ambrozak, D. Koup, R. Gray, G. de Bruyn, G. Gray, C. TI In Vivo Susceptibility of Activated Memory CD4+T-Cells to HIV during Early Subtype C Infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Maenetje, P. W.; Gray, C.] Natl Inst Communicable Dis, Johannesburg, Gauteng, South Africa. [Casazza, J.; Ambrozak, D.; Koup, R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gray, G.; de Bruyn, G.] Perinatal HIV Res Unit Soweto, Johannesburg, Gauteng, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 19 EP 19 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800043 ER PT J AU Wang, YE Li, B Carlson, JM Streeck, H Gladden, AD Schneidewind, A Power, KA Toth, I Frahm, N Alter, G Brander, C Carrington, M Walker, BD Altfeld, M Heckerman, D Allen, T AF Wang, Y. E. Li, B. Carlson, J. M. Streeck, H. Gladden, A. D. Schneidewind, A. Power, K. A. Toth, I. Frahm, N. Alter, G. Brander, C. Carrington, M. Walker, B. D. Altfeld, M. Heckerman, D. Allen, T. TI Protective HLA Class I Alleles Restrict Acute-Phase CD8 Responses that Select for Viral Escape in Highly Conserved Regions of HIV SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Wang, Y. E.; Li, B.; Streeck, H.; Gladden, A. D.; Schneidewind, A.; Power, K. A.; Toth, I.; Frahm, N.; Alter, G.; Brander, C.; Altfeld, M.; Allen, T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. [Heckerman, D.] Microsoft Res, Redmond, WA USA. [Carrington, M.] NCI, Lab Genom Div, Frederick, MD 21701 USA. [Walker, B. D.] Howard Hughes Med Inst, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 21 EP 22 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800050 ER PT J AU Van Ryk, D Arthos, J Cicala, C Martinelli, E Goode, D Gopaul, R Macleod, K Pascuccio, M McNally, J Wei, D Fauci, A AF Van Ryk, D. Arthos, J. Cicala, C. Martinelli, E. Goode, D. Gopaul, R. Macleod, K. Pascuccio, M. McNally, J. Wei, D. Fauci, A. TI HIV gp120 Binds to Integrin a4b7 by Mimicking its Natural Ligands; a Novel Role for the V2-Loop SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Van Ryk, D.; Arthos, J.; Cicala, C.; Martinelli, E.; Goode, D.; Gopaul, R.; Macleod, K.; Pascuccio, M.; McNally, J.; Wei, D.; Fauci, A.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 22 EP 22 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800051 ER PT J AU Ofek, G Schief, WR Guenaga, FJ Wyatt, R Baker, D Kwong, PD AF Ofek, G. Schief, W. R. Guenaga, F. J. Wyatt, R. Baker, D. Kwong, P. D. TI Mimicry of a Conformational State of an HIV-1 Neutralizing Determinant Through Computational Immunogen Design SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Ofek, G.; Guenaga, F. J.; Wyatt, R.; Kwong, P. D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Schief, W. R.; Baker, D.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 24 EP 24 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800057 ER PT J AU Zak, DE Kupko, J Andersen-Nissen, E Park, H Hansen, S Mullen, K Kennedy, K Seder, R Picker, L McElrath, MJ Aderem, A AF Zak, D. E. Kupko, J. Andersen-Nissen, E. Park, H. Hansen, S. Mullen, K. Kennedy, K. Seder, R. Picker, L. McElrath, M. J. Aderem, A. TI Application of Systems Biology to Identify Predictors of HIV Vaccine Immunogenicity SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Zak, D. E.; Kupko, J.; Kennedy, K.; Aderem, A.] Inst Syst Biol, Seattle, WA USA. [Andersen-Nissen, E.; McElrath, M. J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Park, H.; Hansen, S.; Mullen, K.; Picker, L.] Oregon Hlth & Sci Univ, Beaverton, OR USA. [Seder, R.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 28 EP 28 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800067 ER PT J AU Hudgens, MG Wu, C Gilbert, PB Self, SG Mascola, J Barouch, DH AF Hudgens, M. G. Wu, C. Gilbert, P. B. Self, S. G. Mascola, J. Barouch, D. H. TI Power to Detect Vaccine Effects in Repeated Low-Dose Challenge Experiments SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Hudgens, M. G.; Wu, C.] Univ N Carolina, Chapel Hill, NC USA. [Gilbert, P. B.; Self, S. G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Mascola, J.] NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Barouch, D. H.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 40 EP 40 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800095 ER PT J AU Douagi, I Forsell, MN Sundling, C O'Dell, S Dosenovic, P Li, Y Mascola, JR Lore, K Wyatt, RT Hedestam, GBK AF Douagi, I. Forsell, M. N. Sundling, C. O'Dell, S. Dosenovic, P. Li, Y. Mascola, J. R. Lore, K. Wyatt, R. T. Hedestam, G. B. Karlsson TI Impact of In Vivo CD4 Binding Following HIV-1 Env Protein Trimer Immunizations of Rhesus Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Douagi, I.; Forsell, M. N.; Sundling, C.; Dosenovic, P.; Hedestam, G. B. Karlsson] Karolinska Inst, Swedish Inst Infect Dis Control, Stockholm, Sweden. [O'Dell, S.; Li, Y.; Mascola, J. R.; Wyatt, R. T.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Lore, K.] Karolinska Inst, Ctr Infect Dis, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 45 EP 46 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800109 ER PT J AU Chen, W Dimitrov, DS AF Chen, W. Dimitrov, D. S. TI Human Domain Antibodies Targeting Conserved Sterically Restricted Regions on gp120 as Exceptionally Potent Cross-Reactive HIV-1 Neutralizers SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Chen, W.; Dimitrov, D. S.] NCI Frederick, NIH, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 49 EP 49 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800118 ER PT J AU Dosenovic, P Chakrabarti, B Douagi, I Forsell, M Phogat, A Li, Y Paulie, S Hoxie, J Wyatt, R Hedestam, GK AF Dosenovic, P. Chakrabarti, B. Douagi, I. Forsell, M. Phogat, A. Li, Y. Paulie, S. Hoxie, J. Wyatt, R. Hedestam, G. Karlsson TI Use of an HIV-1 Env-specific B cell ELISpot Assay for Quantitative and Qualitative Analysis of Env-Specific B Cell Responses following Immunization SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Dosenovic, P.; Douagi, I.; Hedestam, G. Karlsson] Karolinska Inst, Stockholm, Sweden. [Chakrabarti, B.; Forsell, M.; Phogat, A.; Li, Y.; Wyatt, R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Paulie, S.] Nacka, Mabtech, Stockholm, Sweden. [Hoxie, J.] Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 52 EP 52 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800126 ER PT J AU Wu, X Zhou, T O'Dell, S Wyatt, R Kwong, P Mascola, J AF Wu, X. Zhou, T. O'Dell, S. Wyatt, R. Kwong, P. Mascola, J. TI b12 Resistance in Acute Clade B and C HIV-1 Arises from Antigenic Variation within the CD4-Binding Loop and Steric Occlusion by Native Envelope Trimer SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Wu, X.; Zhou, T.; O'Dell, S.; Wyatt, R.; Kwong, P.; Mascola, J.] NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 52 EP 52 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800125 ER PT J AU Li, Y Svehla Louder, M Migueles, S Wycuff, D Wu, X Phogat, A Shaw, G Hoxie, J Connors, M Mascola, J Wyatt, RT AF Li, Y. Svehla Louder, M. Migueles, S. Wycuff, D. Wu, X. Phogat, A. Shaw, G. Hoxie, J. Connors, M. Mascola, J. Wyatt, R. T. TI Identification of an HIV-1 Broadly Neutralizing Serum Displaying Potential Dual Anti-Env Specificity SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Svehla; Louder, M.; Migueles, S.; Wycuff, D.; Wu, X.; Phogat, A.; Connors, M.; Mascola, J.; Wyatt, R. T.] NIAID, NIH, VRC, Bethesda, MD 20892 USA. [Shaw, G.] Univ Alabama, Dept Med & Microbiol, Birmingham, AL USA. [Hoxie, J.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 55 EP 56 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800135 ER PT J AU Robinson, HL Lai, L Zhao, J AF Robinson, H. L. Lai, L. Zhao, J. TI Correlation of Non-Neutralizing but High Avidity Clade-Specific Binding to Incident Isolates with Resistance to Neutralization by IgG1b12 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Robinson, H. L.] GeoVax Inc, Atlanta, GA USA. [Lai, L.] Yerkes Natl Primate Res Ctr, Atlanta, GA USA. [Zhao, J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 57 EP 58 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800140 ER PT J AU Zhu, H Zhang, J Han, L Chen, R Shao, Y AF Zhu, H. Zhang, J. Han, L. Chen, R. Shao, Y. TI Feasibility of International Standard AIDS Clinical Research in Rural China SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Zhu, H.; Zhang, J.; Han, L.; Shao, Y.] China CDC, Beijing, Peoples R China. [Chen, R.] NIH USA, Washington, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 67 EP 67 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800166 ER PT J AU Monaco, A Buonaguro, L Sabatino, M Pos, Z Stroncek, DF Wang, E Lewis, GK Tornesello, M Marincola, FM Buonaguro, FM AF Monaco, A. Buonaguro, L. Sabatino, M. Pos, Z. Stroncek, D. F. Wang, E. Lewis, G. K. Tornesello, M. Marincola, F. M. Buonaguro, F. M. TI Peripheral Blood Mononuclear Cells Activated by HIV-VLPs in Correlation with HIV-1 Seropositivity Status: Transcriptional Insights SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Monaco, A.; Sabatino, M.; Pos, Z.; Stroncek, D. F.; Wang, E.; Marincola, F. M.] NIH, IDIS, Dpt Transfus Med, Bethesda, MD 20892 USA. [Lewis, G. K.] Univ Maryland, IHV, Bethesda, MD USA. [Buonaguro, L.; Tornesello, M.; Buonaguro, F. M.] Natl Canc Inst Fond Pascale, Naples, Campania, Italy. RI Tornesello, Maria Lina/A-1564-2009; Monaco, Alessandro/O-5338-2015 OI Tornesello, Maria Lina/0000-0002-3523-3264; Monaco, Alessandro/0000-0002-9941-7003 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 71 EP 71 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800176 ER PT J AU Frahm, N Dai, J Geraghty, D Mehrotra, D Carrington, M Cooper, CJ Hural, J Corey, L Buchbinder, S Robertson, MN Self, SG McElrath, MJ AF Frahm, N. Dai, J. Geraghty, D. Mehrotra, D. Carrington, M. Cooper, C. J. Hural, J. Corey, L. Buchbinder, S. Robertson, M. N. Self, S. G. McElrath, M. J. TI Influence of HLA Class I Distribution on Set-Point Viral Load in HIV-Infected Cases from the STEP (Merck 023/HVTN 502) Trial SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Geraghty, D.; Robertson, M. N.] Merck Res Labs, ID Vaccine Clin Res, Upper Gwynedd, PA USA. [Carrington, M.] SAIC Frederick Inc, NCI Frederick, Lab Genom Divers, Frederick, MD USA. [Buchbinder, S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Corey, L.; Self, S. G.; McElrath, M. J.] U Washington, Fred Hutchinson Canc Res Ctr, HVTN, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 74 EP 74 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800184 ER PT J AU Wong, AH Williams, K Reddy, S Van Der Stok, M Giddy, J Wilson, D Alter, G Ghebremichael, MS Carrington, M Ndung'u, T Walker, B Altfeld, M Carr, WH AF Wong, A. H. Williams, K. Reddy, S. Van der Stok, M. Giddy, J. Wilson, D. Alter, G. Ghebremichael, M. S. Carrington, M. Ndung'u, T. Walker, B. Altfeld, M. Carr, W. H. TI Alterations in Natural Killer Cell Receptor Profiles during HIV-1 Disease Progression among Chronically Infected South African Adults SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Wong, A. H.; Williams, K.; Reddy, S.; Van der Stok, M.; Alter, G.; Ndung'u, T.; Walker, B.; Altfeld, M.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA USA. [Giddy, J.] MCcord Hosp, Durban, Kwazulu Natal, South Africa. [Wilson, D.] Edendale Hosp, Dept Med, Edendale, Kwazulu Natal, South Africa. [Ghebremichael, M. S.] Harvard Univ, Boston, MA 02115 USA. [Ghebremichael, M. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Carrington, M.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Carr, W. H.] Univ Kwazulu Natal, Doris Duke Med Res Ctr, Durban, Kwazulu Natal, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 83 EP 84 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800208 ER PT J AU Cicala, C Arthos, J Van Ryk, D Martinelli, E Goode, D Gopaul, R Macleod, K McNally, J Pascuccio, M Zhen, X Veenstra, T Wei, D Fauci, A AF Cicala, C. Arthos, J. Van Ryk, D. Martinelli, E. Goode, D. Gopaul, R. Macleod, K. McNally, J. Pascuccio, M. Zhen, X. Veenstra, T. Wei, D. Fauci, A. TI HIV gp120 Signaling through Integrin a4b7 Promotes the Formation of Virological Synapses SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Cicala, C.; Arthos, J.; Van Ryk, D.; Martinelli, E.; Goode, D.; Gopaul, R.; Macleod, K.; McNally, J.; Pascuccio, M.; Wei, D.; Fauci, A.] NIAID, NIH, Bethesda, MD 20892 USA. [Zhen, X.; Veenstra, T.] SAIC, LIB, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 90 EP 91 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800227 ER PT J AU Podack, ER Strbo, N Pahwa, S Franchini, G Felber, BK Pavlakis, GN Kolber, M AF Podack, E. R. Strbo, N. Pahwa, S. Franchini, G. Felber, B. K. Pavlakis, G. N. Kolber, M. TI Mucosal HIV Immunity Generated by gp96-SIV/HIV Peptide Complexes Secreted by Allogeneic Cell SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Podack, E. R.; Strbo, N.; Pahwa, S.; Kolber, M.] Univ Miami, Miami, FL USA. [Franchini, G.; Felber, B. K.; Pavlakis, G. N.] NCI, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 91 EP 91 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800229 ER PT J AU Wyatt, L Earl, P Xiao, W Americo, J Cotter, C Vogt, J Moss, B AF Wyatt, L. Earl, P. Xiao, W. Americo, J. Cotter, C. Vogt, J. Moss, B. TI Novel Methods to Enhance Stable Expression of Foreign Genes in Recombinant MVA Vaccines SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Wyatt, L.; Earl, P.; Xiao, W.; Americo, J.; Vogt, J.; Moss, B.] NIAID, LVD, NIH, Bethesda, MD 20892 USA. [Cotter, C.] Henry M Jackson Fdn, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 94 EP 95 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800238 ER PT J AU Gudmundsdotter, L Nilsson, C Sandstrom, E Hejdeman, B Robb, M Marovich, M Michael, N Moss, B Earl, P Biberfeld, G Wahren, B AF Gudmundsdotter, L. Nilsson, C. Sandstrom, E. Hejdeman, B. Robb, M. Marovich, M. Michael, N. Moss, B. Earl, P. Biberfeld, G. Wahren, B. TI Expression of HIV-1 Genes from a Modified Vaccinia Ankara (MVA) Vector Overrides the Pre-Existing Vector Immunity in a Human Vaccine Trial SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Gudmundsdotter, L.] Karolinska Inst, Stockholm, Sweden. [Nilsson, C.; Biberfeld, G.; Wahren, B.] Swedish Inst Infect Dis Control, Stockholm, Sweden. [Sandstrom, E.; Hejdeman, B.] Soder Sjukhuset, Stockholm, Sweden. [Robb, M.; Marovich, M.; Michael, N.] Walter Reed Army Inst Res, Rockville, MD USA. [Moss, B.; Earl, P.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 98 EP 98 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800248 ER PT J AU Schuetz, A Haule, A Schunk, M Maboko, L Kroidl, A Hoelscher, M Marovich, M Robb, M Michael, N Graham, B Cox, J de Souza, M AF Schuetz, A. Haule, A. Schunk, M. Maboko, L. Kroidl, A. Hoelscher, M. Marovich, M. Robb, M. Michael, N. Graham, B. Cox, J. de Souza, M. TI Cellular Immune Responses Assessed by ICS and ELISpot in Volunteers Enrolled in a Phase I/II Multiclade HIV-1 DNA Plasmid/rAd5 Boost Vaccine Trial SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Schuetz, A.; Marovich, M.; Robb, M.; Michael, N.; Cox, J.] USMHRP Henry M Jackson Fdn, Mbeya, Tanzania. [Haule, A.; Maboko, L.; Kroidl, A.] Mbeya Med Res Programme, Mbeya, Tanzania. [Schunk, M.; Hoelscher, M.] Univ Munich, Dept Infect Dis & Trop Med, Munich, Bavaria, Germany. [Graham, B.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [de Souza, M.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 102 EP 102 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800258 ER PT J AU Eller, L Eller, M Naluyima, P Kyabaggu, D Wabwire-Mangen, F Marovich, M Cox, J Michael, N Graham, B Kibuuka, H Robb, M de Souza, M AF Eller, L. Eller, M. Naluyima, P. Kyabaggu, D. Wabwire-Mangen, F. Marovich, M. Cox, J. Michael, N. Graham, B. Kibuuka, H. Robb, M. de Souza, M. TI Cellular Immune Responses in Ugandan Volunteers Enrolled in a Phase 1 HIV-1 DNA (VRC-HIVDNA009-00-VP)/rAd5 (VRC-HIVADV014-00-VP) Boost Vaccine Trial SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Eller, L.; Eller, M.; Marovich, M.; Cox, J.; Michael, N.; Robb, M.] Makerere Univ, Walter Reed Project, US Mil HIV Res Program, Kampala, Uganda. [Graham, B.; Kibuuka, H.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [de Souza, M.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 105 EP 105 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800266 ER PT J AU Mark, KE Ding, Y Morgan, C Galloway, C Graham, BS Koblin, BA McElrath, MJ Duerr, A AF Mark, K. E. Ding, Y. Morgan, C. Galloway, C. Graham, B. S. Koblin, B. A. McElrath, M. J. Duerr, A. TI Mucosal Sampling in an Early Phase HIV Vaccine Clinical Trial (HVTN069) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Mark, K. E.] Univ Washington, Seattle, WA 98195 USA. [Ding, Y.; Morgan, C.; Galloway, C.; McElrath, M. J.; Duerr, A.] Fred Hutchinson Canc Res Inst, Seattle, WA USA. [Graham, B. S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Koblin, B. A.] New York Blood Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 108 EP 108 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800273 ER PT J AU Goepfert, P Robinson, H Qin, L Hay, C Frey, S Blattner, W Wright, P Baden, L Elizaga, M Hural, J De Rosa, SC Defawe, OD Wyatt, L Moss, B AF Goepfert, P. Robinson, H. Qin, L. Hay, C. Frey, S. Blattner, W. Wright, P. Baden, L. Elizaga, M. Hural, J. De Rosa, S. C. Defawe, O. D. Wyatt, L. Moss, B. TI GeoVax Clade B DNA/MVA HIV Vaccine Induces Persistent Multifunctional Immune Responses when Administered to Healthy HIV Seronegative Adults (HVTN 065) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Goepfert, P.] Univ Alabama, Birmingham, AL USA. [Robinson, H.] GeoVax Inc, Atlanta, GA USA. [Qin, L.; Elizaga, M.; Hural, J.; De Rosa, S. C.; Defawe, O. D.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hay, C.] Univ Rochester, Rochester, NY USA. [Frey, S.] St Louis Univ, St Louis, MO 63103 USA. [Blattner, W.] Inst Human Virol, Baltimore, MD USA. [Wright, P.] Vanderbilt Univ, Nashville, TN USA. [Baden, L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wyatt, L.; Moss, B.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 110 EP 110 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800278 ER PT J AU Riou, C Burgers, WA Mlotshwa, M Rosa, DD Mlisana, K Koup, R Roederer, M Karim, SA Williamson, C Gray, CM AF Riou, C. Burgers, W. A. Mlotshwa, M. Rosa, D. de Assis Mlisana, K. Koup, R. Roederer, M. Karim, S. Abdool Williamson, C. Gray, C. M. TI Less Differentiated and More Long-Lived CD8+T Memory Cells during Early Subtype C HIV-1 Infection Correlates with Lower Viral Set Point SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Riou, C.; Mlotshwa, M.; Rosa, D. de Assis; Gray, C. M.] NICD, Johannesburg, Gauteng, South Africa. [Burgers, W. A.; Williamson, C.] UCT, Inst Infect Dis, Cape Town, Western Cape, South Africa. [Mlisana, K.; Karim, S. Abdool] Ctr AIDS Programme Res S Africa, Durban, Kwazulu Natal, South Africa. [Koup, R.; Roederer, M.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 126 EP 127 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800324 ER PT J AU Ferrari, G Garcia-Louzao, A Cox, J Sambor, A D'Souza, P Gray, C Jaimes, M Maecker, H Levine, G Koup, R Denny, T AF Ferrari, G. Garcia-Louzao, A. Cox, J. Sambor, A. D'Souza, P. Gray, C. Jaimes, M. Maecker, H. Levine, G. Koup, R. Denny, T. TI Establishing PBMC Repository for T Cell Assays Optimization and Proficiency Testing in CTC-VIMC Laboratories SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Ferrari, G.; Maecker, H.] Duke Univ, Med Ctr, Durham, NC USA. [Garcia-Louzao, A.; Denny, T.] Duke Human Vaccine Inst, Durham, NC USA. [Cox, J.] Int AIDS Vaccine Initiat, Rockville, MD USA. [Sambor, A.] Henry M Jackson Fdn, Rockville, MD USA. [D'Souza, P.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Gray, C.] Natl Inst Communicable Dis, Johannesburg, South Africa. [Jaimes, M.] BD, San Jose, CA USA. [Levine, G.] FNIH, Bethesda, MD USA. [Koup, R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 127 EP 128 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800326 ER PT J AU Frahm, N Price, DA Hartman, K Pereyra, F Walker, BD Douek, DC Brander, C AF Frahm, N. Price, D. A. Hartman, K. L. Pereyra, F. Walker, B. D. Douek, D. C. Brander, C. TI The Functional Avidity of HIV-Specific CTL Responses is Associated with Control of Viral Replication In Vivo SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Frahm, N.] Fred Hutchinson Canc Res Ctr, HVTN, Seattle, WA 98104 USA. [Price, D. A.; Douek, D. C.] NIAID, Human Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hartman, K. L.; Pereyra, F.; Walker, B. D.; Brander, C.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA USA. [Hartman, K. L.; Pereyra, F.; Walker, B. D.; Brander, C.] HMS, Charlestown, MA USA. RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 131 EP 131 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800335 ER PT J AU Manches, O Munn, D Fallahi, A Lifson, J Chaperot, L Plumas, J Bhardwaj, N AF Manches, O. Munn, D. Fallahi, A. Lifson, J. Chaperot, L. Plumas, J. Bhardwaj, N. TI HIV-Activated Plasmacytoid Dendritic Cells Induce Regulatory T Cells through an Indoleamine 2, 3 Dioxygenase Dependent Mechanism SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Manches, O.; Fallahi, A.; Bhardwaj, N.] NYU, Inst Canc, New York, NY USA. [Munn, D.] Med Coll Georgia, Immunotherapy Ctr, Augusta, GA 30912 USA. [Lifson, J.] NCI, AIDS & Canc Virus Program, Frederick, MD 21701 USA. [Chaperot, L.; Plumas, J.] Etab Francais Sang, Dept R&D, Grenoble, Isere, France. [Chaperot, L.; Plumas, J.] INSERM, U823, Grenoble, Isere, France. RI Plumas, Joel/N-2516-2013; chaperot, laurence/N-2927-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 133 EP 133 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800342 ER PT J AU Valentin, A von Gegerfelt, A Rosati, M Patel, V Miteloudis, G Alicea, C Jalah, R Khan, A Draghia-Akli, R Pavlakis, GN Felber, BK AF Valentin, A. von Gegerfelt, A. Rosati, M. Patel, V. Miteloudis, G. Alicea, C. Jalah, R. Khan, A. Draghia-Akli, R. Pavlakis, G. N. Felber, B. K. TI Persistent Virological Benefit in SIV-infected Macaques upon Therapeutic Vaccination with DNA Vectors by In Vivo Electroporation SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Valentin, A.; von Gegerfelt, A.; Rosati, M.; Patel, V.; Miteloudis, G.; Alicea, C.; Jalah, R.; Pavlakis, G. N.; Felber, B. K.] NCI, Frederick, MD 21701 USA. [Khan, A.; Draghia-Akli, R.] VGX Pharmaceut, The Woodlands, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 146 EP 147 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800378 ER PT J AU von Briesen, H Fenyo, E Holmes, H Karamov, EV Meyerhans, A Morgado, M Mullins, JI Osmanov, S Preiser, W Scarlatti, G Sharma, O Finzi, D Sutthent, R Zimmermann, H AF von Briesen, H. Fenyo, E. Holmes, H. Karamov, E. V. Meyerhans, A. Morgado, M. Mullins, J. I. Osmanov, S. Preiser, W. Scarlatti, G. Sharma, O. Finzi, D. Sutthent, R. Zimmermann, H. TI Global HIV Vaccine Research Cryorepository - GHRC SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [von Briesen, H.] Fraunhofer Inst Biomed Engn, St Ingbert, Saarland, Germany. [Fenyo, E.] Lund Univ, S-22100 Lund, Sweden. [Meyerhans, A.; Zimmermann, H.] Univ Saarland, Saarland, Germany. [Mullins, J. I.] Univ Washington, Seattle, WA 98195 USA. Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. [Sharma, O.; Finzi, D.] NIH, Bethesda, MD USA. RI Meyerhans, Andreas/D-3382-2014 OI Meyerhans, Andreas/0000-0003-0620-5317 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 150 EP 150 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800387 ER PT J AU Alexandre, KB Gray, E Pantophlet, R Chikwamba, R McMahon, J O'Keefe, B Morris, L AF Alexandre, K. B. Gray, E. Pantophlet, R. Chikwamba, R. McMahon, J. O'Keefe, B. Morris, L. TI IgG1b12 Binding of HIV-1 is Increased in the Presence of the Mannose-binding Lectin, Griffithsin SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT AIDS Vaccine 2008 Conference CY OCT 13-16, 2008 CL Cape Town, SOUTH AFRICA SP NIAID, Div AIDS, NIH, Div AIDS C1 [Alexandre, K. B.; Gray, E.; Morris, L.] Natl Inst Communicable Dis, Johannesburg, South Africa. [Pantophlet, R.] Scripps Res Inst, La Jolla, CA USA. [Chikwamba, R.] Ctr Sci & Ind Res, Pretoria, South Africa. [McMahon, J.; O'Keefe, B.] NCI Frederick, Ctr Canc Res, Frederick, MD USA. Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2008 VL 24 BP 151 EP 152 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 367CT UT WOS:000260530800391 ER PT J AU Simms, JA Steensland, P Medina, B Abernathy, KE Chandler, LJ Wise, R Bartlett, SE AF Simms, Jeffrey A. Steensland, Pia Medina, Brian Abernathy, Kenneth E. Chandler, L. Judson Wise, Roy Bartlett, Selena E. TI Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE animal models; alcohol; addiction; rats; acamprosate; naltrexone ID HYPOTHALAMIC STIMULATION; PERIODIC WITHDRAWAL; ALCOHOL-DRINKING; SELECTION; ACAMPROSATE; ABSTINENCE; PREFERENCE; EXPOSURE; EFFICACY AB Background: There has been some difficulty getting standard laboratory rats to voluntarily consume large amounts of ethanol without the use of initiation procedures. It has previously been shown that standard laboratory rats will voluntarily consume high levels of ethanol if given intermittent-access to 20% ethanol in a 2-bottle-choice setting [Wise, Psychopharmacologia 29 (1973), 203]. In this study, we have further characterized this drinking model. Methods: Ethanol-naive Long-Evans rats were given intermittent-access to 20% ethanol (three 24-hour sessions per week). No sucrose fading was needed and water was always available ad libitum. Ethanol consumption, preference, and long-term drinking behaviors were investigated. Furthermore, to pharmacologically validate the intermittent-access 20% ethanol drinking paradigm, the efficacy of acamprosate and naltrexone in decreasing ethanol consumption were compared with those of groups given continuous-access to 10 or 20% ethanol, respectively. Additionally, ethanol consumption was investigated in Wistar and out-bred alcohol preferring (P) rats following intermittent-access to 20% ethanol. Results: The intermittent-access 20% ethanol 2-bottle-choice drinking paradigm led standard laboratory rats to escalate their ethanol intake over the first 5 to 6 drinking sessions, reaching stable baseline consumption of high amounts of ethanol (Long-Evans: 5.1 +/- 0.6; Wistar: 5.8 +/- 0.8 g/kg/24 h, respectively). Furthermore, the cycles of excessive drinking and abstinence led to an increase in ethanol preference and increased efficacy of both acamprosate and naltrexone in Long-Evans rats. P-rats initiate drinking at a higher level than both Long-Evans and Wistar rats using the intermittent-access 20% ethanol paradigm and showed a trend toward a further escalation in ethanol intake over time (mean ethanol intake: 6.3 +/- 0.8 g/kg/24 h). Conclusion: Standard laboratory rats will voluntarily consume ethanol using the intermittent-access 20% ethanol drinking paradigm without the use of any initiation procedures. This model promises to be a valuable tool in the alcohol research field. C1 [Simms, Jeffrey A.; Steensland, Pia; Medina, Brian; Bartlett, Selena E.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. [Abernathy, Kenneth E.; Chandler, L. Judson] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Wise, Roy] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Bartlett, SE (reprint author), Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, 5858 Horton St,Suite 200, Emeryville, CA 94608 USA. EM selenab@gallo.ucsf.edu RI Wise, Roy/A-6465-2012; Bartlett, Selena/J-1345-2012; OI Bartlett, Selena/0000-0002-1741-3958; Steensland, Pia/0000-0003-4443-5017 FU UCSF; Department of Defense [W81XWH-06-1-0240, W81XWH-07-1-0075]; Foundation BLANCEFLOR Boncompagni-Ludovisi, nee Bildt; The Sweden-America Foundation; The Swedish Brain Foundation [AA010983]; Indiana University [AA015512-02] FX This work was supported by funding from the State of California for Medical Research through UCSF to SEB and Department of Defense Grants W81XWH-06-1-0240 and W81XWH-07-1-0075 to SEB, and by The Foundation BLANCEFLOR Boncompagni-Ludovisi, nee Bildt, The Sweden-America Foundation and The Swedish Brain Foundation awarded to PS, by AA010983 awarded to LJC, and by AA015512-02 that supports the P-rats at Indiana University. We thank Tiffany Ho and Haley Pierson for excellent technical assistance with the behavioral experiments. NR 24 TC 184 Z9 184 U1 0 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD OCT PY 2008 VL 32 IS 10 BP 1816 EP 1823 DI 10.1111/j.1530-0277.2008.00753.x PG 8 WC Substance Abuse SC Substance Abuse GA 349TV UT WOS:000259307100014 PM 18671810 ER PT J AU Lippincott, MF Desai, A Zalos, G Carlow, A De Jesus, J Blum, A Smith, K Rodrigo, M Patibandla, S Chaudhry, H Glaser, AP Schenke, WH Csako, G Waclawiw, MA Cannon, RO AF Lippincott, Margaret F. Desai, Aditi Zalos, Gloria Carlow, Andrea De Jesus, Janet Blum, Arnon Smith, Kevin Rodrigo, Maria Patibandla, Sushmitha Chaudhry, Hira Glaser, Alexander P. Schenke, William H. Csako, Gyorgy Waclawiw, Myron A. Cannon, Richard O., III TI Predictors of endothelial function in employees with sedentary occupations in a worksite exercise program SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; PROGENITOR CELLS; PHYSICAL-ACTIVITY; DEPENDENT VASODILATION; CARDIOVASCULAR RISK; TRAINING INCREASES; NITRIC-OXIDE; FITNESS; HEALTH; DYSFUNCTION AB A sedentary workforce may be at increased risk for future cardiovascular disease. Exercise at the work site has been advocated, but effects on endothelium as a biomarker of risk and relation to weight loss, lipid changes, or circulating endothelial progenitor cells (EPCs) have not been reported. Seventy-two office and laboratory employees (58 women; average age 45 years, range 22 to 62; 26 with body mass index values >30 kg/m(2)) completed 3 months of participation in the National Heart, Lung, and Blood Institute's Keep the Beat program, with the determination of vital signs, laboratory data, and peak oxygen consumption (VO2) during treadmill exercise. Brachial artery endothelium was tested by flow-mediated dilation (FMD), which at baseline was inversely associated with Framingham risk score (r = -0.3689, p <0.0001). EPCs were quantified by colony assay. With exercise averaging 98 +/- 47 minutes each workweek, there was improvement in FMD (from 7.8 +/- 3.4% to 8.5 +/- 3.0%, p = 0.0096) and peak VO2 (+1.2 +/- 3.1 ml O-2/kg/min, p = 0.0028), with reductions in diastolic blood pressure (-2 +/- 8 mm Hg, p = 0.0478), total cholesterol (-8 +/- 25 mg/dl, p = 0.0131), and low-density lipoprotein cholesterol (-7 +/- 19 mg/dl, p = 0.0044) but with a marginal reduction in weight (-0.5 +/- 2.1 kg, p = 0.0565). By multiple regression modeling, lower baseline FMD, greater age, reductions in total and low-density lipoprotein cholesterol and diastolic blood pressure, and increases in EPC colonies and peak VO2 were jointly statistically significant predictors of change in FMD and accounted for 47% of the variability in FMD improvement with program participation. Results were similar when modeling was performed for women only. In contrast, neither adiposity at baseline nor change in weight was a predictor of improved endothelial function. In conclusion, daily exercise achievable at their work sites by employees with sedentary occupations improves endothelial function, even with the absence of weight loss, which may decrease cardiovascular risk, if sustained. (C) 2008 Elsevier Inc. All rights reserved. C1 [Lippincott, Margaret F.; Desai, Aditi; Zalos, Gloria; Carlow, Andrea; Blum, Arnon; Smith, Kevin; Rodrigo, Maria; Patibandla, Sushmitha; Chaudhry, Hira; Glaser, Alexander P.; Schenke, William H.; Cannon, Richard O., III] NHLBI, Translat Med Branch, Bethesda, MD 20892 USA. [De Jesus, Janet] NHLBI, Off Director, Bethesda, MD 20892 USA. [Waclawiw, Myron A.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Csako, Gyorgy] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Translat Med Branch, Bldg 10, Bethesda, MD 20892 USA. EM cannonr@nih.gov OI Lippincott, Margaret/0000-0002-3533-1999 FU National Heart, Lung, and Blood Institute and the Clinical Center, NIH FX This research was funded by the intramural research programs of the National Heart, Lung, and Blood Institute and the Clinical Center, NIH. NR 23 TC 18 Z9 18 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD OCT 1 PY 2008 VL 102 IS 7 BP 820 EP 824 DI 10.1016/j.amjcard.2008.05.020 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 354CI UT WOS:000259616100005 PM 18805104 ER PT J AU Gluck, ME Venti, CA Salbe, AD Krakoff, J AF Gluck, Marci E. Venti, Colleen A. Salbe, Arline D. Krakoff, Jonathan TI Nighttime eating: commonly observed and related to weight gain in an inpatient food intake study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID X-RAY ABSORPTIOMETRY; OBESE-PATIENTS; DISORDER; QUESTIONNAIRE; INDIVIDUALS; OUTPATIENTS; POPULATION; PREVALENCE; PATTERNS; SURGERY AB Background: Nighttime food intake has rarely been studied in inpatient settings and only one study observed a relation between self-reported nighttime eating and weight gain. Objective: We investigated the prevalence of nighttime eating and its effect on weight change. Design: Healthy nondiabetic Pima Indians (n = 117; 67M, 50 F) and whites (n = 43; 29 M, 13 F) were admitted to a clinical research unit. After consuming a standardized diet for 3 d, participants ate ad libitum from a computer-operated vending machine that recorded the time of food selection. Energy intake was calculated as mean kcal/d. Follow-up weight was available for 94 volunteers. Results: Fifty-five subjects (36%) were nighttime eaters (NEs; persons who ate between 2300 and 0500 on >= 1 of the 3 d). Prevalence was similar among whites and Pima Indians (37% and 35%, respectively). There were no significant differences in body mass index or percentage body fat between NEs and non-NEs. NEs consumed more calories per day (4758) than did non-NEs (4244; P = 0.02), but the percentage of calories from macronutrients did not differ. NEs consumed approximate to 15% (690 kcal) of their daily energy during nighttime episodes. After control for baseline weight and follow-up time ((x) over bar +/- SD: 3.4 +/- 1.8 y), NEs (n = 29) gained more weight (6.2 kg) than did non-NEs (n = 65; 1.7 kg; P = 0.03). Conclusions: Nighttime eating was common, and it predicted weight gain. It remains to be determined whether this behavior indicates abnormal sleep patterns leading to nighttime wakefulness and food intake in those prone to weight gain. C1 [Gluck, Marci E.; Venti, Colleen A.; Krakoff, Jonathan] NIDDK, ODCRS, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. [Salbe, Arline D.] Kronos Longev Res Inst, Phoenix, AZ USA. RP Gluck, ME (reprint author), NIDDK, ODCRS, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St,Room 541, Phoenix, AZ 85016 USA. EM gmarci@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 38 TC 38 Z9 38 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD OCT 1 PY 2008 VL 88 IS 4 BP 900 EP 905 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 358FX UT WOS:000259903600006 PM 18842774 ER PT J AU Zimmermann, MB Fucharoen, S Winichagoon, P Sirankapracha, P Zeder, C Gowachirapant, S Judprasong, K Tanno, T Miller, JL Hurrell, RF AF Zimmermann, Michael B. Fucharoen, Suthat Winichagoon, Pattanee Sirankapracha, Pornpan Zeder, Christophe Gowachirapant, Sueppong Judprasong, Kunchit Tanno, Toshihiko Miller, Jeffery L. Hurrell, Richard F. TI Iron metabolism in heterozygotes for hemoglobin E (HbE), alpha-thalassemia 1, or beta-thalassemia and in compound heterozygotes for HbE/beta-thalassemia SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CELL-CYCLE DISTRIBUTION; SERUM FERRITIN LEVELS; IDIOPATHIC HEMOCHROMATOSIS; ERYTHROPOIETIC CELLS; LOADING ANEMIAS; FOOD IRON; ABSORPTION; OVERLOAD; TRAIT; HEPCIDIN AB Background: Despite large populations carrying traits for thalassemia in countries implementing universal iron fortification, there are few data on the absorption and utilization of iron in these persons. Objective: We aimed to determine whether iron absorption or utilization (or both) in women heterozygous for beta-thalassemia, alpha-thalassemia 1, or hemoglobin E(HbE) differed from that in control subjects and compound HbE/beta-thalassemia heterozygotes. Design: In Thai women (n = 103), red blood cell indexes, iron status, non-transferrin-bound iron, and growth differentiation factor 15 were measured, and body iron was calculated. Fractional iron absorption was measured from meals fortified with isotopically labeled ((57)Fe) Fe sulfate, and iron utilization was measured by the infusion of ((58)Fe) Fe citrate. Results: Iron utilization was approximate to 15% lower in alpha-thalassemia 1 or beta-thalassemia heterozygotes than in controls. When corrected for differences in serum ferritin, absorption was significantly higher in the alpha-and beta-thalassemia groups, but not the HbE heterozygotes, than in controls. HbE/beta-thalassemia compound heterozygotes had lower iron utilization and higher iron absorption and body iron than did controls. Nontransferrin-bound iron and growth differentiation factor 15 were higher in the compound heterozygotes, but not in the other groups, than in the controls. Conclusions: In alpha-thalassemia 1 and beta-thalassemia heterozygotes with ineffective erythropoesis, dietary iron absorption is not adequately down-regulated, despite a modest increase in body iron stores. In populations with a high prevalence of these traits, a program of iron fortification could include monitoring for possible iron excess and for iron deficiency. C1 [Zimmermann, Michael B.] ETH, Swiss Fed Inst Technol, Human Nutr Lab, CH-8092 Zurich, Switzerland. [Fucharoen, Suthat; Sirankapracha, Pornpan] Mahidol Univ, Thalassemia Res Ctr, Inst Sci & Technol Res & Dev, Salaya, Nakon Pathom, Thailand. [Winichagoon, Pattanee; Gowachirapant, Sueppong; Judprasong, Kunchit] Mahidol Univ, Inst Nutr, Salaya, Nakon Pathom, Thailand. [Tanno, Toshihiko; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. RP Zimmermann, MB (reprint author), ETH, Swiss Fed Inst Technol, Human Nutr Lab, Schmelzbergstr 7,LFV E19, CH-8092 Zurich, Switzerland. EM michael.zimmermann@ilw.agrl.ethz.ch RI Zimmermann, Michael/C-3062-2016 FU SUSTAIN (Washington, DC); The Global Alliance for Improved Nutrition (Geneva, Switzerland); International Atomic Energy Agency (Vienna, Austria); Swiss Federal Institute of Technology (ETH) Zurich (Zurich, Switzerland) FX Supported by SUSTAIN (Washington, DC), The Global Alliance for Improved Nutrition (Geneva, Switzerland), the International Atomic Energy Agency (Vienna, Austria), and the Swiss Federal Institute of Technology (ETH) Zurich (Zurich, Switzerland). SF is a senior research scholar of The Thailand Research Fund. NR 45 TC 22 Z9 26 U1 1 U2 4 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD OCT 1 PY 2008 VL 88 IS 4 BP 1026 EP 1031 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 358FX UT WOS:000259903600022 PM 18842790 ER PT J AU He, K Liu, K Daviglus, ML Mayer-Davis, E Jenny, NS Jiang, R Ouyang, P Steffen, LM Siscovick, D Wu, CL Barr, RG Tsai, M Burke, GL AF He, Ka Liu, Kiang Daviglus, Martha L. Mayer-Davis, Elisabeth Jenny, Nancy Swords Jiang, Rui Ouyang, Pamela Steffen, Lyn M. Siscovick, David Wu, Colin Barr, R. Graham Tsai, Michael Burke, Gregory L. TI Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CORONARY-HEART-DISEASE; PERIPHERAL ARTERIAL-DISEASE; ANKLE BRACHIAL INDEX; ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; DIETARY SUPPLEMENTATION; POSTMENOPAUSAL WOMEN; NONHUMAN-PRIMATES; CONTROLLED-TRIALS AB Background: Data on the relations of different types of fish meals and long- chain n-3 polyunsaturated fatty acids (PUFAs) to measures of atherosclerosis are sparse. Objective: We examined intakes of long-chain n-3 PUFAs and fish in relation to clinical measures of subclinical atherosclerosis. Design: A cross-sectional study was conducted in a multiethnic group of 5488 adults aged 45-84 y and free of clinical cardiovascular disease. Diet was assessed by using self-administered food-frequency questionnaires. Subclinical atherosclerosis was determined by measurements of common carotid intima-media thickness (cCIMT, > 80th percentile), internal CIMT (iCIMT, > 80th percentile), coronary artery calcium score (CAC score, > 0), or ankle-brachial index (ABI, < 0.90). Results: After adjustment for potential confounders, intakes of long-chain n-3 PUFAs and nonfried (broiled, steamed, baked, or raw) fish were inversely related to subclinical atherosclerosis determined by cCIMT but not by iCIMT, CAC score, or ABI. The multivariate odds ratio comparing the highest to the lowest quartile of dietary exposures in relation to subclinical atherosclerosis determined by cCIMT was 0.69 (95% CI: 0.55, 0.86; P for trend < 0.01) for n-3 PUFA intake; 0.80 (95% CI: 0.64, 1.01; P = 0.054) for nonfried fish consumption; and 0.90 (95% CI: 0.73, 1.11; P = 0.38) for fried fish consumption. Conclusions: This study indicates that the dietary intake of long-chain n-3 PUFAs or nonfried fish is associated with a lower prevalence of subclinical atherosclerosis classified by cCIMT, although significant changes in iCIMT, CAC score, and ABI were not observed. Our findings also suggest that the association of fish and atherosclerosis may vary depending on the type of fish meal consumed and the measures of atherosclerosis. C1 [He, Ka] Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. [He, Ka] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [He, Ka; Mayer-Davis, Elisabeth] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Liu, Kiang; Daviglus, Martha L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Jenny, Nancy Swords] Univ Vermont, Coll Med, Colchester, VT, England. [Jiang, Rui; Barr, R. Graham] Columbia Univ, Med Ctr, New York, NY USA. [Ouyang, Pamela] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Steffen, Lyn M.; Tsai, Michael] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Siscovick, David] Univ Washington, Sch Med, Seattle, WA USA. [Wu, Colin] NHLBI, Bethesda, MD 20892 USA. [Burke, Gregory L.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. RP He, K (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Nutr, 2202 McGavran Greenberg Hall,CB 7461, Chapel Hill, NC 27599 USA. EM kahe@unc.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [N01-HC-95159, N01-HC-95161, N01-HC95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, HL077612] FX Supported by grants no. N01-HC-95159, N01-HC-95161, N01-HC95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, and HL077612 from the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 46 TC 41 Z9 42 U1 0 U2 4 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 OCT 1 PY 2008 VL 88 IS 4 BP 1111 EP 1118 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 358FX UT WOS:000259903600033 PM 18842801 ER PT J AU Jatoi, I Anderson, WF Rosenberg, PS AF Jatoi, Ismail Anderson, William F. Rosenberg, Philip S. TI Qualitative Age-interactions in Breast Cancer A Tale of Two Diseases? SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Review DE Breast cancer; qualitative age-interactions; early-onset; late-onset; low-risk; high-risk ID UNITED-STATES; WOMEN; RISK; HETEROGENEITY; DIAGNOSIS; MORTALITY; TRENDS; TRIAL AB A qualitative age-interaction is defined as the reversal of relative risks or rates according to age at Onset. Once thought rare, qualitative age-interactions are commonly reported in studies that examine the etiology, prognosis, and treatment of breast cancer. Thus, nulliparity, obesity, and oral contraceptives decrease breast cancer risk in younger women but increase risk in older women. High-risk tumors are more common in younger women, whereas low-risk tumors are more common among the elderly, with bimodal peak frequencies at ages 50 and 70, respectively. Curves depicting the annual hazard of breast cancer death for women with high-risk (early-onset) and low-risk (late-onset) turners are shaped differently and move in opposite directions. Additionally, mammography screening and neo-adjuvant chemotherapy seem to have opposing effects in women with early and late-onset tumors. Taken together. these qualitative age-interactions may indicate that early and late-onset breast cancers are different diseases, derived from different pathways. C1 [Jatoi, Ismail] Natl Naval Med Ctr, Breast Care Ctr, Dept Surg, Bethesda, MD 20889 USA. [Jatoi, Ismail] Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. [Anderson, William F.; Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. RP Jatoi, I (reprint author), Natl Naval Med Ctr, Breast Care Ctr, Dept Surg, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM ismail.jatoi@us.army.mil FU NIH; National Cancer Institute FX This work was supported in part by the Intramural Research Program of the NIH/National Cancer Institute. NR 20 TC 17 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD OCT PY 2008 VL 31 IS 5 BP 504 EP 506 DI 10.1097/COC.0b013e3181844d1c PG 3 WC Oncology SC Oncology GA 361JD UT WOS:000260123000017 PM 18838890 ER PT J AU Accetta, NA Gladstone, EH DiSogra, C Wright, EC Briggs, M Narva, AS AF Accetta, Nancy A. Gladstone, Elisa H. DiSogra, Charles Wright, Elizabeth C. Briggs, Michael Narva, Andrew S. TI Prevalence of estimated GFR reporting among US clinical laboratories SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE estimated glomerular filtration rate (eGFR); laboratory reporting; serum creatinine; kidney disease ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; SERUM CREATININE; PROGRAM AB Background: Routine laboratory reporting of estimated glomerular filtration rate (eGFR) may help clinicians detect kidney disease. The current national prevalence of eGFR reporting in clinical laboratories is unknown; thus, the extent of the situation of laboratories not routinely reporting eGFR with serum creatinine results is not quantified. Design: Observational analysis. Setting: National Kidney Disease Education Program survey of clinical laboratories conducted in 2006 to 2007 by mail, web, and telephone follow-up. Participants: A national random sample, 6,350 clinical laboratories, drawn from the Federal Clinical Laboratory Improvement Amendments database and stratified by 6 major laboratory types/groupings. Predictors: Laboratory reports serum creatinine results. Outcomes: Reporting eGFR values with serum creatinine results. Measurements: Percentage of laboratories reporting eGFR along with reporting serum creatinine values, reporting protocol, eGFR formula used, and style of reporting cutoff values. Results: Of laboratories reporting serum creatinine values, 38.4% report eGFR (physician off ices, 25.8%; hospitals, 43.6%; independents, 38.9%; community clinics, 47.2%; health fair/insurance/public health, 45.5%; and others, 43.2%). Physician office laboratories have a reporting prevalence lower than other laboratory types (P < 0.001). Of laboratories reporting eGFR, 66.7% do so routinely with all adult serum creatinine determinations; 71.6% use the 4-variable Modification of Diet in Renal Disease Study equation; and 45.3% use the ">60 mUmin/1.73 m(2)" reporting convention. Independent laboratories are least likely to routinely report eGFR (50.6%; P < 0.05) and most likely to report only when specifically requested (45.4%; P < 0.05). High-volume laboratories across all strata are more likely to report eGFR (P < 0.001). Limitations: Self-reporting by laboratories, federal database did not have names of laboratory directors/managers (intended respondents), assumed accuracy of federal database for sample purposes. Conclusions: Routine eGFR reporting with serum creatinine values is not yet universal, and laboratories vary in their reporting practices. C1 [Accetta, Nancy A.; Gladstone, Elisa H.; Wright, Elizabeth C.; Briggs, Michael; Narva, Andrew S.] NIDDK, Natl Kidney Dis Educ Program, NIH, Bethesda, MD 20892 USA. [DiSogra, Charles] Field Res Corp, San Francisco, CA USA. RP Narva, AS (reprint author), NIDDK, Natl Kidney Dis Educ Program, NIH, 2 Democracy Plaza,Rm 645,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov FU NKDEP; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX We gratefully acknowledge the assistance of Anna Zawislanski, MPH, from the NKDEP.; Support: This research was funded by the NKDEP, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.; Financial Disclosure: None. NR 12 TC 27 Z9 27 U1 0 U2 3 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 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD OCT PY 2008 VL 52 IS 4 BP 778 EP 787 DI 10.1053/j.ajkd.2008.05.023 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 357NR UT WOS:000259853900020 PM 18676076 ER PT J AU Schell-Apacik, CC Wagner, K Bihler, M Ertl-Wagner, B Heinrich, U Klopocki, E Kalscheuer, VM Muenke, M von Voss, H AF Schell-Apacik, Chayim Can Wagner, Kristina Bihler, Moritz Ertl-Wagner, Birgit Heinrich, Uwe Klopocki, Eva Kalscheuer, Vera M. Muenke, Maximilian von Voss, Hubertus TI Agenesis and Dysgenesis of the Corpus Callosum: Clinical, Genetic and Neuroimaging Findings in a Series of 41 Patients SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE agenesis or dysgenesis of the corpus callosum; clinical-genetic study; MR imaging ID MENTAL-RETARDATION; PARTIAL TRISOMY; SPINAL-CORD; GUIDANCE; COMMISSURES; BRAIN; AXONS AB Agenesis of the corpus callosum (ACC) is among the most frequent human brain malformations with an incidence of 0.5-70 in 10,000. It is a heterogeneous condition, for which several different genetic causes are known, for example, ACC as part of monogenic syndromes or complex chromosomal rearrangements. We systematically evaluated the data of 172 patients with documented corpus callosum abnormalities in the records, and 23 patients with chromosomal rearrangements known to be associated with corpus callosum changes. All available neuroimaging data, including CT and MRI, were re-evaluated following a standardized protocol. Whenever feasible chromosome and subtelomere analyses as well as molecular genetic testing were performed in patients with disorders of the corpus callosum in order to identify a genetic diagnosis. Our results showed that 41 patients with complete absence (agenesis of the corpus callosum-ACC) or partial absence (dysgenesis of the corpus callosum-DCC) were identified. Out of these 28 had ACC, 13 had DCC. In 11 of the 28 patients with ACC, the following diagnoses could be established: Mowat-Wilson syndrome (n=2), Walker-Warburg syndrome (n=1), oro-facial-digital syndrome type 1 (n=1), and chromosomal rearrangements (n=7), including a patient with in apparently balanced reciprocal translocation, which led to the disruption and a predicted loss of function in the FOXG1B gene. The cause of the ACC in 17 patients remained unclear. In 2 of the 13 patients with DCC, unbalanced chromosomal rearrangements could he detected (n=2), while the cause of DCC in 11 patients remained unclear. In our series of cases a variety of genetic causes of disorders of the Corpus callosum were identified with cytogenetic anomalies representing the most common Underlying etiology. (c) 2008 Wiley-Liss, Inc. C1 [Schell-Apacik, Chayim Can] Univ Munich, Kinderzentrum Munchen, Inst Social Pediat & Adolescent Med, Med Genet Unit, D-81377 Munich, Germany. [Ertl-Wagner, Birgit] Univ Munich, Inst Clin Radiol, D-81377 Munich, Germany. [Heinrich, Uwe] Ctr Human Genet & Lab Med, Martinsried, Germany. [Klopocki, Eva] Charite Univ Med Berlin, Inst Med Genet, D-13353 Berlin, Germany. [Kalscheuer, Vera M.] Max Planck Inst Mol Genet, Berlin, Germany. [Muenke, Maximilian] NHGRI, NIH, Bethesda, MD 20892 USA. RP Schell-Apacik, CC (reprint author), Univ Munich, Kinderzentrum Munchen, Inst Social Pediat & Adolescent Med, Med Genet Unit, Heiglhofstr 63, D-81377 Munich, Germany. EM schell-apacik@gmx.de RI Klopocki, Eva/B-6823-2017; OI Klopocki, Eva/0000-0003-1438-2081; Kalscheuer, Vera/0000-0001-6898-3259 FU Else Kroener-Fresenius Foundation FX We sincerely thank the patients and their families for participation in this study, M. Wettwer for performing the chromosome and subtelomere analyses, R. Ullmann and the Max-Planck-Institute of Molecular Genetics, Berlin, for providing the BAC array for array-CGH analysis as well as F. Trotier for her technical assistance. This work was supported by the Else Kroener-Fresenius Foundation. NR 35 TC 56 Z9 58 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT 1 PY 2008 VL 146A IS 19 BP 2501 EP 2511 DI 10.1002/ajmg.a.32476 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 362MV UT WOS:000260202700008 PM 18792984 ER PT J AU Goodwin, TM Nwankwo, OA O'Leary, LD O'Leary, D Romero, R Korst, LM AF Goodwin, Thomas Murphy Nwankwo, Odinaka A. O'Leary, Linda Davis O'Leary, Dennis Romero, Roberto Korst, Lisa M. TI The first demonstration that a subset of women with hyperemesis gravidarum has abnormalities in the vestibuloocular reflex pathway SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med DE autorotation; hyperemesis gravidarum; nausea; vestibular; vestibuloocular reflex; vomiting ID MIGRAINE HEADACHE; UNDERSTANDING MECHANISMS; OVARIAN HORMONES; MOTION SICKNESS; HUMAN-PREGNANCY; NAUSEA; SUSCEPTIBILITY; PATHOGENESIS; THIRST AB OBJECTIVE: The vestibular system is a major pathway to nausea and vomiting, and the vestibuloocular reflex (VOR) is a central component; its function can be studied using the vestibular autorotation test (VAT). We hypothesize that women with hyperemesis gravidarum (HG) may have VOR abnormalities. STUDY DESIGN: Women with HG were compared with women without HG using the VAT. Horizontal and vertical VOR gains and phases were evaluated at 3 frequency ranges: low (2.0 to 3.5 Hz), medium (greater than 3.5 to 5.0 Hz), and high (greater than 5.0 to 6.0 Hz) during pregnancy and postpartum. RESULTS: Twenty women with HG and 48 unaffected women were evaluated in early pregnancy. Women with HG had higher horizontal gains at all 3 frequency ranges. Horizontal phase differences were also observed at medium frequencies. No VAT differences were noted postpartum. CONCLUSION: Women experiencing HG had a higher mean VOR horizontal gain and lower horizontal phase when compared with unaffected women. C1 [Goodwin, Thomas Murphy; Nwankwo, Odinaka A.; Korst, Lisa M.] Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. [O'Leary, Linda Davis; O'Leary, Dennis] Univ So Calif, Keck Sch Med, Dept Otolaryngol, Los Angeles, CA 90033 USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. RP Goodwin, TM (reprint author), Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. FU Intramural NIH HHS; NICHD NIH HHS [N01 HD023342] NR 29 TC 1 Z9 1 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2008 VL 199 IS 4 AR 417.e1 DI 10.1016/j.ajog.2008.07.003 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 360GJ UT WOS:000260045700036 PM 18928993 ER PT J AU Spinnato, JA Freire, S Silva, JLPE Rudge, MVC Martins-Costa, S Koch, MA Goco, N Santos, CD Cecatti, JG Costa, R Ramos, JG Moss, N Sibai, BM AF Spinnato, Joseph A., II Freire, Salvio Pinto e Silva, Joao Luiz Cunha Rudge, Marilza Vieira Martins-Costa, Sergio Koch, Matthew A. Goco, Norman Santos, Cleide de Barros Cecatti, Jose Guilherme Costa, Roberto Ramos, Jose Geraldo Moss, Nancy Sibai, Baha M. TI Antioxidant supplementation and premature rupture of the membranes: a planned secondary analysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med DE antioxidants; premature rupture of the membranes; prematurity; prevention; vitamin C; vitamin E ID PLACEBO-CONTROLLED TRIAL; VITAMIN-C; RANDOMIZED-TRIAL; PREECLAMPSIA; RISK; WOMEN; ACID AB OBJECTIVE: The purpose of this study was to determine if antioxidant supplementation during pregnancy reduces the incidence of premature rupture of the membranes (PROM). STUDY DESIGN: A placebo-controlled, double-blind trial was conducted. PROM and preterm PROM (PPROM) were planned secondary outcomes of the trial. Women between 12(0/7) and 19(6/7) weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomized to daily treatment with both vitamin C (1000 mg) and E (400 IU) or placebo. RESULTS: Outcome data for PROM were available for 697 of 739 patients. The rates of PROM (37/349 [10.6%] vs 19/348 [5.5%]; adjusted risk ratio [RR] 1.89 [95.42% CI, 1.11-3.23]; P = .015), and PPROM (16/349 [4.6%] vs 6/348 [1.7%]; RR 2.68 [1.07-6.71]; P = .025) were increased in the antioxidant group. CONCLUSION: Contrary to expectations, vitamins C and E supplementation in this dose combination may be associated with an increased risk of PROM and PPROM. C1 [Spinnato, Joseph A., II; Sibai, Baha M.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Freire, Salvio; Santos, Cleide de Barros] Univ Fed Pernambuco, Hosp Clin, Recife, PE, Brazil. [Pinto e Silva, Joao Luiz; Cecatti, Jose Guilherme] Univ Estadual Campinas, Campinas, SP, Brazil. [Cunha Rudge, Marilza Vieira; Costa, Roberto] Univ Estadual Paulista, Botucatu, SP, Brazil. [Martins-Costa, Sergio; Ramos, Jose Geraldo] Univ Fed Rio Grande do Sul, Hosp & Clin, Porto Alegre, RS, Brazil. [Koch, Matthew A.; Goco, Norman] RTI Int, Res Triangle Pk, NC USA. [Moss, Nancy] NICHHD, Bethesda, MD 20892 USA. RP Spinnato, JA (reprint author), Univ Cincinnati, Coll Med, Cincinnati, OH USA. RI Rudge, Marilza /C-8338-2012 OI Rudge, Marilza /0000-0002-9227-832X FU NICHD NIH HHS [U01 HD040565, 1 U01 HD40565, U01 HD040565-01, U01 HD040565-02, U01 HD040565-03, U01 HD040565-04, U01 HD040565-05, U01 HD040565-05S1] NR 19 TC 6 Z9 7 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2008 VL 199 IS 4 AR 433.e1 DI 10.1016/j.ajog.2008.07.011 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 360GJ UT WOS:000260045700042 PM 18928997 ER PT J AU Vaisbuch, E Romero, R Erez, O Kusanovic, JP Gotsch, F Than, NG Mazaki-Tovi, S Mittal, P Edwin, S Hassan, SS AF Vaisbuch, Edi Romero, Roberto Erez, Offer Kusanovic, Juan Pedro Gotsch, Francesca Than, Nandor G. Mazaki-Tovi, Shali Mittal, Pooja Edwin, Sam Hassan, Sonia S. TI Total hemoglobin concentration in amniotic fluid is increased in intraamniotic infection/inflammation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med DE chorioamnionitis; microbial invasion of the amniotic cavity; pregnancy; preterm prelabor rupture of membranes (PPROM); preterm labor; vaginal bleeding ID MATERNAL HEMORRHAGE; INTRAUTERINE INFECTION; MICROBIAL INVASION; BACTERIAL-GROWTH; ECHOGENIC BOWEL; PRETERM LABOR; AMNIOCENTESIS; BROWN; IRON; CIRCUMVALLATE AB OBJECTIVE: Discolored amniotic fluid (AF) has been associated with intraamniotic infection/inflammation (IAI) in patients with preterm labor (PTL). The presence of hemoglobin and its catabolic products has been implicated as a cause for AF discoloration. The aim of this study was to determine whether there is an association between total hemoglobin concentration in AF and gestational age, spontaneous labor (term and preterm), and the presence or absence of IAI. STUDY DESIGN: This cross-sectional study included patients in the following groups: (1) mid trimester (n = 65 patients); (2) term not in labor (n = 22 patients); (3) term in labor (n = 47 patients); (4) spontaneous PTL who delivered at term (n = 92 patients); (5) PTL without IAI who delivered preterm (n = 76 patients); (6) PTL with IAI (n = 81 patients); (7) preterm prelabor rupture of the membranes (PPROM) with IAI (n = 48 patients); and (8) PPROM without IAI (n = 49 patients). Total hemoglobin concentrations in amniotic fluid were determined by an enzyme-linked immunoassay. Nonparametric statistics were used for analysis. RESULTS: Hemoglobin was detected in all AF samples (n = 480). The median AF total hemoglobin concentration at term was significantly higher than in mid trimester (520.6 ng/mL [interquartile range (IQR), 271.2-1549.2] vs 58.5 ng/mL [IQR, 26.1-200.8]; P = .001]). Among patients with PTL, the median AF total hemoglobin concentration was significantly higher in patients with IAI than in patients without IAI (4671.7 ng/mL [IQR, 1294.2-8620.7] vs 2013.6 ng/mL [IQR, 629.2-5420.4]; P = .01) or women who delivered at term (1143.4 ng/mL [IQR, 451.8-4037.9]; P = .001). Similarly, among patients with PPROM, the median AF total hemoglobin concentration was significantly higher in patients with IAI than in patients without IAI (10753.7 ng/mL [IQR, 2053.9-56026.6] vs 2281 ng/mL [IQR, 938.2-9191.7]; P = .02). Women at term in labor had a higher median hemoglobin concentration than did women who were not in labor (1952.6 ng/mL [IQR, 709.6-6289.2] vs 520.6 ng/mL [IQR, 271.1-1549.2]; P = .003). CONCLUSION: The AF concentration of immunoreactive total hemoglobin increases with advancing gestational age, and is elevated in pregnancies that are complicated with IAI. Spontaneous labor at term is associated with higher AF concentrations of total hemoglobin. C1 [Vaisbuch, Edi; Erez, Offer; Kusanovic, Juan Pedro; Gotsch, Francesca; Than, Nandor G.; Mazaki-Tovi, Shali; Mittal, Pooja; Edwin, Sam; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Vaisbuch, Edi; Erez, Offer; Kusanovic, Juan Pedro; Gotsch, Francesca; Than, Nandor G.; Mazaki-Tovi, Shali; Mittal, Pooja; Edwin, Sam; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Vaisbuch, Edi; Erez, Offer; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Mittal, Pooja; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Intramural NIH HHS [ZIA HD002400-18] NR 39 TC 3 Z9 3 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2008 VL 199 IS 4 AR 426.e1 DI 10.1016/j.ajog.2008.06.075 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 360GJ UT WOS:000260045700039 PM 18928995 ER PT J AU Forooghian, F Macdonald, IM Heckenlively, JR Heon, E Gordon, LK Hooks, JJ Detrick, B Nussenblatt, RB AF Forooghian, Farzin Macdonald, Ian M. Heckenlively, John R. Heon, Elise Gordon, Lynn K. Hooks, John J. Detrick, Barbara Nussenblatt, Robert B. TI The need for standardization of antiretinal antibody detection and measurement SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CANCER-ASSOCIATED RETINOPATHY; ALPHA-ENOLASE AUTOANTIBODIES; PARANEOPLASTIC RETINOPATHY; AUTOIMMUNE RETINOPATHY; RETINAL AUTOANTIBODIES; RECOVERIN ANTIBODIES; PHOTORECEPTOR DEGENERATION; RETINITIS-PIGMENTOSA; ENDOMETRIAL CANCER; APOPTOTIC DEATH AB PURPOSE: To review the current literature on the detection and measurement of antiretinal antibodies. DESIGN: Collaborative essay. METHODS: Literature review and interpretation. RESULTS: There is strong evidence to suggest a role for antiretinal antibodies, particularly those targeting recoverin and alpha-enolase, in the pathogenesis of autoimmune retinopathy (AIR). Additionally, numerous other autoantibodies have been described as putative mediators of retinal degeneration and more remain to be discovered. However, assay methods described in the literature by many laboratories for the detection of circulating antiretinal antibodies have been varied and diverse, making it difficult to interpret and compare their results. CONCLUSIONS: There is currently little standardization of laboratory methods used to detect and monitor antiretinal antibodies. To measure and monitor levels of circulating antiretinal antibodies optimally in patients with AIR, development of standardized assays with stringent internal controls is required. A multicenter collaborative and validation effort is encouraged to reach a consensus on this issue. C1 [Hooks, John J.; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Forooghian, Farzin] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Macdonald, Ian M.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Heckenlively, John R.] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Heon, Elise] Univ Toronto, Dept Ophthalmol & Vis Sci, Toronto, ON, Canada. [Heon, Elise] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Gordon, Lynn K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Jules Stein Eye Inst,Ocular Inflammatory Dis Ctr, Los Angeles, CA 90095 USA. [Gordon, Lynn K.] Greater Los Angeles Vet Affairs Healthcare Serv, Los Angeles, CA USA. [Nussenblatt, Robert B.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Rm 10N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov OI MacDonald, Ian/0000-0001-7472-8385 FU NATIONAL EYE INSTITUTE INTRAMURAL RESEARCH PROGRAM, NATIONAL INSTITUTES of Health, Bethesda, Maryland FX THIS STUDY WAS SUPPORTED BY THE NATIONAL EYE INSTITUTE INTRAMURAL RESEARCH PROGRAM, NATIONAL INSTITUTES of Health, Bethesda, Maryland. The authors indicate no financial conflict of interest. Involved in design and conduct of study (F.F., I.M.M., J.R.H., E.H., L.K.G., J.H.J., B.D., R.B.N.); collection, management, analysis, and interpretation of the data (F.F., I.M.M., J.R.H., E.H., L.K.G., J.H.J., B.D., R.B.N.); and preparation, review, and approval of the manuscript (F.F., I.M.M., J.R.H., E.H., L.K.G., J.H.J., B.D., R.B.N.). The authors thank Dr Robert Fariss, National Eye Institute, Bethesda, Maryland for his technical advice on immunohistochemical detection of antiretinal antibodies. NR 62 TC 25 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD OCT PY 2008 VL 146 IS 4 BP 489 EP 495 DI 10.1016/j.ajo.2008.05.046 PG 7 WC Ophthalmology SC Ophthalmology GA 355XH UT WOS:000259742200003 PM 18672221 ER PT J AU Isenberg, JS Maxhimer, JB Hyodo, F Perndrak, ML Ridnour, LA DeGraff, WG Tsokos, M Wink, DA Roberts, DD AF Isenberg, Jeff S. Maxhimer, Justin B. Hyodo, Fuminori Perndrak, Michael L. Ridnour, Lisa A. DeGraff, William G. Tsokos, Maria Wink, David A. Roberts, David D. TI Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NITRIC-OXIDE; IONIZING-RADIATION; IN-VIVO; ISCHEMIC TISSUE; MICE; TUMOR; RESPONSES; GROWTH; RADIORESISTANCE; ACTIVATION AB Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known cytoprotective activity of nitric oxide (NO) is blocked by thrombospondin-1, a potent antagonist of NO/cGMP signaling in ischemic soft tissues, suggesting that thrombospondin-1 signaling via its receptor CD47 could correspondingly increase radiosensitivity. We show here that soft tissues in thrombospondin-1-null mice are remarkably resistant to radiation injury. Twelve hours after 25-Gy hindlimb, irradiation, thrombospondin-1-null mice showed significantly less cell death in both muscle and bone marrow. Two months after irradiation, skin and muscle units in null mice showed minimal histological evidence of radiation injury and near full retention of mitochondrial function. Additionally, both tissue perfusion and acute vascular responses to NO were preserved in irradiated thrombospondin-1-null hindlimbs. The role of thrombospondin-1 in radiosensitization is specific because thrombospondin-2-null mice were not protected. However, mice lacking CD47 showed radioresistance similar to thrombospondin-1-null mice. Both thrombospondin-1- and CD47-dependent radiosensitization is cell autonomous because vascular cells isolated from the respective null mice showed dramatically increased survival and improved proliferative capacity after irradiation in vitro. Therefore, thrombospondin-1/CD47 antagonists may have selective radioprotective activity for normal tissues. C1 [Isenberg, Jeff S.; Maxhimer, Justin B.; Perndrak, Michael L.; Tsokos, Maria; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hyodo, Fuminori; Ridnour, Lisa A.; DeGraff, William G.; Wink, David A.] NCI, Ctr Radiat Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10,Room 2A33 10 Ctr Dr,MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural Research Program of the National Institutes of Health; National Cancer linstitute; Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer linstitute, Center for Cancer Research (to D.D.R. M3, D.A.W). NR 48 TC 39 Z9 39 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2008 VL 173 IS 4 BP 1100 EP 1112 DI 10.2353/ajpath.2008.080237 PG 13 WC Pathology SC Pathology GA 354OD UT WOS:000259648000018 PM 18787106 ER PT J AU Han, BG Hao, CM Tchekneva, EE Wang, YY Lee, CA Ebrahim, B Harris, RC Kern, TS Wasserman, DH Breyer, MD Qi, Z AF Han, Byoung Geun Hao, Chuan-Ming Tchekneva, Elena E. Wang, Ying-Ying Lee, Chieh Allen Ebrahim, Benyamin Harris, Raymond C. Kern, Timothy S. Wasserman, David H. Breyer, Matthew D. Qi, Zhonghua TI Markers of glycemic control in the mouse: comparisons of 6-h- and overnight-fasted blood glucoses to Hb A(1c) SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE glycosylated hemoglobin; methodology; mice ID DEPENDENT DIABETES-MELLITUS; PLASMA-GLUCOSE; DCA 2000; MICE; HEMOGLOBIN; NEPHROPATHY; INSULIN; COMPLICATIONS; HBA1C; STRAINS AB The present studies examined the relationship between fasting blood glucose and Hb A(1c) in C57BL/6J, DBA/2J, and KK/H1J mice with and without diabetes mellitus. Daily averaged blood glucose levels based on continuous glucose monitoring and effects of 6-h vs. overnight fasting on blood glucose were determined. Daily averaged blood glucose levels were highly correlated with Hb A1c, as determined with a hand-held automated device using an immunodetection method. R(2) values were 0.90, 0.95, and 0.99 in KK/HIJ, C57BL/6J, and DBA/2J, respectively. Six-hour fasting blood glucose correlated more closely with the level of daily averaged blood glucose and with Hb A(1c) than did blood glucose following an overnight fast. To validate the immunoassay-determined Hb A(1c), we also measured total glycosylated hemoglobin using boronate HPLC. Hb A(1c) values correlated well with total glycosylated hemoglobin in all three strains but were relatively lower than total glycosylated hemoglobin in diabetic DBA/2J mice. These results show that 6-h fasting glucose provides a superior index of glycemic control and correlates more closely with Hb A(1c) than overnight-fasted blood glucose in these strains of mice. C1 [Han, Byoung Geun; Hao, Chuan-Ming; Tchekneva, Elena E.; Wang, Ying-Ying; Ebrahim, Benyamin; Harris, Raymond C.; Breyer, Matthew D.; Qi, Zhonghua] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Lee, Chieh Allen; Kern, Timothy S.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Wasserman, David H.; Breyer, Matthew D.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN USA. [Wasserman, David H.; Breyer, Matthew D.; Qi, Zhonghua] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. RP Qi, Z (reprint author), Eli Lilly & Co, Lilly Res Labs, 355 E Merrill St, Indianapolis, IN 46225 USA. OI Han, Byoung-Geun/0000-0002-3246-2993 FU NIDDK NIH HHS [DK-59637] NR 36 TC 22 Z9 22 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD OCT PY 2008 VL 295 IS 4 BP E981 EP E986 DI 10.1152/ajpendo.90283.2008 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 359DW UT WOS:000259967600028 PM 18664598 ER PT J AU Illek, B Fu, Z Schwarzer, C Banzon, T Jalickee, S Miller, SS Machen, TE AF Illek, Beate Fu, Zhu Schwarzer, Christian Banzon, Tina Jalickee, Stephen Miller, Sheldon S. Machen, Terry E. TI Flagellin-stimulated Cl- secretion and innate immune responses in airway epithelia: role for p38 SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE cystic fibrosis transmembrane conductance regulator; inflammation; airway epithelial secretion; interleukin-1 beta; Pseudomonas aeruginosa ID NF-KAPPA-B; TRANSMEMBRANE CONDUCTANCE REGULATOR; TOLL-LIKE RECEPTOR-5; PSEUDOMONAS-AERUGINOSA INFECTION; CYSTIC-FIBROSIS; BACTERIAL FLAGELLIN; BICARBONATE SECRETION; CHLORIDE SECRETION; CALU-3 CELLS; CFTR AB Illek B, Fu Z, Schwarzer C, Banzon T, Jalickee S, Miller SS, Machen TE. Flagellin-stimulated Cl- secretion and innate immune responses in airway epithelia: role for p38. Am J Physiol Lung Cell Mol Physiol 295: L531-L542, 2008. First published July 25, 2008; doi: 10.1152/ajplung.90292.2008.-Activation of an innate immune response in airway epithelia by the human pathogen Pseudomonas aeruginosa requires bacterial expression of flagellin. Addition of flagellin (10(-7) M) to airway epithelial cell monolayers (Calu-3, airway serous cell-like) increased Cl- secretion (I-Cl) beginning after 3-10 min, reaching a plateau after 20-45 min at Delta I-Cl = 15-50 mu A/cm(2). Similar, although 10-fold smaller, responses were observed in well-differentiated bronchial epithelial cultures. Flagellin stimulated ICl in the presence of maximally stimulating doses of the purinergic agonist ATP, but had no effects following forskolin. IL-1 beta ( produced by both epithelia and neutrophils during infections) stimulated ICl similar to flagellin. Flagellin-, IL-1 beta-, ATP-, and forskolin-stimulated ICl were inhibited by cystic fibrosis transmembrane conductance regulator (CFTR) blockers GlyH101, CFTRinh172, and glibenclamide. Neither flagellin nor IL-1 beta altered transepithelial fluxes of membrane-impermeant dextran ( 10 kDa) or lucifer yellow ( mol wt = 457), but both activated p38, NF-kappa B, and IL-8 secretion. Blockers of p38 (SB-202190 and SB-203580) reduced flagellin-and IL-1 beta- stimulated ICl by 33-50% but had smaller effects on IL-8 and NF-kappa B. It is concluded that: 1) flagellin and IL-1 beta activated p38, NF-kappa B, IL-8, and CFTR-dependent anion secretion without altering tight junction permeability; 2) p38 played a role in regulating ICl and IL-8 but not NF-kappa B; and 3) p38 was more important in flagellin- than IL-1 beta-stimulated responses. During P. aeruginosa infections, flagellin and IL-1 beta are expected to increase CFTR-dependent ion and fluid flow into and bacterial clearance from the airways. In cystic fibrosis, the secretory response would be absent, but activation of p38, NF-kappa B, and IL-8 would persist. C1 [Illek, Beate; Fu, Zhu; Schwarzer, Christian; Machen, Terry E.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Banzon, Tina; Jalickee, Stephen; Miller, Sheldon S.] NEI, NIH, Bethesda, MD 20892 USA. RP Machen, TE (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 231 LSA, Berkeley, CA 94720 USA. EM tmachen@berkeley.edu FU Cystic Fibrosis Foundation [MACH03, MACHEN07G0, ILLEK08G0]; CF Research, Inc.; National Institutes of Health (NIH) [1R01-DK-51799, NCCAM P01-AT-002620]; NIH, National Eye Institute FX This work was supported by grants from the Cystic Fibrosis Foundation (MACH03, MACHEN07G0, ILLEK08G0), CF Research, Inc., and National Institutes of Health (NIH) (1R01-DK-51799 and NCCAM P01-AT-002620). This work was also supported by the Intramural Research Program of the NIH, National Eye Institute. NR 54 TC 17 Z9 18 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD OCT PY 2008 VL 295 IS 4 BP L531 EP L542 DI 10.1152/ajplung.90292.2008 PG 12 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 367EH UT WOS:000260534800001 PM 18658272 ER PT J AU Periwal, V Chow, CC Bergman, RN Ricks, M Vega, GL Sumner, AE AF Periwal, Vipul Chow, Carson C. Bergman, Richard N. Ricks, Madia Vega, Gloria L. Sumner, Anne E. TI Evaluation of quantitative models of the effect of insulin on lipolysis and glucose disposal SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE free fatty acids; insulin resistance; mathematical model ID FREE FATTY-ACID; DEPENDENT DIABETES-MELLITUS; AFRICAN-AMERICANS; MINIMAL-MODEL; TRIGLYCERIDE LEVELS; TOLERANCE TEST; FASTING TRIGLYCERIDE; SEX-DIFFERENCES; RESISTANCE; SENSITIVITY AB The effects of insulin on the suppression of lipolysis are neither fully understood nor quantified. We examined a variety of mathematical models analogous to the minimal model of glucose disposal (MMG) to quantify the combined influence of insulin on lipolysis and glucose disposal during an insulin-modified frequently sampled intravenous glucose tolerance test. The tested models, which include two previously published ones, consisted of separate compartments for plasma free fatty acids (FFA), glucose, and insulin. They differed in the number of compartments and in the action of insulin to suppress lipolysis that decreased the plasma FFA level. In one category of models, a single insulin compartment acted on both glucose and FFA simultaneously. In a second category, there were two insulin compartments, each acting on FFA and glucose independently. For each of these two categories, we tested 11 variations of how insulin suppressed lipolysis. We also tested a model with an additional glucose compartment that acted on FFA. These 23 models were fit to the plasma FFA and glucose concentrations of 102 subjects individually. Using Bayesian model comparison methods, we selected the model that best balanced fit and minimized model complexity. In the best model, insulin suppressed lipolysis via a Hill function through a remote compartment that acted on both glucose and FFA simultaneously, and glucose dynamics obeyed the classic MMG. C1 [Bergman, Richard N.] Univ So Calif, Sch Med, Dept Physiol, Los Angeles, CA USA. [Ricks, Madia; Sumner, Anne E.] NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Vega, Gloria L.] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA. RP Chow, CC (reprint author), NIDDK, NIH, LBM, Bldg 12A,Rm 4007,MSC 5621, Bethesda, MD 20892 USA. EM carsonc@mail.nih.gov RI Chow, Carson/A-7970-2009; Periwal, Vipul/I-1728-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK27619, DK29867]; Veterans Affairs Merit Review FX This work was supported by the Intramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). In addition, support was provided by NIDDK Grants DK27619 and DK29867 (to R. N. Bergman) and the Veterans Affairs Merit Review (to G. L. Vega). NR 32 TC 16 Z9 17 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD OCT PY 2008 VL 295 IS 4 BP R1089 EP R1096 DI 10.1152/ajpregu.90426.2008 PG 8 WC Physiology SC Physiology GA 355IP UT WOS:000259702900010 PM 18685069 ER PT J AU Reichel, V Miller, DS Fricker, G AF Reichel, Valeska Miller, David S. Fricker, Gert TI Texas Red transport across rat and dogfish shark (Squalus acanthias) choroid plexus SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE organic anion transport; confocal imaging; organic anion transporter; organic anion transporting polypeptide; multidrug resistance-associated protein ID ORGANIC ANION TRANSPORT; FLUORESCEIN-METHOTREXATE TRANSPORT; SUBSTRATE-SPECIFICITY; EXPRESSION; INVOLVEMENT; FLOUNDER; OAT3; MICE AB Confocal microscopy and image analysis were used to compare driving forces, specificity, and regulation of transport of the fluorescent organic anion, Texas Red (sulforhodamine 101 free acid; TR), in lateral choroid plexus (CP) isolated from rat and an evolutionarily ancient vertebrate, dogfish shark (Squalus acanthias). CP from both species exhibited concentrative, specific, and metabolism-dependent TR transport from bath to subepithelial/vascular space; at steady state, TR accumulation in vascular/subepithelial space was substantially higher than in epithelial cells. In rat CP, steady-state TR accumulation in subepithelial/vascular spaces was reduced by Na(+)-replacement, but was not affected by a 10-fold increase in buffer K(+). In shark CP, Na(+)-replacement did not alter TR accumulation in either tissue compartment; subepithelial/vascular space levels of TR were reduced in high-K(+) medium. In both species, steady-state TR accumulation was not affected by p-aminohippurate or leukotriene C4, suggesting that neither organic anion transporters (SLC22A family) nor multidrug resistance-associated proteins (ABCC family) contributed. In rat CP, digoxin was without effect, indicating that organic anion transporting polypeptide isoform 2 was not involved. Several organic anions reduced cellular and subepithelial/vascular space TR accumulation in both tissues, including estrone sulfate, taurocholate, and the Mrp1 inhibitor MK571. In rat CP, TR accumulation in subepithelial/vascular spaces increased with PKA activation (forskolin), but was not affected by PKC activation (phorbol ester). In shark, neither PKA nor PKC activation specifically affected TR transport. Thus, rat and dogfish shark CP transport TR but do so using different basic mechanisms that respond to different regulatory signals. C1 [Reichel, Valeska; Fricker, Gert] Univ Heidelberg, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany. [Miller, David S.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Reichel, Valeska; Miller, David S.; Fricker, Gert] Mt Desert Isl Biol Lab, Salsbury Cove, ME USA. RP Fricker, G (reprint author), Univ Heidelberg, Inst Pharm & Mol Biotechnol, INF 366, D-69120 Heidelberg, Germany. EM gert.fricker@uni-hd.de FU German Research Foundation [FR1211/12-1, FR1211/13-1]; 3R-Foundation (Switzerland) [91-04]; Boehringer Ingelheim Fonds; National Institute of Environmental Health Sciences [ES-03828]; National Institute of Environmental Health Sciences FX This research was supported, in part, by Grants DFG FR1211/12-1 and FR1211/13-1 from the German Research Foundation, by 3R-Foundation (Switzerland) Grant 91-04, the Boehringer Ingelheim Fonds, National Institute of Environmental Health Sciences Grant ES-03828, and by the Division of Intramural Research of the National Institute of Environmental Health Sciences. NR 23 TC 7 Z9 7 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD OCT PY 2008 VL 295 IS 4 BP R1311 EP R1319 DI 10.1152/ajpregu.90373.2008 PG 9 WC Physiology SC Physiology GA 355IP UT WOS:000259702900038 PM 18650317 ER PT J AU Velan, SS Said, N Durst, C Frisbee, S Frisbee, J Raylman, RR Thomas, MA Rajendran, VM Spencer, RG Alway, SE AF Velan, S. Sendhil Said, Nicholas Durst, Christopher Frisbee, Stephanie Frisbee, Jefferson Raylman, Raymond R. Thomas, M. Albert Rajendran, Vazhaikkurichi M. Spencer, Richard G. Alway, Stephen E. TI Distinct patterns of fat metabolism in skeletal muscle of normal-weight, overweight, and obese humans SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE magnetic resonance spectroscopy; lipid unsaturation; intramyocellular lipid; extramyocellular lipid ID INSULIN-RESISTANCE; ACID-COMPOSITION; IN-VIVO; DESATURASE ACTIVITIES; DELTA(5) DESATURASES; LIPID-PEROXIDATION; DIABETES-MELLITUS; PROTON MR; SPECTROSCOPY; MECHANISMS AB The link between body weight, lipid metabolism, and health risks is poorly understood and difficult to study. Magnetic resonance spectroscopy (MRS) permits noninvasive investigation of lipid metabolism. We extended existing two-dimensional MRS techniques to permit quantification of intra-and extramyocellular lipid (IMCL and EMCL, respectively) compartments and their degree of unsaturation in human subjects and correlated these results with body mass index (BMI). Using muscle creatine for normalization, we observed a statistically significant (P < 0.01) increase in the IMCL-to-creatine ratio with BMI (n = 8 subjects per group): 5.9 +/- 1.7 at BMI < 25, 10.9 +/- 1.82 at 25 < BMI < 30, and 13.1 +/- 0.87 at BMI > 30. Similarly, the degree of IMCL unsaturation decreased significantly (P < 0.01) with BMI: 1.51 < 0.08 at BMI < 25, 1.30 +/- 0.11 at 25 < BMI < 30, and 0.90 +/- 0.14 at BMI > 30. We conclude that important aspects of lipid metabolism can be evaluated by two-dimensional MRS and propose that degree of unsaturation measured noninvasively may serve as a biomarker for lipid metabolic defects associated with obesity. C1 [Velan, S. Sendhil; Said, Nicholas; Durst, Christopher; Raylman, Raymond R.] W Virginia Univ, Ctr Adv Imaging & Radiol, Morgantown, WV 26506 USA. [Frisbee, Stephanie; Frisbee, Jefferson] W Virginia Univ, Ctr Interdisciplinary Res Cardiovasc Sci, Morgantown, WV 26506 USA. [Frisbee, Stephanie] W Virginia Univ, Dept Community Med, Morgantown, WV 26506 USA. [Frisbee, Stephanie] W Virginia Univ, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA. [Rajendran, Vazhaikkurichi M.] W Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA. [Rajendran, Vazhaikkurichi M.] W Virginia Univ, Dept Microbiol, Morgantown, WV 26506 USA. [Rajendran, Vazhaikkurichi M.] W Virginia Univ, Dept Immunol, Morgantown, WV 26506 USA. [Alway, Stephen E.] W Virginia Univ, Dept Exercise Physiol, Morgantown, WV 26506 USA. [Thomas, M. Albert] Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. [Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. RP Velan, SS (reprint author), W Virginia Univ, Ctr Adv Imaging & Radiol, Morgantown, WV 26506 USA. EM svelan@hsc.wvu.edu RI Thomas, m. albert/A-6176-2012; Velan, S. Sendhil/B-6374-2017; OI Velan, S. Sendhil/0000-0002-4096-0722; Durst, Christopher/0000-0003-4236-7524 FU Health Sciences Center; West Virginia University; National Institute on Aging; National Institute of Diabetes and Digestive and Kidney Diseases Research [DK-018777] FX This research was supported by a Health Sciences Center Grant from West Virginia University (S. S. Velan) and in part by the Intramural Research Program of the National Institute on Aging (R. G. Spencer) and National Institute of Diabetes and Digestive and Kidney Diseases Research Grant DK-018777 (V. M. Rajendran). NR 44 TC 25 Z9 25 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD OCT PY 2008 VL 295 IS 4 BP R1060 EP R1065 DI 10.1152/ajpregu.90367.2008 PG 6 WC Physiology SC Physiology GA 355IP UT WOS:000259702900007 PM 18667716 ER PT J AU Castrop, H Schnermann, J AF Castrop, Hayo Schnermann, Jurgen TI Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE differential splicing; macula densa; tubuloglomerular feedback; renin ID THICK ASCENDING LIMB; K-CL COTRANSPORTER; NA+/MYO-INOSITOL COTRANSPORTER; CELLULAR CONDUCTIVE PATHWAYS; REGULATED UREA TRANSPORTER; MACULA DENSA CELLS; BARTTERS-SYNDROME; RENIN SECRETION; RAT-KIDNEY; HYPOKALEMIC ALKALOSIS AB The renal Na-K-2Cl cotransporter (NKCC2, BSC1) is selectively expressed in the apical membrane of cells of the thick ascending limb of the loop of Henle (TAL) and macula densa. NKCC2-dependent salt transport constitutes the major apical entry pathway for transepithelial salt reabsorption in the TAL. Although NKCC2 is encoded by a single gene (Slc12a1), differential splicing of the NKCC2 pre-mRNA results in the formation of several alternate transcripts. Thus three full-length splice isoforms of NKCC2 differ in their variable exon 4, resulting in transcripts for NKCC2B, NKCC2A, and NKCC2F. In addition to full-length isoforms, variants with truncated COOH-terminal ends have been described. The various splice isoforms of NKCC2 differ in their localization along the TAL and in their transport characteristics. Data in the literature are reviewed to assess the principles of NKCC2 differential splicing, the localization of NKCC2 splice isoforms along the TAL in various species, and the functional characteristics of the splice isoforms. In addition, we discuss the functional significance of NKCC2 isoforms for TAL salt retrieval and for the specific salt sensor function of macula densa cells based on studies using isoform-specific NKCC2-knockout mice. We suggest that different NKCC2 splice variants cooperate in salt retrieval along the TAL and that the coexpression of two splice variants (NKCC2B and NKCC2A) in the macula densa cells facilitates efficient salt sensing over wide ranges of fluctuating salt concentrations. C1 [Castrop, Hayo] Univ Regensburg, Inst Physiol, D-93040 Regensburg, Germany. [Schnermann, Jurgen] NIDDK, NIH, Bethesda, MD USA. RP Castrop, H (reprint author), Univ Regensburg, Inst Physiol, Univ Str 31, D-93040 Regensburg, Germany. EM hayo@castrop.com FU Deutsche Forschungsgemeinschaft [SFB 699/A4]; National Institute of Diabetes and Digestive and Kidney Diseases FX The work in the laboratories of the authors was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 699/A4 to H. Castrop) and by the intramural program of National Institute of Diabetes and Digestive and Kidney Diseases (J. Schnermann). NR 86 TC 36 Z9 37 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT PY 2008 VL 295 IS 4 BP F859 EP F866 DI 10.1152/ajprenal.00106.2008 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 358JM UT WOS:000259913000001 PM 18495801 ER PT J AU Kim, SM Eisner, C Faulhaber-Walter, R Mizel, D Wall, SM Briggs, JP Schnermann, J AF Kim, Soo Mi Eisner, Christoph Faulhaber-Walter, Robert Mizel, Diane Wall, Susan M. Briggs, Josephine P. Schnermann, Jurgen TI Salt sensitivity of blood pressure in NKCC1-deficient mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE radiotelemetry; running wheels; renin; aldosterone; vasodilators; sodium-2 chloride-potassium cotransporter-deficient mice ID VASCULAR SMOOTH-MUSCLE; K-CL COTRANSPORTER; NA+-K+-2CL(-) COTRANSPORTER; NA-K-2CL COTRANSPORTER; CHLORIDE; FUROSEMIDE; SECRETION; NKCC1; EXPRESSION; DEFICIENT AB NKCC1 is a widely expressed isoform of the Na-2Cl-K cotransporter that mediates several direct and indirect vascular effects and regulates expression and release of renin. In this study, we used NKCC1-deficient (NKCC1(-/-)) and wild-type (WT) mice to assess day/night differences of blood pressure (BP), locomotor activity, and renin release and to study the effects of high (8%) or low (0.03%) dietary NaCl intake on BP, activity, and the renin/aldosterone system. On a standard diet, 24- h mean arterial blood pressure (MAP) and heart rate determined by radiotelemetry, and their day/night differences, were not different in NKCC1(-/-) and WT mice. Spontaneous and wheel-running activities in the active night phase were lower in NKCC1(-/-) than WT mice. In NKCC1(-/-) mice on a high-NaCl diet, MAP increased by 10 mmHg in the night without changes in heart rate. In contrast, there was no salt-dependent blood pressure change in WT mice. MAP reductions by hydralazine (1 mg/kg) or isoproterenol (10 mu g/mouse) were significantly greater in NKCC1(-/-) than WT mice. Plasma renin (PRC; ng ANG I(center dot)ml(-1)center dot h(-1)) and aldosterone (aldo; pg/ml) concentrations were higher in NKCC1(-/-) than WT mice (PRC: 3,745 +/- 377 vs. 1,245 +/- 364; aldo: 763 +/- 136 vs. 327 +/- 98). Hyperreninism and hyperaldosteronism were found in NKCC1(-/-) mice during both day and night. High Na suppressed PRC and aldosterone WT in both NKCC1(-/-) and WT mice, whereas a low-Na diet increased PRC and aldosterone in WT but not NKCC1(-/-) mice. We conclude that 24- h MAP and MAP circadian rhythms do not differ between NKCC1(-/-) and WT mice on a standard diet, probably reflecting a balance between anti- and prohypertensive factors, but that blood pressure of NKCC1(-/-) mice is more sensitive to increases and decreases of Na intake. C1 [Kim, Soo Mi; Eisner, Christoph; Faulhaber-Walter, Robert; Mizel, Diane; Briggs, Josephine P.; Schnermann, Jurgen] NIDDK, Natl Inst Hlth, Bethesda, MD 20892 USA. [Wall, Susan M.] Emory Univ, Sch Med, Div Renal, Atlanta, GA 30322 USA. RP Schnermann, J (reprint author), NIDDK, Natl Inst Hlth, 10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; NIDDK [PO1 DK- 061521] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and by NIDDK Grant PO1 DK- 061521, Project 2 ( S. M. Wall). NR 26 TC 25 Z9 26 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT PY 2008 VL 295 IS 4 BP F1230 EP F1238 DI 10.1152/ajprenal.90392.2008 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 358JM UT WOS:000259913000044 PM 18701622 ER PT J AU Pisitkun, T Jacob, V Schleicher, SM Chou, CL Yu, MJ Knepper, MA AF Pisitkun, Trairak Jacob, Vinitha Schleicher, Stephen M. Chou, Chung-Lin Yu, Ming-Jiun Knepper, Mark A. TI Akt and ERK1/2 pathways are components of the vasopressin signaling network in rat native IMCD SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin-2; phosphoinositide 3-kinase; cyclic AMP; calmodulin ID MEDULLARY COLLECTING DUCT; PROTEIN-KINASE-B; G-BETA-GAMMA; CYCLIC-AMP; KIDNEY-CELLS; PHOSPHOINOSITIDE 3-KINASE-GAMMA; WATER CHANNEL; LC-MS/MS; ACTIVATION; PHOSPHORYLATION AB Vasopressin regulates water excretion through effects on the renal collecting duct. Vasopressin signaling in the inner medullary collecting duct (IMCD) is mediated by V2 receptor occupation coupled to the generation of cyclic AMP. Here, we employ a "systems" approach to analysis of vasopressin signaling. The objective is to investigate roles of activation of the Akt and ERK1/2 MAP kinase pathways, as well as Ca(2+) mobilization, in IMCD cells isolated from rat kidney. The V2 receptor-selective vasopressin analog dDAVP increased the state of Akt activation (increased phosphorylation at T308 and S473) and decreased the state of ERK1/2 activation (decreased phosphorylation at T202 and Y204). Akt activation was blocked by an inhibitor of PI3K, LY294002. In microdissected IMCD segments, nonperiodic spike-like increases in intracellular Ca(2+) (FLUO-4) were accelerated by vasopressin. Chelation of Ca(2+) or calmodulin inhibition markedly decreased Akt phosphorylation. Decreased ERK1/2 phosphorylation was associated with a decrease in MEK1/2 phosphorylation and an increase in c-Raf phosphorylation at S259 (an inhibitory site). Based on the current findings integrated with previous findings in the IMCD, we now report a 33-node vasopressin signaling network involved in vasopressin regulation of IMCD function. C1 [Pisitkun, Trairak; Jacob, Vinitha; Schleicher, Stephen M.; Chou, Chung-Lin; Yu, Ming-Jiun; Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU NHLBI [Z01-HL- 01285-KE] FX This work was supported by the intramural budget of the NHLBI (Z01-HL- 01285-KE). NR 43 TC 45 Z9 47 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT PY 2008 VL 295 IS 4 BP F1030 EP F1043 DI 10.1152/ajprenal.90339.2008 PG 14 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 358JM UT WOS:000259913000020 PM 18667481 ER PT J AU Schliebe, N Strotmann, R Busse, K Mitschke, D Biebermann, H Schomburg, L Kohrle, J Baer, J Rompler, H Wess, J Schoneberg, T Sangkuhl, K AF Schliebe, Nicole Strotmann, Rainer Busse, Kathy Mitschke, Doreen Biebermann, Heike Schomburg, Lutz Koehrle, Josef Baer, Jorg Roempler, Holger Wess, Juergen Schoeneberg, Torsten Sangkuhl, Katrin TI V2 vasopressin receptor deficiency causes changes in expression and function of renal and hypothalamic components involved in electrolyte and water homeostasis SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE vasopressin receptor; diabetes insipidus; G protein-coupled receptor; signal transduction; hypernatremia ID NEPHROGENIC DIABETES-INSIPIDUS; EPITHELIAL SODIUM-CHANNEL; LITHIUM-INDUCED NDI; THYROID-HORMONE ACTION; NA-K-ATPASE; ALTERED EXPRESSION; COLLECTING DUCT; GENE-EXPRESSION; MESSENGER-RNA; PROXIMAL TUBULE AB Polyuria, hypernatremia, and hypovolemia are the major clinical signs of inherited nephrogenic diabetes insipidus (NDI). Hypernatremia is commonly considered a secondary sign caused by the net loss of water due to insufficient insertion of aquaporin-2 water channels into the apical membrane of the collecting duct cells. In the present study, we employed transcriptome-wide expression analysis to study gene expression in V2 vasopressin receptor (Avpr2)-deficient mice, an animal model for X-linked NDI. Gene expression changes in NDI mice indicate increased proximal tubular sodium reabsorption. Expression of several key genes including Na(+)-K(+)-ATPase and carbonic anhydrases was increased at the mRNA levels and accompanied by enhanced enzyme activities. In addition, altered expression was also observed for components of the eicosanoid and thyroid hormone pathways, including cyclooxygenases and deiodinases, in both kidney and hypothalamus. These effects are likely to contribute to the clinical NDI phenotype. Finally, our data highlight the involvement of the renin-angiotensin-aldosterone system in NDI pathophysiology and provide clues to explain the effectiveness of diuretics and indomethacin in the treatment of NDI. C1 [Schliebe, Nicole; Strotmann, Rainer; Busse, Kathy; Mitschke, Doreen; Baer, Jorg; Roempler, Holger; Schoeneberg, Torsten; Sangkuhl, Katrin] Univ Leipzig, Fac Med, Inst Biochem, D-04103 Leipzig, Germany. [Biebermann, Heike] Humboldt Univ, Fac Med, Charite, Inst Expt Pediat Endocrinol, Berlin, Germany. [Schomburg, Lutz; Koehrle, Josef] Humboldt Univ, Fac Med, Charite, Inst Expt Endocrinol, Berlin, Germany. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Schoneberg, T (reprint author), Univ Leipzig, Fac Med, Inst Biochem, Johannisallee 30, D-04103 Leipzig, Germany. EM schoberg@medizin.uni-leipzig.de OI Kohrle, Josef/0000-0002-9187-9078 FU Deutsche Forschungsgemeinschaft [624/2-1, GRK 1097] FX This work was sponsored by Deutsche Forschungsgemeinschaft (Scho 624/2-1, GRK 1097), Bundesministerium fur Bildung und Forschung, Interdisziplinares Zentrum fur Klinische Forschung (IZKF) Leipzig and the Leipzig Formel 1 program to K. Sangkuhl and H. Rompler. NR 98 TC 8 Z9 8 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT PY 2008 VL 295 IS 4 BP F1177 EP F1190 DI 10.1152/ajprenal.00465.2007 PG 14 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 358JM UT WOS:000259913000038 PM 18715941 ER PT J AU Bloch, M Althabe, F Onyamboko, M Kaseba-Sata, C Castilla, EE Freire, S Garces, AL Parida, S Goudar, SS Kadir, MM Goco, N Thornberry, J Daniels, M Bartz, J Hartwell, T Moss, N Goldenberg, R AF Bloch, Michele Althabe, Fernando Onyamboko, Marie Kaseba-Sata, Christine Castilla, Eduardo E. Freire, Salvio Garces, Ana L. Parida, Sailajanandan Goudar, Shivaprasad S. Kadir, Muhammad Masood Goco, Norman Thornberry, Jutta Daniels, Magdalena Bartz, Janet Hartwell, Tyler Moss, Nancy Goldenberg, Robert TI Tobacco use and secondhand smoke exposure during pregnancy: An investigative survey of women in 9 developing nations SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID CIGARETTE-SMOKING; INDIA; PATTERNS; HEALTH; RISK; INTERVENTIONS; CONSUMPTION; PROGRESSION; INFECTION; COUNTRIES AB Objectives. We examined pregnant women's use of cigarettes and other tobacco products and the exposure of pregnant women and their young children to secondhand smoke (SHS) in 9 nations in Latin America, Asia, and Africa. Methods. Face-to-face surveys were administered to 7961 pregnant women (more than 700 per site) between October 2004 and September 2005. Results. At all Latin American sites, pregnant women commonly reported that they had ever tried cigarette smoking (range: 78.3% [Uruguay] to 35.0% [Guatemala]). The highest levels of current smoking were found in Uruguay (18.3%), Argentina (10.3%), and Brazil (6.1%). Experimentation with smokeless tobacco occurred in the Democratic Republic of the Congo and India; one third of all respondents in Orissa, India, were current smokeless tobacco users. SHS exposure was common: between 91.6% (Pakistan) and 17.1% (Democratic Republic of the Congo) of pregnant women reported that smoking was permitted in their home. Conclusions. Pregnant women's tobacco use and SHS exposure are current or emerging problems in several low- and middle-income nations, jeopardizing ongoing efforts to improve maternal and child health. C1 [Bloch, Michele] NCI, Tobacco Control Res Branch, NIH, Bethesda, MD 20892 USA. [Moss, Nancy] NICHHD, NIH, Bethesda, MD 20892 USA. [Althabe, Fernando] Hosp Clin Montevideo, Montevideo, Uruguay. [Onyamboko, Marie] Univ Kinshasa, Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Kaseba-Sata, Christine] Univ Teaching Hosp, Lusaka, Zambia. [Castilla, Eduardo E.] Latin Amer Collaborat Study Congenital Malformat, Rio De Janeiro, Brazil. [Freire, Salvio] Univ Fed Pernambuco, Hosp Clin, Recife, PE, Brazil. [Garces, Ana L.] Multidisciplinary Hlth Inst, Guatemala City, Guatemala. [Parida, Sailajanandan] Sriram Chandra Bhanj Med Coll, Cuttack, Orissa, India. [Goudar, Shivaprasad S.] Jawaharlal Nehru Med Coll, Karnatak Lingayat Educ Soc, Belgaum, India. [Kadir, Muhammad Masood] Aga Khan Univ, Karachi, Pakistan. [Goco, Norman; Thornberry, Jutta; Daniels, Magdalena; Bartz, Janet; Hartwell, Tyler] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. [Goldenberg, Robert] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. RP Bloch, M (reprint author), NCI, Tobacco Control Res Branch, NIH, Bethesda, MD 20892 USA. EM blochm@mail.nih.gov OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU National Institute of Child Health and Human Development; National Cancer Institute; US National Institutes of Health; US Department of Health and Human Services Office oil Women's Health; Bill and Melinda Gates Foundation [U01-HD40477, U01-HD43475, U01-HD43464, U01-HID40561, U01-HD40565, U01-HD40657, U01-HD40574, U01-HD42372, U01-HD40607, U01-HD40636] FX Financial support for this research was provided by the National Institute of Child Health and Human Development and the National Cancer Institute, US National Institutes of Health; the US Department of Health and Human Services Office oil Women's Health; and the Bill and Melinda Gates Foundation. (grant numbers U01-HD40477, U01-HD43475, U01-HD43464, U01-HID40561, U01-HD40565, U01-HD40657, U01-HD40574, U01-HD42372, U01-HD40607, U01-HD40636). NR 57 TC 63 Z9 65 U1 0 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2008 VL 98 IS 10 BP 1833 EP 1840 DI 10.2105/AJPH.2007.117887 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 354HT UT WOS:000259630400023 PM 18309125 ER PT J AU Than, NG Kim, SS Abbas, A Han, YM Hotra, J Tarca, AL Erez, O Wildman, DE Kusanovic, JP Pineles, B Montenegro, D Edwin, SS Mazaki-Tovi, S Gotsch, F Espinoza, J Hassan, SS Papp, Z Romero, R AF Than, Nandor Gabor Kim, Sung-Su Abbas, Asad Han, Yu Mi Hotra, John Tarca, Adi L. Erez, Offer Wildman, Derek E. Kusanovic, Juan Pedro Pineles, Beth Montenegro, Daniel Edwin, Samuel S. Mazaki-Tovi, Shali Gotsch, Francesca Espinoza, Jimmy Hassan, Sonia S. Papp, Zoltan Romero, Roberto TI Chorioamnionitis and increased galectin-1 expression in PPROM - An anti-inflammatory response in the fetal membranes? SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 14-17, 2007 CL Reno, NV SP Soc Gynecol Invest DE chorioamniotic fibroblast/myofibroblast and macrophage; chorioamniotic membranes; inflammation; lectin; pre-labor rupture of membranes; pre-term delivery ID AMNIOTIC-FLUID INTERLEUKIN-6; PRETERM PREMATURE RUPTURE; HUMAN-PLACENTA; T-CELLS; INFLAMMATORY RESPONSE; EXTRACELLULAR-MATRIX; ENDOTHELIAL-CELLS; PARTURITION; TOLERANCE; APOPTOSIS AB Problem Galectin-1 can regulate immune responses upon infection and inflammation. We determined galectin-1 expression in the chorioamniotic membranes and its changes during histological chorioamnionitis. Method of study Chorioamniotic membranes were obtained from women with normal pregnancy (n = 5) and from patients with pre-term pre-labor rupture of the membranes (PPROM) with (n = 8) and without histological chorioamnionitis (n = 8). Galectin-1 mRNA and protein were localized by in situ hybridization and immunohistochemistry. Galectin-1 mRNA expression was also determined by quantitative reverse transcriptase polymerase chain reaction. Results Galectin-1 mRNA and protein were detected in the amniotic epithelium, chorioamniotic fibroblasts/myofibroblasts and macrophages, chorionic trophoblasts, and decidual stromal cells. In patients with PPROM, galectin-1 mRNA expression in the fetal membranes was higher (2.07-fold, P = 0.002) in those with chorioamnionitis than in those without. Moreover, chorioamionitis was associated with a strong galectin-1 immunostaining in amniotic epithelium, chorioamniotic mesodermal cells, and apoptotic bodies. Conclusion Chorioamnionitis is associated with an increased galectin-1 mRNA expression and strong immunoreactivity of the chorioamniotic membranes; thus, galectin-1 may be involved in the regulation of the inflammatory responses to chorioamniotic infection. C1 [Than, Nandor Gabor; Kim, Sung-Su; Abbas, Asad; Han, Yu Mi; Hotra, John; Tarca, Adi L.; Erez, Offer; Wildman, Derek E.; Kusanovic, Juan Pedro; Pineles, Beth; Montenegro, Daniel; Edwin, Samuel S.; Mazaki-Tovi, Shali; Gotsch, Francesca; Espinoza, Jimmy; Hassan, Sonia S.; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Erez, Offer; Wildman, Derek E.; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Espinoza, Jimmy; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Wildman, Derek E.; Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Papp, Zoltan] Semmelweis Univ, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary. RP Than, NG (reprint author), Wayne State Univ, NICHD, Perinatol Res Branch, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; nthan@med.wayne.edu FU Intramural NIH HHS [Z01 HD002400-16] NR 65 TC 14 Z9 14 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD OCT PY 2008 VL 60 IS 4 BP 298 EP 311 DI 10.1111/j.1600-0897.2008.00624.x PG 14 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 345AY UT WOS:000258969600003 PM 18691335 ER PT J AU Than, NG Romero, R Erez, O Kusanovic, JP Tarca, AL Edwin, SS Kim, JS Hassan, SS Espinoza, J Mittal, P Mazaki-Tovi, S Friel, L Gotsch, F Vaisbuch, E Camacho, N Papp, Z AF Than, Nandor Gabor Romero, Roberto Erez, Offer Kusanovic, Juan Pedro Tarca, Adi L. Edwin, Samuel S. Kim, Jung-Sun Hassan, Sonia S. Espinoza, Jimmy Mittal, Pooja Mazaki-Tovi, Shali Friel, Lara Gotsch, Francesca Vaisbuch, Edi Camacho, Natalia Papp, Zoltan TI A role for mannose-binding lectin, a component of the innate immune system in pre-eclampsia SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med (SMFM) DE maternal systemic inflammation; MBL genotypes; pattern-recognition receptor single nucleotide polymorphism ID ISCHEMIA-REPERFUSION INJURY; BLOOD MONONUCLEAR-CELLS; NORMAL HUMAN-PREGNANCY; TNF-ALPHA RELEASE; COMPLEMENT ACTIVATION; SERINE PROTEASES; METABOLIC CHARACTERISTICS; INFLAMMATORY RESPONSE; RECURRENT MISCARRIAGE; CLINICAL-IMPLICATIONS AB Problem Mannose-binding lectin (MBL) is a pattern-recognition receptor that activates complement and modulates inflammation. Homozygosity for the most common allele of the MBL2 gene that is associated with high MBL serum concentrations is more prevalent among patients with pre-eclampsia. The objective of this study was to determine maternal plasma MBL concentrations in normal pregnant women and patients with pre-eclampsia. Method of study This cross-sectional study included normal pregnant women (n = 187) and patients with pre-eclampsia (n = 99). Maternal plasma MBL concentrations were determined by ELISA. Results Women with pre-eclampsia had a higher median maternal plasma MBL concentration than normal pregnant women. MBL concentration distribution curves were three-modal, the subintervals in normal pregnancy were low (< 143.7), intermediate (143.7-1898.9) and high (> 1898.9 ng/mL). The proportion of normal pregnant women was larger in the low subinterval, while the proportion of patients with pre-eclampsia was larger in the high subinterval (P = 0.02). Normal pregnant women in the high subinterval had a larger rate of placental underperfusion than those in the low and intermediate subintervals (P = 0.02). Conclusions The median maternal plasma MBL concentration is elevated in patients with pre-eclampsia and a larger proportion of these patients are in the high subinterval than normal pregnant women, suggesting that this component of the innate immune system is involved in the mechanisms of disease in pre-eclampsia. C1 [Than, Nandor Gabor; Romero, Roberto; Erez, Offer; Kusanovic, Juan Pedro; Tarca, Adi L.; Edwin, Samuel S.; Kim, Jung-Sun; Hassan, Sonia S.; Espinoza, Jimmy; Mittal, Pooja; Friel, Lara; Gotsch, Francesca; Vaisbuch, Edi; Camacho, Natalia] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Romero, Roberto; Erez, Offer; Kusanovic, Juan Pedro; Hassan, Sonia S.; Espinoza, Jimmy; Mittal, Pooja; Mazaki-Tovi, Shali; Friel, Lara; Camacho, Natalia] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kim, Jung-Sun] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Papp, Zoltan] Semmelweis Univ, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary. RP Than, NG (reprint author), Wayne State Univ, NICHD, Perinatol Res Branch, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM nthan@med.wayne.edu; prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Intramural NIH HHS [Z01 HD002400-16] NR 99 TC 27 Z9 31 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD OCT PY 2008 VL 60 IS 4 BP 333 EP 345 DI 10.1111/j.1600-0897.2008.00631.x PG 13 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 345AY UT WOS:000258969600007 PM 18727690 ER PT J AU Sampaio, EP Elloumi, HZ Zelazny, A Ding, L Paulson, ML Sher, A Bafica, AL Shea, YR Holland, SM AF Sampaio, Elizabeth P. Elloumi, Houda Z. Zelazny, Adrian Ding, Li Paulson, Michelle L. Sher, Alan Bafica, Andre L. Shea, Yvonne R. Holland, Steven M. TI Mycobacterium abscessus and M-avium trigger Toll-like receptor 2 and distinct cytokine response in human cells SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE tumor necrosis factor-alpha; M. abscessus; M. avium; chemokines; Toll-like receptor 2 ID TUMOR-NECROSIS-FACTOR; RAPIDLY GROWING MYCOBACTERIA; DISORDERS AFFECTING INNATE; HOST GENETIC-FACTORS; NON-HIV PATIENTS; NONTUBERCULOUS MYCOBACTERIA; GLYCOPEPTIDOLIPID BIOSYNTHESIS; MACROPHAGE ACTIVATION; TUBERCULOSIS STRAINS; ADAPTIVE IMMUNITY AB Mycobacterium avium (MAV) and M. abscessus (MAB) are ubiquitous environmental organisms increasingly recognized to cause chronic lung disease in patients with apparently normal immune function. Little is yet known about their human pathophysiology. Our objective was to examine cytokine and chemokine responses (protein and gene expression) and signaling pathways triggered by reference and clinical isolates of MAB and MAV in human peripheral blood mononuclear cells, monocytes, and murine bone marrow-derived macrophages in vitro. MAB-induced TNF-alpha production was higher than that induced by MAV. IFN-gamma, IL-1 beta, and the chemokines macrophage inflammatory protein-1 alpha and regulated on activation, normal T cell expressed and secreted were equally up-regulated. Differences between MAB and MAV do not require replication and are heat stable. We found no differential effect due to rough or smooth colonies within the same species. Similar to MAV, MAB triggered mitogen-activated protein kinase (MAPK) signaling and nuclear factor-kappa B translocation. Induction of TNF-alpha was dependent on MAPK pathways, since pre-incubation of cells with signaling inhibitors led to more than 85% reduction in cytokine secretion. MAB also triggered a Toll-like receptor 2(TLR2)-mediated response that led to TNF-alpha production by human monocytes. Accordingly, stimulation of murine TLR2- or myeloid differentiation factor 88-deficient bone marrow-derived macrophages did not elicit TNF-alpha, reinforcing a critical role for TLR2 in MAB-induced cell activation. We concluded that MAB signals human cells through MAPK and TLR2 pathways and triggers more pronounced pro-inflammatory cytokines and chemokines than MAV. C1 [Sampaio, Elizabeth P.] NIAID, Lab Clin Infect Dis, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Sher, Alan; Bafica, Andre L.] NIAID, Immunobiol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Shea, Yvonne R.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Sampaio, Elizabeth P.] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21045900 Rio De Janeiro, Brazil. RP Sampaio, EP (reprint author), NIAID, Lab Clin Infect Dis, Immunopathogenesis Sect, NIH, CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM sampaioe@niaid.nih.gov RI Vacinas, Inct/J-9431-2013 FU National Institutes of Health [ZO1-AI-00647-06]; NIH/FIOCRUZ FX This study was supported by the Division of Intramural Research of the MAID, National Institutes of Health ZO1-AI-00647-06 (to S.M.H.) and funding from the NIH/FIOCRUZ interchange research program. NR 44 TC 21 Z9 21 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD OCT PY 2008 VL 39 IS 4 BP 431 EP 439 DI 10.1165/rcmb.2007-0413OC PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 353CU UT WOS:000259544500008 PM 18441280 ER PT J AU Tang, LH Shia, J Soslow, RA Dhall, D Wong, WD O'Reilly, E Qin, J Paty, P Weiser, MR Guillem, J Temple, L Sobin, LH Klimstra, DS AF Tang, Laura H. Shia, Jinru Soslow, Robert A. Dhall, Deepti Wong, W. Douglas O'Reilly, Eileen Qin, Jing Paty, Philip Weiser, Martin R. Guillem, Jose Temple, Larissa Sobin, Leslie H. Klimstra, David S. TI Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE goblet cell carcinoid; carcinoid; signet ring cell carcinoma; appendix; Krukenberg tumor ID VERMIFORM APPENDIX; GENETIC ALTERATIONS; COLORECTAL-CANCER; HISTOGENESIS; METASTASES; NEOPLASMS; MUCIN; P53 AB Appendiceal tumors exhibiting both neuroendocrine and glandular differentiation are uncommon and have caused difficulty in pathologic classification, prediction of prognosis, and clinical management. Previously, such lesions have been variously designated as adenocarcinoid, goblet cell carcinoid (GCC), and mixed adenocarcinoma carcinoid. In this study, we undertook a retrospective investigation of 63 such cases and classified them as typical GCC (group A) and adenocarcinoma ex GCC on the basis of the histologic features of the tumor at the primary site. The adenocarcinoma ex GCC group was further divided into signet ring cell type (group B) and poorly differentiated adenocarcinoma type (group C). The clinical characteristics and prognosis were compared within these groups and with conventional de novo appendiceal adenocarcinomas. Both groups A and B tumors shared a similar immunoprofile, which included generally focal immunoreactivity for neuroendocrine markers, and a normal intestinal type mucin glycoprotein profile (negative MUC1 expression and preserved MUC2 immunoreactivity). The proliferative index was relatively low in these tumors and slightly increased from groups A to B tumors (11% to 16%). Both (3-catenin and E-cadherin exhibited a normal membranous staining pattern in groups A and B tumors. The poorly differentiated adenocarcinomas ex GCC (group C) demonstrated abnormal p53 and (P-catenin immunoreactivity. The mean follow-up time was 49 +/- 5 (SE) months. The overall disease-specific survival for all subtypes was 77%, with 46% of patients without evidence of disease and 31 % alive with disease. The mean survival was 43 +/- 7 months. All the patients with clinical stage of I or IIA disease had a favorable outcome after appropriate surgery with or without chemotherapy. Although most patients (63%) with GCC presented at an advanced clinical stage, their clinical outcome could be differentiated by subclassification of tumors. The stage IV-matched 5-year survival was 100%, 38%, and 0% for groups A, B, and C, respectively. In conclusion, GCC is a distinctive appendiceal neoplasm that exhibits unique pathologic features and clinical behavior. They display a spectrum of histologic features and possess the potential to transform to an adenocarcinoma phenotype of either signet ring cell or poorly differentiated adenocarcinoma types. Careful evaluation of the morphologic features of GCCs and appropriate pathologic classification are crucial for clinical management and prediction of outcome. Surgical management with right hemicolectomy is recommended after appendectomy for most cases, particularly those with an adenocarcinoma component (groups B and C). C1 [Tang, Laura H.; Shia, Jinru; Soslow, Robert A.; Dhall, Deepti; Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Wong, W. Douglas; Paty, Philip; Weiser, Martin R.; Guillem, Jose; Temple, Larissa] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [O'Reilly, Eileen] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Qin, Jing] Armed Forces Inst Pathol, Dept Hepat & Gastrointestinal Pathol, Washington, DC 20306 USA. [Sobin, Leslie H.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Klimstra, DS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10065 USA. EM klimstrd@mskcc.org OI Shia, Jinru/0000-0002-4351-2511 FU Sackler's foundation FX This study was partially supported by Sackler's foundation. NR 40 TC 79 Z9 84 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2008 VL 32 IS 10 BP 1429 EP 1443 DI 10.1097/PAS.0b013e31817f1816 PG 15 WC Pathology; Surgery SC Pathology; Surgery GA 355BQ UT WOS:000259684300001 PM 18685490 ER PT J AU Levy, MZ Quispe-Machaca, VR Ylla-Velasquez, JL Waller, LA Richards, JM Rath, B Borrini-Mayori, K del Carpio, JGC Cordova-Benzaquen, E McKenzie, FE Wirtz, RA Maguire, JH Gilman, RH Bern, C AF Levy, Michael Z. Quispe-Machaca, Victor R. Ylla-Velasquez, Jose L. Waller, Lance A. Richards, Jean M. Rath, Bruno Borrini-Mayori, Katty del Carpio, Juan G. Cornejo Cordova-Benzaquen, Eleazar McKenzie, F. Ellis Wirtz, Robert A. Maguire, James H. Gilman, Robert H. Bern, Caryn TI Impregnated netting slows infestation by Triatoma infestans SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID INSECTICIDE-TREATED BEDNETS; CHAGAS-DISEASE CONTROL; TRYPANOSOMA-CRUZI; AMERICAN TRYPANOSOMIASIS; NORTHWESTERN ARGENTINA; TRANSMISSION; POPULATIONS; REDUVIIDAE; HEMIPTERA; DISPERSAL AB We used sentinel animal enclosures to measure the rate of infestation by the Chagas disease vector, Triatoma infestans, in an urban community of Arequipa, Peru, and to evaluate the effect of deltamethrin-impregnated netting on that rate. Impregnated netting decreased the rate of infestation of sentinel enclosures (rate ratio, 0.23; 95% confidence interval, 0.13-0.38; P < 0.001), controlling for the density of surrounding vector populations and the distance of these to the sentinel enclosures. Most migrant insects were early-stage nymphs, which are less likely to carry the parasitic agent of Chagas disease, Trypanosoma cruzi. Spread of the vector in the city therefore likely precedes spread of the parasite. Netting was particularly effective against adult insects and late-stage nymphs; taking into account population structure, netting decreased the reproductive value of migrant populations from 443.6 to 40.5. Impregnated netting can slow the spread of T. infestans and is a potentially valuable tool in the control of Chagas disease. C1 [Levy, Michael Z.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA 30341 USA. Emory Univ, Div Biol & Biomed Sci, Program Populat Biol Ecol & Evolut, Atlanta, GA 30322 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. Asociac Benef Proyectos Informat Salud Med & Agr, AB PRISMA, Lima 32, Peru. Minist Salud, Direcc Reg, Arequipa, Peru. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. Univ Nacl San Agustin, Fac Med, Arequipa, Peru. Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. RP Levy, MZ (reprint author), NIH, Fogarty Int Ctr, 31 Ctr Dr,MSC2220, Bethesda, MD 20892 USA. EM levymz@yahoo.com FU UNICEF/UNDP/World Bank/WHO Special Program [A50684]; Howard Hughes Pre-doctoral fellowship; Fogarty Center of the NIH; National Institutes of Health [U19-AI-33061, RO1-AI047498.] FX This study received financial support from the UNICEF/UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases (TDR Grant A50684). M.Z.L. was supported by a Howard Hughes Pre-doctoral fellowship. V.Q.M., J.L.Y.V., K.B., and B.R. were supported by a training grant from the Fogarty Center of the NIH. Additional support came from National Institutes of Health Grants U19-AI-33061 and RO1-AI047498. NR 30 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD OCT PY 2008 VL 79 IS 4 BP 528 EP 534 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 357PG UT WOS:000259858000009 PM 18840739 ER PT J AU Talaat, KR Kumarasamy, N Swaminathan, S Gopinath, R Nutman, TB AF Talaat, Kawsar R. Kumarasamy, Nagalingeswaran Swaminathan, Soumya Gopinath, Ramya Nutman, Thomas B. TI Filarial/human immunodeficiency virus coinfection in urban southern India SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID BANCROFTIAN FILARIASIS; LYMPHATIC FILARIASIS; ADULT TANZANIANS; HIV; INFECTION; ONCHOCERCIASIS; REACTIVITY; HELMINTHS; RESPONSES; ANTIGEN AB The disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coinfections. Treatment or prevention of these concomitant infections often improves the quality and duration of life of HIV-infected persons. The impact of helminth infections on infections with HIV is less clear. However, HIV is frequently most problematic in areas where helminth infections are common. In advance of the widespread distribution of drugs for elimination of lymphatic filariasis, we assessed the prevalence of active Wuchereria bancrofti infection among HIV-positive patients in Chennai, India at two time points separated by four years. We found that the overall prevalence of W. bancrofti infections among HIV-positive persons was 5-9.5%, and there were no quantitative differences in circulating filarial antigen levels between HIV-positive and HIV-negative filarial-infected patients. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. YR Gaitonde Ctr AIDS Res & Educ, Madras, Tamil Nadu, India. Indian Council Med Res, TB Res Ctr, Madras, Tamil Nadu, India. Infect Dis Assoc, Howard Cty Gen Hosp, Columbia, MD 21044 USA. Natl Inst Allergy & Infect Dis, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Talaat, KR (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Hampton House Room 249,624 N Broadway, Baltimore, MD 21205 USA. EM ktalaat@jhsph.edu FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health (Bethesda, MD) FX This study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, MD). NR 15 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD OCT PY 2008 VL 79 IS 4 BP 558 EP 560 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 357PG UT WOS:000259858000014 PM 18840744 ER PT J AU Li, X Peterkofsky, A Wang, GS AF Li, Xia Peterkofsky, Alan Wang, Guangshun TI Solution structure of NPr, a bacterial signal-transducing protein that controls the phosphorylation state of the potassium transporter-regulating protein IIA(Ntr) SO AMINO ACIDS LA English DT Article DE IIA(Ntr); NMR; NPr; phosphorylation; signal transduction; TrkA ID HISTIDINE-CONTAINING PROTEIN; DEPENDENT PHOSPHOTRANSFERASE SYSTEM; ESCHERICHIA-COLI; ENZYME IIA(NTR); CHEMICAL-SHIFT; ACTIVE-SITE; 3-DIMENSIONAL STRUCTURES; SECONDARY STRUCTURE; NMR-SPECTROSCOPY; GENE-PRODUCTS AB A nitrogen-related signal transduction pathway, consisting of the three phosphotransfer proteins EI(Ntr), NPr, and IIA(Ntr), was discovered recently to regulate the uptake of K(+) in Escherichia coli. In particular, dephosphorylated IIA(Ntr) inhibits the activity of the K+ transporter TrkA. Since the phosphorylation state of IIA(Ntr) is partially determined by its reversible phosphorylation by NPr, we have determined the three-dimensional structure of NPr by solution NMR spectroscopy. In total, we obtained 973 NOE-derived distance restraints, 112 chemical shift-derived backbone angle restraints, and 35 hydrogen-bond restraints derived from temperature coefficients (wave). We propose that temperature wave is useful for identifying exposed beta-strands and assists in establishing protein folds based on chemical shifts. The deduced structure of NPr contains three alpha-helices and four beta-strands with the three helices all packed on the same face of the beta-sheet. The active site residue His16 of NPr for phosphoryl transfer was found to be neutral and in the N epsilon 2-H tautomeric state. There appears to be increased motion in the active site region of NPr compared to HPr, a homologous protein involved in the uptake and regulation of carbohydrate utilization. C1 [Li, Xia; Wang, Guangshun] Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Peterkofsky, Alan] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, GS (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, 986805 Nebraska Med Ctr,Room ECI3018, Omaha, NE 68198 USA. EM gwang@unmc.edu FU Eppley Institute of the University of Nebraska Medical Center (UNMC); Intramural Research Program of the NIH; NHLBI; UNMC; National Cancer Institute-NIH; Nebraska Research Initiative NRI FX This research was supported by the startup fund from the Eppley Institute of the University of Nebraska Medical Center (UNMC) to G. W. and, in part, by the Intramural Research Program of the NIH, NHLBI to A. P. The support of UNMC also includes the accessibility to the NMR Core Facility (supported by both a CORE grant from the National Cancer Institute-NIH and the Nebraska Research Initiative NRI). We are grateful to Frank Delaglio and Dan Garrett (NIH) for NMR software. We thank Paul Keifer for maintaining the NMR hardware during this study. NR 51 TC 10 Z9 10 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD OCT PY 2008 VL 35 IS 3 BP 531 EP 539 DI 10.1007/s00726-008-0079-9 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343DS UT WOS:000258833500003 PM 18421563 ER PT J AU Schantz, MM Bedner, M Long, SE Molloy, JL Murphy, KE Porter, BJ Putzbach, K Rimmer, CA Sander, LC Sharpless, KE Thomas, JB Wise, SA Wood, LJ Yen, JH Yarita, T NguyenPho, A Sorenson, WR Betz, JM AF Schantz, Michele M. Bedner, Mary Long, Stephen E. Molloy, John L. Murphy, Karen E. Porter, Barbara J. Putzbach, Karsten Rimmer, Catherine A. Sander, Lane C. Sharpless, Katherine E. Thomas, Jeanice B. Wise, Stephen A. Wood, Laura J. Yen, James H. Yarita, Takashi NguyenPho, Agnes Sorenson, Wendy R. Betz, Joseph M. TI Development of saw palmetto (Serenoa repens) fruit and extract standard reference materials SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE saw palmetto; Serenoa repens; fatty acids; phytosterols; certified reference material; standard reference material ID SUPPLEMENTS; SUITE AB As part of a collaboration with the National Institutes of Health's Office of Dietary Supplements and the Food and Drug Administration's Center for Drug Evaluation and Research, the National Institute of Standards and Technology has developed two standard reference materials (SRMs) representing different forms of saw palmetto (Serenoa repens), SRM 3250 Serenoa repens fruit and SRM 3251 Serenoa repens extract. Both of these SRMs have been characterized for their fatty acid and phytosterol content. The fatty acid concentration values are based on results from gas chromatography with flame ionization detection (GC-FID) and mass spectrometry (GC/MS) analysis while the sterol concentration values are based on results from GC-FID and liquid chromatography with mass spectrometry analysis. In addition, SRM 3250 has been characterized for lead content, and SRM 3251 has been characterized for the content of beta-carotene and tocopherols. SRM 3250 (fruit) has certified concentration values for three phytosterols, 14 fatty acids as triglycerides, and lead along with reference concentration values for four fatty acids as triglycerides and 16 free fatty acids. SRM 3251 (extract) has certified concentration values for three phytosterols, 17 fatty acids as triglycerides, beta-carotene, and gamma-tocopherol along with reference concentration values for three fatty acids as triglycerides, 17 fatty acids as free fatty acids, beta-carotene isomers, and delta-tocopherol and information values for two phytosterols. These SRMs will complement other reference materials currently available with concentrations for similar analytes and are part of a series of SRMs being developed for dietary supplements. C1 [Schantz, Michele M.; Bedner, Mary; Long, Stephen E.; Molloy, John L.; Murphy, Karen E.; Porter, Barbara J.; Putzbach, Karsten; Rimmer, Catherine A.; Sander, Lane C.; Sharpless, Katherine E.; Thomas, Jeanice B.; Wise, Stephen A.; Wood, Laura J.; Yarita, Takashi] Natl Inst Stand & Technol, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Yen, James H.] Natl Inst Stand & Technol, Stat Engn Div, Gaithersburg, MD 20899 USA. [NguyenPho, Agnes] Food & Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Sorenson, Wendy R.] Covance Labs, Madison, WI 53704 USA. [Betz, Joseph M.] Natl Inst Hlth, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Schantz, MM (reprint author), Natl Inst Stand & Technol, Div Analyt Chem, Gaithersburg, MD 20899 USA. EM michele.schantz@nist.gov OI Sharpless, Katherine/0000-0001-6569-198X NR 17 TC 14 Z9 17 U1 0 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD OCT PY 2008 VL 392 IS 3 BP 427 EP 438 DI 10.1007/s00216-008-2297-0 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 345NK UT WOS:000259003300012 PM 18677464 ER PT J AU Marszall, MP Moaddel, R Kole, S Gandhari, M Bernier, M Wainer, IW AF Marszall, M. P. Moaddel, R. Kole, S. Gandhari, M. Bernier, M. Wainer, I. W. TI Ligand and protein fishing with heat shock protein 90 coated magnetic beads SO ANALYTICAL CHEMISTRY LA English DT Article ID CHAPERONE; HSP90; RELEASE; CANCER; DOMAIN AB Heat shock protein 90 alpha (Hsp90 alpha) is a molecular chaperone that has been targeted for the development of new anticancer therapies. To date, co-immunoprecipitation (IP) has been primarily used to identify novel client proteins. We now report an alternative approach in which Hsp90 alpha has been immobilized onto the surface of silica-based magnetic beads. The beads were used to isolate known Hsp90 alpha ligands from a mixture containing ligands and nonligands. In addition, they were also used to isolated proteins from a mixture of proteins, as well as a cellular extract. The results indicate that the Hsp90 alpha coated magnetic beads can be used to "fish" from complex chemical and biological mixtures for new lead drug candidates and client proteins. C1 [Marszall, M. P.; Moaddel, R.; Kole, S.; Gandhari, M.; Bernier, M.; Wainer, I. W.] NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Marszall, M. P.] Nicolaus Copernicus Univ Torun, Dept Biopharm, Coll Med Bydgoszcz, PL-85094 Bydgoszcz, Poland. RP Moaddel, R (reprint author), NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM moaddelru@mail.nih.gov RI Marszall, Michal/G-8936-2014; OI Bernier, Michel/0000-0002-5948-368X FU Intramural NIH HHS [Z01 AG000295-06] NR 12 TC 33 Z9 33 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD OCT 1 PY 2008 VL 80 IS 19 BP 7571 EP 7575 DI 10.1021/ac801153h PG 5 WC Chemistry, Analytical SC Chemistry GA 353XS UT WOS:000259603100055 PM 18693748 ER PT J AU Quezado, Z Finkel, JC AF Quezado, Zenaide Finkel, Julia C. TI Airway management in neonates with occipital encephalocele: Easy does it SO ANESTHESIA AND ANALGESIA LA English DT Letter C1 [Quezado, Zenaide; Finkel, Julia C.] George Washington Univ, Childrens Natl Med Ctr, Dept Anesthesiol & Pain Med, Washington, DC 20052 USA. [Quezado, Zenaide] NIH, Ctr Clin, Dept Anesthesia & Surg Serv, Bethesda, MD 20892 USA. RP Quezado, Z (reprint author), George Washington Univ, Childrens Natl Med Ctr, Dept Anesthesiol & Pain Med, Washington, DC 20052 USA. EM zquezado@nih.gov RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU Intramural NIH HHS [ZIA CL009009-02] NR 2 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD OCT PY 2008 VL 107 IS 4 BP 1446 EP 1446 DI 10.1213/ane.0b013e318183374f PG 1 WC Anesthesiology SC Anesthesiology GA 352UE UT WOS:000259522100071 PM 18806073 ER PT J AU Narver, HL Kong, LL Burnett, BG Choe, DW Bosch-Mare, M Taye, AA Eckhaus, MA Sumner, CJ AF Narver, Heather L. Kong, Lingling Burnett, Barrington G. Choe, Dong W. Bosch-Mare, Marta Taye, Addis A. Eckhaus, Michael A. Sumner, Charlotte J. TI Sustained Improvement of Spinal Muscular Atrophy Mice Treated with Trichostatin A Plus Nutrition SO ANNALS OF NEUROLOGY LA English DT Article ID SINGLE NUCLEOTIDE; SMN EXPRESSION; MOUSE MODEL; GENE; HYPOGLYCEMIA; SEVERITY; SURVIVAL; VESSELS; PROTEIN; NERVES AB Early treatment with the histone deacetylase inhibitor, trichostatin A, plus nutritional support extended median survival of spinal muscular atrophy mice by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after trichostatin A was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe spinal muscular atrophy. Early spinal muscular atrophy disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of histone deacetylase inhibitor treatment in human patients. C1 [Kong, Lingling; Choe, Dong W.; Bosch-Mare, Marta; Sumner, Charlotte J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Narver, Heather L.] Natl Inst Neurol Disorders & Stroke, Anim Care Div, NIH, Baltimore, MD USA. [Burnett, Barrington G.; Taye, Addis A.] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD USA. [Eckhaus, Michael A.] Off Res Serv, Div Vet Resources, NIH, Bethesda, MD USA. RP Sumner, CJ (reprint author), Johns Hopkins Univ, Dept Neurol, Meyer 5-119B,600 N Wolfe St, Baltimore, MD 21287 USA. EM csumnerl@jhmi.edu FU National Institute of Neurological Disorders and Stroke (NINDS) Career Transition Award [K22-NS0048199-01]; NINDS Competitive Fellowship Award; NINDS Intramural Funds and Families of Spinal Muscular Atrophy FX This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) Career Transition Award, K22-NS0048199-01, C.J.S.; NINDS Competitive Fellowship Award, B.G.B.) NINDS Intramural Funds and Families of Spinal Muscular Atrophy, CJS.; We thank Drs M. Sendtner and A. Burghes for generously providing the original breeding pairs for the SMA transgenic mice. NR 18 TC 91 Z9 91 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2008 VL 64 IS 4 BP 465 EP 470 DI 10.1002/ana.21449 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 371QC UT WOS:000260845000016 PM 18661558 ER PT J AU Aletaha, D Landewe, R Karonitsch, T Bathon, J Boers, M Bombardier, C Bombardieri, S Choi, H Combe, B Dougados, M Emery, P Gomez-Reino, J Keystone, E Koch, G Kvien, TK Martin-Mola, E Matucci-Cerinic, M Michaud, K O'Dell, J Paulus, H Pincus, T Richards, P Simon, L Siegel, J Smolen, JS Sokka, T Strand, V Tugwell, P van der Heijde, D van Riel, P Vlad, S van Vollenhoven, R Ward, M Weinblatt, M Wells, G White, B Wolfe, F Zhang, B Zink, A Felson, D AF Aletaha, D. Landewe, R. Karonitsch, T. Bathon, J. Boers, M. Bombardier, C. Bombardieri, S. Choi, H. Combe, B. Dougados, M. Emery, P. Gomez-Reino, J. Keystone, E. Koch, G. Kvien, T. K. Martin-Mola, E. Matucci-Cerinic, M. Michaud, K. O'Dell, J. Paulus, H. Pincus, T. Richards, P. Simon, L. Siegel, J. Smolen, J. S. Sokka, T. Strand, V. Tugwell, P. van der Heijde, D. van Riel, P. Vlad, S. van Vollenhoven, R. Ward, M. Weinblatt, M. Wells, G. White, B. Wolfe, F. Zhang, B. Zink, A. Felson, D. TI Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID FUNCTIONAL-CAPACITY; ACTIVITY SCORE; IMPROVEMENT AB Objective: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). Results: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. Conclusions: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses. C1 [Aletaha, D.] Med Univ Vienna, Div Rheumatol, A-1090 Vienna, Austria. [Landewe, R.] Univ Hosp Maastricht, Maastricht, Netherlands. [Bathon, J.] Johns Hopkins Univ, Baltimore, MD USA. [Boers, M.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Bombardier, C.] Inst Work & Hlth, Toronto, ON, Canada. [Bombardieri, S.] Univ Pisa, Pisa, Italy. [Choi, H.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Combe, B.] CHU Montpellier, Montpellier, France. [Dougados, M.] Paris Descartes Univ, Paris, France. [Emery, P.] Univ Leeds, Leeds, W Yorkshire, England. [Gomez-Reino, J.] Univ Santiago Compostela, Sch Med, E-15706 Santiago, Spain. [Keystone, E.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Koch, G.] Univ N Carolina, Chapel Hill, NC USA. [Kvien, T. K.] Diakonhjemmet Hosp, Oslo, Norway. [Martin-Mola, E.] Hosp Univ La Paz, Madrid, Spain. [Matucci-Cerinic, M.] Univ Florence, Florence, Italy. [Michaud, K.; O'Dell, J.] Univ Nebraska, Omaha, NE 68182 USA. [Paulus, H.] Univ Calif Los Angeles, Los Angeles, CA USA. [Pincus, T.] NYU, Hosp Joint Dis, New York, NY USA. [Richards, P.] Univ Bristol, Bristol, Avon, England. [Simon, L.] Beth Israel Deaconess Med, Boston, MA USA. [Siegel, J.] US FDA, Rockville, MD 20857 USA. [Smolen, J. S.] Hietzing Hosp, Vienna, Austria. [Sokka, T.] Jyvaskyla Cent Hosp, Jyvaskyla, Finland. [Strand, V.] Stanford Univ, Portola Valley, CA USA. [Tugwell, P.] Inst Populat Hlth, Ottawa, ON, Canada. [van der Heijde, D.] Leiden Univ, Med Ctr, Leiden, Netherlands. [van Riel, P.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Vlad, S.; Zhang, B.; Felson, D.] Boston Univ, Sch Med, Boston, MA 02118 USA. [van Vollenhoven, R.] Karolinska Univ Hosp, Stockholm, Sweden. [Ward, M.] NIH, Bethesda, MD 20892 USA. [Weinblatt, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wells, G.] Univ Ottawa, Ottawa, ON, Canada. [White, B.] Medimmune, Gaithersburg, MD USA. [Wolfe, F.] Natl Data Bank Rheumat Dis, Wichita, KS USA. [Zink, A.] Charite Univ Med Berlin, Berlin, Germany. RP Aletaha, D (reprint author), Med Univ Vienna, Div Rheumatol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM daniel.aletaha@meduniwien.ac.at OI Felson, David/0000-0002-2668-2447; Tugwell, Peter/0000-0001-5062-0556 FU EULAR; ACR FX This project was fully funded by EULAR and the ACR. NR 19 TC 96 Z9 102 U1 1 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD OCT PY 2008 VL 67 IS 10 BP 1360 EP 1364 DI 10.1136/ard.2008.091454 PG 5 WC Rheumatology SC Rheumatology GA 359FJ UT WOS:000259971500003 PM 18791055 ER PT J AU Karonitsch, T Aletaha, D Boers, M Bombardieri, S Combe, B Dougados, M Emery, P Felson, D Gomez-Reino, J Keystone, E Kvien, TK Martin-Mola, E Matucci-Cerinic, M Richards, P van Riel, P Siegel, J Smolen, JS Sokka, T van der Heijde, D van Vollenhoven, R Ward, M Wells, G Zink, A Landewe, R AF Karonitsch, T. Aletaha, D. Boers, M. Bombardieri, S. Combe, B. Dougados, M. Emery, P. Felson, D. Gomez-Reino, J. Keystone, E. Kvien, T. K. Martin-Mola, E. Matucci-Cerinic, M. Richards, P. van Riel, P. Siegel, J. Smolen, J. S. Sokka, T. van der Heijde, D. van Vollenhoven, R. Ward, M. Wells, G. Zink, A. Landewe, R. TI Methods of deriving EULAR/ACR recommendations on reporting disease activity in clinical trials of patients with rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Review ID COLLEGE-OF-RHEUMATOLOGY; HEALTH-ASSESSMENT QUESTIONNAIRE; PRELIMINARY REMISSION CRITERIA; MODIFYING ANTIRHEUMATIC DRUGS; PLACEBO-CONTROLLED TRIAL; C-REACTIVE PROTEIN; ACTIVITY SCORE; RESPONSE CRITERIA; FOLLOW-UP; RADIOGRAPHIC PROGRESSION AB Objective: To use an evidence-based and consensus-based approach to elaborate recommendations on how to report disease activity in clinical trials of patients with rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods: After an initial expert meeting, during which relevant research questions were identified, a systematic literature search was performed using Medline, Embase and the Cochrane Library as sources. To ensure literature retrieved was comprehensive, we emphasised search algorithms that were sensitive rather than specific. The results of the literature search were discussed by the expert panel, modified and expanded, and were used as the basis for the elaboration of the recommendation in the consensus process. Finally, an independent ACR panel approved these items with some minor modifications. Results: The following pieces of evidence were obtained from the literature search: (1) timing and the sustaining of a response is relevant to achieve better outcomes; (2) composite disease activity indices have been used to define low disease activity and remission and these definitions have been validated as has the American Rheumatism Association (ARA) remission criteria. The "patient-reported symptom state" (PASS) is not yet well validated; (3) evidence was obtained to identify those measures, scales and patient-reported instruments, for which there is a documented association with relevant outcomes; (4) baseline disease activity is associated with disease activity levels at the end of follow-up; and (5) there was not sufficient evidence relating the added benefit of MRI or ultrasound over clinical assessments. Most data stemmed from observational studies rather than clinical trials and literature review was supplemented by input from experts. The results served as the basis for the elaboration of the seven recommendations by the experts. Conclusions: The approach based on scientific evidence from the literature as well as on expert input provided sufficient information to derive recommendations on reporting disease activity in RA clinical trials. The methodology, results and conclusions of this project were endorsed by EULAR and the ACR. C1 [Aletaha, D.] Med Univ Vienna, Div Rheumatol, A-1090 Vienna, Austria. [Boers, M.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Bombardieri, S.] Univ Pisa, Pisa, Italy. [Combe, B.] CHU Montpellier, Montpellier, France. [Dougados, M.] Paris Descartes Univ, Paris, France. [Emery, P.] Univ Leeds, Leeds, W Yorkshire, England. [Felson, D.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Gomez-Reino, J.] Univ Santiago Compostela, Sch Med, E-15706 Santiago, Spain. [Keystone, E.] Univ Toronto, Toronto, ON, Canada. [Kvien, T. K.] Diakonhjemmet Hosp, Oslo, Norway. [Martin-Mola, E.] Hosp Univ La Paz, Madrid, Spain. [Matucci-Cerinic, M.] Univ Florence, Florence, Italy. [Richards, P.] Univ Bristol, Bristol, Avon, England. [van Riel, P.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Siegel, J.] US FDA, Rockville, MD 20857 USA. [Smolen, J. S.] Hietzing Hosp, Vienna, Austria. [Sokka, T.] Jyvaskyla Cent Hosp, Jyvaskyla, Finland. [van der Heijde, D.] Leiden Univ, Med Ctr, Leiden, Netherlands. [van Vollenhoven, R.] Karolinska Univ Hosp, Stockholm, Sweden. [Ward, M.] NIH, Bethesda, MD 20892 USA. [Wells, G.] Univ Ottawa, Ottawa, ON, Canada. [Zink, A.] Charite Univ Med Berlin, Berlin, Germany. [Landewe, R.] Univ Hosp Maastricht, Maastricht, Netherlands. RP Aletaha, D (reprint author), Med Univ Vienna, Div Rheumatol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM daniel.aletaha@meduniwien.ac.at RI Riel, P.L.C.M./H-8082-2014; OI Felson, David/0000-0002-2668-2447 FU EULAR; ACR FX This project was fully funded by EULAR and the ACR. NR 109 TC 12 Z9 12 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD OCT PY 2008 VL 67 IS 10 BP 1365 EP 1373 DI 10.1136/ard.2008.092353 PG 9 WC Rheumatology SC Rheumatology GA 359FJ UT WOS:000259971500004 PM 18791056 ER PT J AU Moutsopoulos, NM Katsifis, GE Angelov, N Leakan, RA Sankar, V Pillemer, S Wahl, SM AF Moutsopoulos, N. M. Katsifis, G. E. Angelov, N. Leakan, R. A. Sankar, V. Pillemer, S. Wahl, S. M. TI Lack of efficacy of etanercept in Sjogren syndrome correlates with failed suppression of tumour necrosis factor alpha and systemic immune activation SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID SALIVARY-GLANDS; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; PERIPHERAL-BLOOD; FACTOR TNF; INTERLEUKIN-10; EXPRESSION; CELLS; INFLAMMATION; INHIBITION AB Objective: To provide insight into the clinical failure of the tumour necrosis factor alpha (TNF alpha) inhibitor, etanercept, in primary Sjogren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. Methods: Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. Results: Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNF alpha were significantly increased after treatment. Conclusion: Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNF alpha and other indicators of immune activation in this patient population. These data suggest that TNF alpha may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets. C1 [Moutsopoulos, N. M.; Katsifis, G. E.; Angelov, N.; Wahl, S. M.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Leakan, R. A.; Sankar, V.; Pillemer, S.] Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Room 320,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. EM SMWahl@mail.nih.gov FU National Institute of Dental and Craniofacial Research FX This work was supported in part by the National Institute of Dental and Craniofacial Research. NR 36 TC 33 Z9 36 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD OCT PY 2008 VL 67 IS 10 BP 1437 EP 1443 DI 10.1136/ard.2007.077891 PG 7 WC Rheumatology SC Rheumatology GA 359FJ UT WOS:000259971500015 PM 18198195 ER PT J AU Nguyen, TL AF Nguyen, Tam Luong TI Targeting RSK: An Overview of Small Molecule Inhibitors SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Serine/threonine kinase; inhibitor; RSK specific ID RIBOSOMAL S6 KINASE; GLYCOGEN-SYNTHASE KINASE-3-BETA; ACTIVATED PROTEIN-KINASE; KAPPA B ALPHA; DOCKING SITE; MAP KINASE; IN-VITRO; SIGNAL-TRANSDUCTION; C INHIBITORS; PHOSPHORYLATION AB Ribosomal S6 kinase (RSK) is a family of serine/threonine kinases that has been identified as a promising anti-cancer target. While a number of protein kinase inhibitors that have potent activity against other serine/threonine kinases were shown to also inactivate RSK, there is keen interest in the three different inhibitor chemotypes that were shown to be RSK specific, since these compounds have tremendous utility as chemical probes in elucidating the biochemistry of the RSK signaling cascade and unraveling the molecular basis of cancer. Because each compound may have therapeutic potential, the nonspecific kinase inhibitors as well as the RSK specific inhibitors will be discussed. C1 NCI, Target Struct Based Drug Discovery Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Nguyen, TL (reprint author), NCI, Target Struct Based Drug Discovery Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. EM nguyent@ncifcrf.gov FU U. S. Army Medical Research and Material Command Research Plan [02-43U-057, Y3-CM-100505]; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX The research described herein was sponsored by the U. S. Army Medical Research and Material Command Research Plan #02-43U-057 and IAA #Y3-CM-100505 (MRMC and NCI). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 46 TC 54 Z9 56 U1 2 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD OCT PY 2008 VL 8 IS 7 BP 710 EP 716 PG 7 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 359OW UT WOS:000259998500002 PM 18855572 ER PT J AU Garg, H Francella, N Tony, KA Augustine, LA Barchi, JJ Fantini, J Puri, A Mootoo, DR Blumenthal, R AF Garg, Himanshu Francella, Nicholas Tony, Kurissery A. Augustine, Line A. Barchi, Joseph J., Jr. Fantini, Jacques Puri, Anu Mootoo, David R. Blumenthal, Robert TI Glycoside analogs of beta-galactosylceramide, a novel class of small molecule antiviral agents that inhibit HIV-1 entry SO ANTIVIRAL RESEARCH LA English DT Article DE HIV-1; galactosyl ceramide; glycosides; anti HIV; fusion; envelope glycoprotein ID CYANOVIRIN-N; CERAMIDE SUBSTITUTE; SOLUBLE ANALOGS; V3 REGION; GP120; FUSION; INFECTION; BINDING; VIRUS; RECEPTOR AB The interaction between HIV gp120 and galactose-containing cell surface glycolipids such as GalCer or Gb(3) is known to facilitate HIV binding to both CD4(+) as well as CD4(-) cells. In an effort to develop small molecule HIV-1 entry inhibitors with improved solubility and efficacy, we have synthesized a series of C-glycoside analogs of GalCeF and tested their anti HIV-1 activity. The analogs were tested for gp120 binding using a HIV-1 (IIIB) V3-loop specific peptide. Two of the six analogs that interfered with gp120 binding also inhibited HIV Env-mediated cell-to-cell fusion and viral entry in the absence of any significant cytotoxicity. Analogs with two side chains did not show inhibition of fusion and/or infection under identical conditions. The inhibition of virus infection seen by these compounds was not coreceptor dependent, as they inhibited CXCR4, CCR5 as well as dual tropic viruses. These compounds showed inhibition of HIV entry at early steps in viral infection since the compounds were inactive if added post viral entry. Temperature-arrested state experiments showed that the compounds act at the level of virus attachment to the cells likely at a pre-CD4 engagement step. These compounds also showed inhibition of VSV glycoprotein-pseudotyped virus. The results presented here show that the glycoside derivatives of GalCer with simple side chains may serve as a novel class of small molecule HIV-1 entry inhibitors that would be active against a number of HIV isolates as well as other enveloped viruses. Published by Elsevier B.V. C1 [Garg, Himanshu; Francella, Nicholas; Puri, Anu; Blumenthal, Robert] NCI, Membrane Struct & Funct Sect, Ctr Canc Res, Nanobiol Program,NIH, Frederick, MD 21702 USA. [Barchi, Joseph J., Jr.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Tony, Kurissery A.; Augustine, Line A.; Mootoo, David R.] CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA. [Fantini, Jacques] Univ Paul Cezanne, Lab Interact Mol & Syst Membranaires, Fac Sci & Tech St Jerome, F-13397 Marseille 20, France. RP Blumenthal, R (reprint author), NCI, Membrane Struct & Funct Sect, Ctr Canc Res, Nanobiol Program,NIH, POB B,Bldg 469,Room 152,Miller Dr, Frederick, MD 21702 USA. EM BlumenthalR@mail.nih.gov RI Barchi Jr., Joseph/N-3784-2014 FU Intramural NIH HHS [Z01 BC008303-35, Z99 CA999999]; NCRR NIH HHS [G12 RR003037, RR-03037]; NIGMS NIH HHS [R01 GM057865, R01 GM57865, S06 GM060654, S06 GM60654] NR 28 TC 25 Z9 29 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD OCT PY 2008 VL 80 IS 1 BP 54 EP 61 DI 10.1016/j.antiviral.2008.04.004 PG 8 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 357YX UT WOS:000259884300006 PM 18538869 ER PT J AU Yang, Y Stewart, PE Shi, XG Li, CH AF Yang, Yu Stewart, Philip E. Shi, Xiaoguang Li, Chunhao TI Development of a transposon mutagenesis system in the oral spirochete Treponema denticola SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID RANDOM INSERTIONAL MUTAGENESIS; ESCHERICHIA-COLI; RIBOSOMAL-RNA; BORRELIA-BURGDORFERI; MUTANTS; INACTIVATION; VIRULENCE; IDENTIFICATION; DIVERSITY; SITE AB Here, we report successful transposon mutagenesis in the oral spirochete Treponema denticola. A modified Himar1 transposon, including a new antibiotic selection cassette for T. denticola, generated mutations affecting cell division, transport, and chemotaxis, among other processes. This random mutagenesis system should facilitate research on the biology and pathogenesis of this spirochete, which is associated with human periodontal diseases. C1 [Yang, Yu; Shi, Xiaoguang; Li, Chunhao] SUNY Buffalo, Dept Oral Biol, Buffalo, NY 14214 USA. [Stewart, Philip E.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Li, CH (reprint author), SUNY Buffalo, Dept Oral Biol, 3435 Main St, Buffalo, NY 14214 USA. EM cli9@buffalo.edu FU U. S. Public Health Service [AR050656, DE018829]; American Heart Association [0735236N] FX This research was supported by U. S. Public Health Service grants AR050656 and DE018829 and American Heart Association grant SDG 0735236N. NR 29 TC 15 Z9 16 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2008 VL 74 IS 20 BP 6461 EP 6464 DI 10.1128/AEM.01424-08 PG 4 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 359KJ UT WOS:000259985300037 PM 18723655 ER PT J AU Leibenluft, E AF Leibenluft, Ellen TI Pediatric bipolar disorder comes of age SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID SEVERE MOOD DYSREGULATION; SPECTRUM DISORDERS; LABELING DEFICITS; I DISORDER; ADOLESCENTS; CHILDREN; SCHIZOPHRENIA; ABNORMALITIES; PHENOTYPE; DIAGNOSES C1 NIMH, Sect Biopolar Spectrum Disorders, Emot & Dev Branch, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Sect Biopolar Spectrum Disorders, Emot & Dev Branch, Bldg 15K,Room 203,MSC-2670, Bethesda, MD 20892 USA. EM leibs@mail.nih.gov FU Intramural NIH HHS [Z01 MH002778-08] NR 31 TC 7 Z9 7 U1 2 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2008 VL 65 IS 10 BP 1122 EP 1124 DI 10.1001/archpsyc.65.10.1122 PG 3 WC Psychiatry SC Psychiatry GA 356WG UT WOS:000259807700002 PM 18838628 ER PT J AU Hasler, G Nugent, AC Carlson, PJ Carson, RE Geraci, M Drevets, WC AF Hasler, Gregor Nugent, Allison C. Carlson, Paul J. Carson, Richard E. Geraci, Marilla Drevets, Wayne C. TI Altered cerebral gamma-aminobutyric acid type A-benzodiazepine receptor binding in panic disorder determined by [(11)C]flumazenil positron emission tomography SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID MEDIAL PREFRONTAL CORTEX; REFERENCE TISSUE MODELS; C-11 FLUMAZENIL; CONDITIONED FEAR; RESONANCE SPECTROSCOPY; PROSPECTIVE COMMUNITY; IOMAZENIL-SPECT; GABA LEVELS; BRAIN; ANXIETY AB Context: The benzodiazepine (BZD) receptor system has been implicated in the pathophysiologic mechanism of panic disorder (PD) by indirect evidence from pharmacological challenge studies and by direct evidence from single-photon emission computed tomography and positron emission tomography neuroimaging studies. However, the results of previous neuroimaging studies are in disagreement, possibly because of experimental design limitations related to sample size, matching between patients and controls, and confounding medication effects. Objective: To compare BZD receptor binding between subjects with PD and healthy control subjects. Design: Cross-sectional study for association. Setting: Psychiatric outpatient clinic of the National Institute of Mental Health. Participants: Fifteen subjects with PD who were naive to BZD drug exposure and were not receiving other drug treatment, and 18 healthy controls. Intervention: Images of BZD receptor binding were acquired using positron emission tomography and flumazenil tagged with carbon 11. Main Outcome Measures: The BZD receptor binding potential was assessed by a simplified reference tissue-tracer kinetic model. Results: The BZD receptor binding potential was decreased in multiple areas of the frontal, temporal, and parietal cortices and was increased in the hippocampus/parahippocampal region in subjects with PD vs controls. The most significant decrease was located in the dorsal anterolateral prefrontal cortex (DALPFC); the most significant increase, in the hippocampus/parahippocampal gyrus. These abnormalities were not accounted for by comorbid depression. In subjects with PD, the severity of panic and anxiety symptoms correlated positively with BZD receptor binding in the DALPFC but negatively with binding in the hippocampus/parahippocampal gyrus. Conclusions: These data provide evidence of abnormal BZD-gamma-aminobutyric acid type A receptor binding in PD, suggesting that basal and/or compensatory changes in inhibitory neurotransmission play roles in the pathophysiologic mechanism of PD. They also provide evidence of an impairment of frontal-limbic interaction in the modulation of anxiety responses, consistent with previous functional and structural neuroimaging studies in PD. C1 [Hasler, Gregor] Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. [Nugent, Allison C.; Carlson, Paul J.; Geraci, Marilla; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Carson, Richard E.] Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT USA. [Carson, Richard E.] Yale Univ, Sch Med, Dept Biomed Engn, New Haven, CT USA. RP Hasler, G (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM g.hasler@bluewin.ch RI Carson, Richard/H-3250-2011; Hasler, Gregor/E-4845-2012; OI Carson, Richard/0000-0002-9338-7966; Hasler, Gregor/0000-0002-8311-0138; Nugent, Allison/0000-0003-2569-2480 FU National Institutes of Mental Health FX Funding/Support: This study was supported by the Intramural Research Program of the National Institutes of Mental Health. NR 55 TC 51 Z9 56 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2008 VL 65 IS 10 BP 1166 EP 1175 DI 10.1001/archpsyc.65.10.1166 PG 10 WC Psychiatry SC Psychiatry GA 356WG UT WOS:000259807700007 PM 18838633 ER PT J AU Blair, K Geraci, M Devido, J McCaffrey, D Chen, G Vythilingam, M Ng, P Hollon, N Jones, M Blair, RJR Pine, DS AF Blair, Karina Geraci, Marilla Devido, Jeffrey McCaffrey, Daniel Chen, Gang Vythilingam, Meena Ng, Pamela Hollon, Nick Jones, Matthew Blair, R. J. R. Pine, Daniel S. TI Neural response to self- and other referential praise and criticism in generalized social phobia SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID AMYGDALA ACTIVATION; ANXIETY DISORDER; BRAIN ACTIVATION; EMOTIONAL FACES; VISUAL SCANPATH; FMRI; INDIVIDUALS; ATTENTION; PSYCHOPATHY; RECOGNITION AB Context: Generalized social phobia (GSP) is characterized by fear/avoidance of social situations. Previous studies have examined the neural responses in GSP to one class of social stimuli, facial expressions. However, studies have not examined the neural response in GSP to another equally important class of social stimuli, the communication of praise or criticism. Objective: To examine the neural response to receipt of praise or criticism in GSP; specifically, to determine whether patients with GSP show an increased response to the receipt of both praise and criticism and whether self-relevance modulates this relationship. Design: Case-control study. Setting: Government clinical research institute. Participants: Unmedicated individuals with GSP (n = 17) and age-, IQ-, and sex-matched healthy comparison individuals (n = 17). Main Outcome Measure: Blood oxygenation level dependent signal, as measured via functional magnetic resonance imaging. During functional magnetic resonance imaging scans, individuals read positive (eg, You are beautiful), negative (eg, You are ugly), and neutral (eg, You are human) comments that could be either about the self or about somebody else (eg, He is beautiful). Results: Hypothesized significant group x valence x referent interactions were observed within regions of the medial prefrontal cortex and bilateral amygdala. In these regions, the patients with GSP showed significantly increased blood oxygenation level-dependent responses, relative to comparison individuals, to negative comments (criticism) referring to themselves. However, in contrast, there were no significant group differences with respect to negative comments referring to others or neutral or positive comments referring to self or others. Conclusions: These results implicate the medial prefrontal cortex, involved in the representation of the self, together with the amygdala, in the pathophysiology of GSP. Further, findings demonstrate a meaningful effect of psychological context on neural-circuitry hyperactivity in GSP. C1 [Blair, Karina; Geraci, Marilla; Devido, Jeffrey; McCaffrey, Daniel; Vythilingam, Meena; Ng, Pamela; Hollon, Nick; Jones, Matthew; Blair, R. J. R.; Pine, Daniel S.] NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Blair, K (reprint author), NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM peschark@mail.nih.gov FU National Institutes of Health; National Institute of Mental Health FX Funding/Support: This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. NR 44 TC 85 Z9 87 U1 5 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2008 VL 65 IS 10 BP 1176 EP 1184 DI 10.1001/archpsyc.65.10.1176 PG 9 WC Psychiatry SC Psychiatry GA 356WG UT WOS:000259807700008 PM 18838634 ER PT J AU Miller, FG AF Miller, Franklin G. TI Deceptive research SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Letter C1 NIH, Dept Clin Bioeth Clin Ctr, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth Clin Ctr, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2008 VL 65 IS 10 BP 1225 EP 1226 DI 10.1001/archpsyc.65.10.1225-b PG 5 WC Psychiatry SC Psychiatry GA 356WG UT WOS:000259807700017 PM 18838641 ER PT J AU Goker-Alpan, O Lopez, G Vithayathil, J Davis, J Hallett, M Sidransky, E AF Goker-Alpan, Ozlem Lopez, Grisel Vithayathil, Joseph Davis, Joie Hallett, Mark Sidransky, Ellen TI The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations SO ARCHIVES OF NEUROLOGY LA English DT Article ID GAUCHER-DISEASE; OLFACTORY FUNCTION; RISK-FACTOR; GENE; LRRK2 AB Background: Mutations in the glucocerebrosidase gene (GBA) result in Gaucher disease and can be associated with a phenotype characterized by adult-onset progressive neurologic deterioration and parkinsonism. Objective: To define the clinical and neurologic spectrum of parkinsonian manifestations associated with GBA mutations. Design, Setting, and Patients: A prospective case series of 10 patients (7 men and 3 women) with parkinsonism and GBA mutations evaluated at the National Institutes of Health Clinical Center. Main Outcome Measures: The GBA genotypes were identified by means of DNA sequencing. Tests evaluating neurologic, motor, cognitive, ocular, and olfactory functions were performed and the results were analyzed by a single team. Results: Genotyping identified GBA mutations N370S, L444P, and c.84dupG and recombinant alleles. The mean age at onset of parkinsonian manifestations was 49 years (range, 39-65 years), disease duration was 7.8 years ( range, 1.2-16.0 years), and Unified Parkinson Disease Rating Scale part III score was 26.3 (range, 13-38). Half of the patients reported cognitive changes later in the disease course. Six patients were diagnosed as having Parkinson disease, 3 as having Lewy body dementia, and 1 as having a "Parkinson plus" syndrome. The most frequent nonmotor finding was olfactory dysfunction. Atypical manifestations included myoclonus, electroencephalographic abnormalities, and seizures. Conclusions: In the homozygous and heterozygous states, GBA mutations are associated with a spectrum of parkinsonian phenotypes ranging from Parkinson disease, mostly of the akinetic type, to a less common phenotype characteristic of Lewy body dementia. C1 [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Lopez, Grisel; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Med Neurol Branch, NIH, Bethesda, MD USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, 35 Convent Dr,MSC 3708,Bldg 35,Room 1A213, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS [Z01 HG200336-02] NR 28 TC 96 Z9 97 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD OCT PY 2008 VL 65 IS 10 BP 1353 EP 1357 DI 10.1001/archneur.65.10.1353 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 359JY UT WOS:000259984200013 PM 18852351 ER PT J AU Strasak, AM Kelleher, CC Klenk, J Brant, LJ Ruttmann, E Rapp, K Concin, H Diem, G Pfeiffer, KP Ulmer, H AF Strasak, Alexander M. Kelleher, Cecily C. Klenk, Jochen Brant, Larry J. Ruttmann, Elfriede Rapp, Kilian Concin, Hans Diem, Guenter Pfeiffer, Karl P. Ulmer, Hanno CA VHM&PP Study Grp TI Longitudinal change in serum gamma-glutamyltransferase and cardiovascular disease mortality - A prospective population-based study in 76 113 Austrian adults SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE cardiovascular disease mortality; gamma-glutamyltransferase; longitudinal change; risk factor; epidemiology ID CORONARY-HEART-DISEASE; MIDDLE-AGED MEN; ALCOHOL-CONSUMPTION; RISK-FACTORS; LONG-TERM; METABOLIC SYNDROME; SEX-DIFFERENCES; BLOOD-PRESSURE; WEIGHT CHANGE; BODY-WEIGHT AB Objective-The purpose of this study was to investigate the association of longitudinal change in serum gamma-glutamyltransferase (GGT) with mortality from cardiovascular disease (CVD). Methods and Results-A population-based cohort of 76 113 Austrian men and women with 455 331 serial GGT measurements was prospectively followed-up for a median of 10.2 years after assessment of longitudinal GGT change during an average period of 6.9 years. Cox proportional hazards regression with time-varying covariates was used to evaluate GGT change as an independent predictor for CVD death. Independently of baseline GGT and other classical CVD risk factors, a pronounced increase in GGT (7-year change > 9.2 U/ L) was significantly associated with increased total CVD mortality in men (P = 0.005); the adjusted hazard ratio (95% confidence interval) in comparison to stable GGT (7-year change -0.7 to 1.3 U/L) was 1.40 (1.09 to 1.81). Similarly, total CVD risk was elevated for increasing GGT in women, although effects were less pronounced and statistically significant only in subanalyses regarding coronary heart disease. Age of participants significantly modified the relation between GGT change and CVD mortality, with markedly stronger associations to be observable for younger individuals. Conclusion -Our study is the first to demonstrate that a longitudinal increase in GGT, independently of baseline GGT and even within its normal range, significantly increases risk of fatal CVD. C1 [Strasak, Alexander M.; Pfeiffer, Karl P.; Ulmer, Hanno] Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria. [Kelleher, Cecily C.] Univ Coll Dublin, Sch Publ Hlth & Populat Sci, Dublin, Ireland. [Klenk, Jochen; Rapp, Kilian] Univ Ulm, Inst Epidemiol, D-89069 Ulm, Germany. [Brant, Larry J.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Ruttmann, Elfriede] Innsbruck Med Univ, Dept Cardiac Surg, Innsbruck, Austria. [Concin, Hans; Diem, Guenter; Ulmer, Hanno] Agcy Prevent & Social Med, Bregenz, Austria. RP Ulmer, H (reprint author), Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Schoepfstr 41, A-6020 Innsbruck, Austria. EM hanno.ulmer@i-med.ac.at RI Ruttmann, Elfriede/D-6501-2011; vhmpp, aks/F-9756-2012; Klenk, Jochen/C-2164-2012; Ulmer, Hanno/C-3488-2011; OI Ulmer, Hanno/0000-0001-5911-1002; Klenk, Jochen/0000-0002-5987-447X FU Austrian National Bank [OENB12737]; National Institute on Aging FX This work was supported by Austrian National Bank Grant OENB12737 (to H. U.). Dr Brant was supported by funds from the intramural research program of the National Institute on Aging. NR 45 TC 54 Z9 55 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT 1 PY 2008 VL 28 IS 10 BP 1857 EP 1865 DI 10.1161/ATVBAHA.108.170597 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 349JX UT WOS:000259278200028 PM 18617645 ER PT J AU O'Hanlon, TP Rider, LG Schiffenbauer, A Targoff, IN Malley, K Pandey, JP Miller, FW AF O'Hanlon, Terrance P. Rider, Lisa G. Schiffenbauer, Adam Targoff, Ira N. Malley, Karen Pandey, Janardan P. Miller, Frederick W. TI Immunoglobulin Gene Polymorphisms Are Susceptibility Factors in Clinical and Autoantibody Subgroups of the Idiopathic Inflammatory Myopathies SO ARTHRITIS AND RHEUMATISM LA English DT Article ID TRANSFER RNA-SYNTHETASES; CLASS-II HAPLOTYPE; PROTECTIVE FACTORS; GM ALLOTYPES; JUVENILE DERMATOMYOSITIS; MYOSITIS AUTOANTIBODIES; AUTOIMMUNE-DISEASES; IMMUNOGENETIC RISK; SYSTEMIC-SCLEROSIS; HLA AB Objective. To investigate possible associations of GM and KM markers with adult and juvenile forms of the idiopathic inflammatory myopathies (IIMs) in Caucasian and African American patients. Methods. We performed serologic analyses of polymorphic determinants associated with immunoglobulin gamma heavy chains (GM) and kappa light chains (KM) in large populations of Caucasian patients (n= 514 [297 adults and 217 children]) and African American patients (n = 123 [73 adults and 50 children]) with IIM representing the major clinical and autoantibody groups. Results. For Caucasian patients with dermatomyositis (DM), the Gm 3 23 5,13 phenotype was a risk factor in both adults (odds ratio [OR] 2.2, corrected P [P-corr] = 0.020) and children (OR 2.2, P-corr = 0.0013). Of interest, the GM 13 allotype was a risk factor for juvenile DM in both Caucasian subjects (OR 3.9, P-corr < 0.0001) and African American subjects (OR 4.8, P-corr = 0.033). However, the Gm 1,3,17 5,13,21 phenotype was a risk factor for juvenile DM in Caucasian subjects but not African American subjects. Among the IIM autoantibody groups, Gm 3 23 5,13 was a risk factor in Caucasian adults with anti-Jo-1 autoantibodies (OR 3.4, P-corr = 0.0031), while the GM 3 allotype was protective in adults with anti-threonyl-transfer RNA synthetase or anti-U RNP autoantibodies (OR 0.1, P-corr = 0.047 and OR 0.2, P-corr = 0.034, respectively). In contrast, GM 6 was a risk factor in African American adults with anti-signal recognition particle autoantibodies (OR 7.5, P-corr = 0.041). Conclusion. These data suggest that polymorphic alleles of GM and KM loci are differentially associated with IIM subgroups defined by age, ethnicity, clinical features, and autoantibody status, and expand the list of immune response genes C1 [O'Hanlon, Terrance P.; Rider, Lisa G.; Miller, Frederick W.] NIEHS, NIH, Bethesda, MD 20892 USA. [Schiffenbauer, Adam] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Targoff, Ira N.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City Vet Affairs Med Ctr, Oklahoma City, OK USA. [Targoff, Ira N.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Malley, Karen] Malley Res Programming Inc, Rockville, MD USA. [Pandey, Janardan P.] Med Univ S Carolina, Charleston, SC 29425 USA. RP O'Hanlon, TP (reprint author), NIEHS, NIH, 9 Mem Dr,Room 1W101,MSC 0958, Bethesda, MD 20892 USA. EM ohanlont@niehs.nih.gov OI Schiffenbauer, Adam/0000-0001-9964-9966; Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural NIH HHS [Z99 ES999999]; NIAMS NIH HHS [P30 AR053483] NR 35 TC 20 Z9 20 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD OCT PY 2008 VL 58 IS 10 BP 3239 EP 3246 DI 10.1002/art.23899 PG 8 WC Rheumatology SC Rheumatology GA 359YO UT WOS:000260024400033 PM 18821675 ER PT J AU Michael, S Auld, D Klumpp, C Jadhav, A Zheng, W Thorne, N Austin, CP Inglese, J Simeonov, A AF Michael, Sam Auld, Douglas Klumpp, Carleen Jadhav, Ajit Zheng, Wei Thorne, Natasha Austin, Christopher P. Inglese, James Simeonov, Anton TI A Robotic Platform for Quantitative High-Throughput Screening SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Review ID MICROPLATE CYTOMETRY; MOLECULAR LIBRARIES; CHEMICAL LIBRARIES; DRUG DISCOVERY; ASSAY; CELL; MINIATURIZATION; INHIBITORS; RECEPTOR; KINASE AB High-throughput screening (HTS) is increasingly being adopted in academic institutions, where the decoupling of screening and drug development has led to unique challenges, as well as novel uses of instrumentation, assay formulations, and software tools. Advances in technology have made automated unattended screening in the 1,536-well plate format broadly accessible and have further facilitated the exploration of new technologies and approaches to screening. A case in point is our recently developed quantitative HTS (qHTS) paradigm, which tests each library compound at multiple concentrations to construct concentration-response curves (CRCs) generating a comprehensive data set for each assay. The practical implementation of qHTS for cell-based and biochemical assays across libraries of >100,000 compounds (e. g., between 700,000 and 2,000,000 sample wells tested) requires maximal efficiency and miniaturization and the ability to easily accommodate many different assay formats and screening protocols. Here, we describe the design and utilization of a fully integrated and automated screening system for qHTS at the National Institutes of Health's Chemical Genomics Center. We report system productivity, reliability, and flexibility, as well as modifications made to increase throughput, add additional capabilities, and address limitations. The combination of this system and qHTS has led to the generation of over 6 million CRCs from >120 assays in the last 3 years and is a technology that can be widely implemented to increase efficiency of screening and lead generation. C1 [Michael, Sam; Auld, Douglas; Klumpp, Carleen; Jadhav, Ajit; Zheng, Wei; Thorne, Natasha; Austin, Christopher P.; Inglese, James; Simeonov, Anton] Natl Human Genome Res Inst, NIH Chem Genom Ctr, NIH, Bethesda, MD 20850 USA. RP Simeonov, A (reprint author), Natl Human Genome Res Inst, NIH Chem Genom Ctr, NIH, Bethesda, MD 20850 USA. EM asimeono@mail.nih.gov OI Zheng, Wei/0000-0003-1034-0757 FU NIH; National Human Genome Research Institute FX This research was supported by the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, NIH. We thank Paul Queeney, Rose Hughes, and Ben Baumann(Kalypsys) for expert help with system set-up and initial training and Daniel Sipes (GNF Systems) for helpful discussions. NR 43 TC 61 Z9 64 U1 2 U2 12 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD OCT PY 2008 VL 6 IS 5 BP 637 EP 657 DI 10.1089/adt.2008.150 PG 21 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 385QR UT WOS:000261829200002 PM 19035846 ER PT J AU Heuer, L Ashwood, P Schauer, J Goines, P Krakowiak, P Hertz-Picciotto, I Hansen, R Croen, LA Pessah, IN Van de Water, J AF Heuer, Luke Ashwood, Paul Schauer, Joseph Goines, Paula Krakowiak, Paula Hertz-Picciotto, Irva Hansen, Robin Croen, Lisa A. Pessah, Isaac N. Van de Water, Judy TI Reduced Levels of Immunoglobulin in Children With Autism Correlates With Behavioral Symptoms SO AUTISM RESEARCH LA English DT Article DE Autism; immunoglobulin; behavior; IgG ID SPECTRUM DISORDERS; IMMUNE INTERACTIONS; REGRESSIVE AUTISM; PTEN MUTATION; BRAIN; SERUM; IGG; PREVALENCE; DEFICIENCY; PHENOTYPE AB Objectives: To assay if plasma antibody levels in children with autism or developmental delays (DD) differ from those with typical development as an indicator of immune function and to correlate antibody levels with severity of behavioral Symptoms. Methods: Plasma was collected from children with autistic disorder (AU; n = 116), DD but not autism (n = 32), autism spectrum disorder but not full autism (n = 27), and age-matched typically developing (TD) controls (n = 96). Samples were assayed for systemic levels of immunoglobulin (IgG, IgM, IgA, and IgE) by enzyme-linked immunosorbent assay. Subjects with autism were evaluated using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, and all subjects were scored on the Aberrant Behavior Checklist (ABC) by the parents. Numerical scores for each of the ABC subscales as well as the total scores were then correlated with Ig levels. Results : Children with AU have a significantly reduced level of plasma IgG (5.39 +/- 0.29 mg/mL) compared to the TD (7.72 +/- 0.28mg/mL; P<0.001) and DD children (8.23 +/- 0.49mg/mL; P<0.001). Children with autism also had a reduced level of plasma IgM (0.670.06mg/mL) compared to TD (0.79 +/- 0.05mg/mL; P<0.05). Ig levels were negatively correlated with ABC scores for all children (IgG: r=-0.334, P<0.0001; IgM: r=-0.167, P=0.0285). Conclusion: Children with AU have significantly reduced levels of plasma IgG and IgM compared to both DD and TD controls, suggesting an underlying defect in immune function. This reduction in specific Ig levels correlates with behavioral severity, where those patients with the highest scores in the behavioral battery have the most reduced levels of IgG and IgM. C1 [Heuer, Luke; Schauer, Joseph; Goines, Paula; Van de Water, Judy] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Ashwood, Paul] Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. [Krakowiak, Paula; Hertz-Picciotto, Irva] Univ Calif Davis, Dept Publ Hlth Sci, Div Epidemiol, Davis, CA 95616 USA. [Hansen, Robin] Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA. [Croen, Lisa A.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Pessah, Isaac N.] Univ Calif Davis, Dept Vet Mol Biosci, Davis, CA 95616 USA. [Heuer, Luke; Ashwood, Paul; Schauer, Joseph; Goines, Paula; Krakowiak, Paula; Hertz-Picciotto, Irva; Hansen, Robin; Pessah, Isaac N.; Van de Water, Judy] Univ Calif Davis, MIND Inst, Davis, CA 95616 USA. [Heuer, Luke; Ashwood, Paul; Schauer, Joseph; Goines, Paula; Krakowiak, Paula; Hertz-Picciotto, Irva; Hansen, Robin; Pessah, Isaac N.; Van de Water, Judy] Univ Calif Davis, NIEHS Ctr Childrens Environm Hlth, Davis, CA 95616 USA. RP Van de Water, J (reprint author), Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, 451 E Hlth Sci Dr, Davis, CA 95616 USA. EM javandewater@ucdavis.edu FU NIEHS [IPOIES11269-01]; US EPA [R829388] FX Grant sponsor: NIEHS; Grant number: IPOIES11269-01; Grant sponsor: US EPA; Grant number: R829388. NR 50 TC 76 Z9 79 U1 0 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1939-3792 J9 AUTISM RES JI Autism Res. PD OCT PY 2008 VL 1 IS 5 BP 275 EP 283 DI 10.1002/aur.42 PG 9 WC Behavioral Sciences; Psychology, Developmental SC Behavioral Sciences; Psychology GA 497CM UT WOS:000270032000003 PM 19343198 ER PT J AU Johnson, C Mhatre, A Arias, J AF Johnson, Christopher Mhatre, Amy Arias, Jonathan TI NPR1 preferentially binds to the DNA-inactive form of Arabidopsis TGA2 SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE Basic/leucine-zipper domain; bZIP; Dimerization; NPR1; TGA factor; TGA2 ID SYSTEMIC ACQUIRED-RESISTANCE; BZIP TRANSCRIPTION FACTORS; PR GENE-EXPRESSION; SALICYLIC-ACID; COILED COILS; DISEASE RESISTANCE; PROTEIN; ACTIVATION; SEQUENCES; MUTANT AB Systemic acquired resistance (SAR) is triggered by hormone defense cues and is associated with the onset of expression of pathogenesis- related (PR) genes that encode for anti-microbial proteins in plants. In the case of PR-1, transcriptional activation involves promoter-specific recruitment of transcription factors such as TGA2 through a mechanism that may involve transient physical interaction with the NPR1 protein. This stimulus-inducible recruitment process has yet to be fully explained at the functional and mechanistic level. To investigate this question further, we initially looked to see whether NPR1 preferentially forms a complex the DNA bound or unbound fraction of TGA2. As shown here, NPR1 appears to preferentially interact the non-DNA bound fraction of TGA2. We subsequently Mutated this transcription factor to identify key in its conserved carboxyl terminal (CT) domain that mediate complex formation with NPR1. These revealed that two non-overlapping regions of the CT domain of TGA2 bind independently to The specificity and biological significance of these findings were inferred with a mutant form of NPR1 fails to activate SAR in vivo. These and other findings raise the possibility that NPR1 may transiently with the DNA unbound fraction of TGA2 to promote its recruitment to an active form on cognate promoters. Published by Elsevier B.V. C1 [Johnson, Christopher; Mhatre, Amy; Arias, Jonathan] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. RP Arias, J (reprint author), NIH, 6701 Rockledge Dr,MSC 7840,Room 5170, Bethesda, MD 20892 USA. EM ariasj@mail.nih.gov FU National Science Foundation [MCB-0404746]; University of Maryland FX We thank Xinnian Dong for the NPR1 cDNA clone. We also thank Francoise Thibaud-Nissen for insightful comments on the manuscript. This work was supported by the National Science Foundation 2010 Program (MCB-0404746) to J.A. and a grant to A.M. from the University of Maryland Baltimore County's EMBARC summer program. We also thank Justin Rosenau for his help in preparing recombinant protein. NR 35 TC 9 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD OCT PY 2008 VL 1779 IS 10 BP 583 EP 589 DI 10.1016/j.bbagrm.2008.05.007 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 365ZM UT WOS:000260448700001 PM 18571510 ER PT J AU Shearer, J Fueger, PT Wang, ZZ Bracy, DP Wasserman, DH Rottman, JN AF Shearer, Jane Fueger, Patrick T. Wang, ZhiZhang Bracy, Deanna P. Wasserman, David H. Rottman, Jeffrey N. TI Metabolic implications of reduced heart-type fatty acid binding protein in insulin resistant cardiac muscle SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Obesity; Glucose; Fatty acid; Hyperinsulinemic-euglycemic clamp ID ACTIVATED RECEPTOR-ALPHA; SKELETAL-MUSCLE; GLUCOSE-UPTAKE; HEXOKINASE-II; MICE; EXERCISE; RATS; ADIPOSE; TISSUES; DIET AB Insulin resistance is characterized by elevated rates of cardiac fatty acid utilization resulting in reduced efficiency and cardiomyopathy. One potential therapeutic approach is to limit the uptake and oxidation of fatty acids. The aims of this study were to determine whether a quantitative reduction in heart-type fatty acid binding protein (FABP3) normalizes cardiac substrate utilization without altering cardiac function. Transgenic (FABP3(+/-)) and wild-type (WT) littermates were studied following low fat (LF) or high fat (HF) diets, with HF resulting in obese, insulin-resistant mice. Cardiovascular function (systolic blood pressure, % fractional shortening) and heart dimension were measured at weaning and every month afterward for 3 mo. During this period cardiovascular function was the same independent of genotype and diet. Catheters were surgically implanted in the carotid artery and jugular vein for sampling and infusions in mice at 4 mo of age. Following 5 d recovery, mice underwent either a saline infusion or a hyperinsulinemic-euglycemic clamp (4 mU kg(-1) min(-1)). Indices of long chain fatty acid and glucose utilization (R-f, R-g; tmol g wet weight(-1) min(-1)) were obtained using 2-deoxy[H-3]glucose and [I-125]-15-rho-iodophenyl)-3-R,S-methylpentadecanoic acid. FABI3(+/-) had enhanced cardiac R, compared with WT during saline infusion in both LF and Hr. FABP3(+/-) abrogated the HF-induced decrement in insulin-stimulated cardiac R-g. On a HF diet, FABP(+/-) but not WT had an increased reliance on fatty acids (Rf) during insulin stimulation. In conclusion, cardiac insulin resistance and glucose uptake is largely corrected by a reduction in FABP3 in vivo without contemporaneous deleterious effects on cardiac function. (C) 2008 Elsevier B.V. All rights reserved. C1 [Shearer, Jane; Fueger, Patrick T.; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Wang, ZhiZhang; Rottman, Jeffrey N.] Vanderbilt Univ, Sch Med, Dept Cardiol, Nashville, TN 37212 USA. [Wang, ZhiZhang; Bracy, Deanna P.; Wasserman, David H.; Rottman, Jeffrey N.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. RP Shearer, J (reprint author), Univ Calgary, Fac Kinesiol, 2500 Univ Dr NW, Calgary, AB T2N 1N4, Canada. EM jshearer@ucalgary.ca RI Fueger, Patrick/G-8956-2013 FU Alberta Heritage Foundation for Medical Research; Heart and Stroke Foundation; Canadian Diabetes Association; CIHR, Genome Canada US); NIDDK [DK-54902, U24-DK-59636] FX JS holds salary support awards from the Alberta Heritage Foundation for Medical Research, the Heart and Stroke Foundation and the Canadian Diabetes Association. This work is supported by the CIHR, Genome Canada US) and NIDDK (DK-54902, U24-DK-59636). The authors would like to thank Mrs. Freyja James for her excellent technical assistance and Mrs. Wanda L. Snead for the measurement of mouse insulin of the Vanderbilt Mouse Metabolic Phenotyping Hormone Assay Core. NR 44 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD OCT PY 2008 VL 1782 IS 10 BP 586 EP 592 DI 10.1016/j.bbadis.2008.07.003 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 363ML UT WOS:000260271300006 PM 18692568 ER PT J AU Buehler, PW Alayash, AI AF Buehler, Paul W. Alayash, Abdu I. TI All hemoglobin-based oxygen carriers are not created equally SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article; Proceedings Paper CT Conference on Hemoglobin-Based Oxygen Carriers as Blood Substitutes CY APR, 2008 CL Bethesda, MD SP NIH, FDA DE Hemoglobin; Blood substitutes; Oxidation; Nitric oxide ID BLOOD SUBSTITUTES; SCAVENGER RECEPTOR; ANTIOXIDANT ROLE; NITRIC-OXIDE; HAPTOGLOBIN; OXIDATION; CD163; HEME AB Hemoglobin (Hb)-based oxygen carriers (HBOCs) also known as "blood substitutes" have been under active clinical development over the last two decades. Cell-free Hb outside its natural protective red blood cell environment, as is the case with all HBOCs, has been shown to be vasoactive in part due to the scavenging of vascular endothelial nitric oxide (NO) and may in some instances induce heme-mediated oxidative stress. Chemical modification intended to stabilize HBOCs in the tetrameric or polymeric forms introduces conformational constraints that result in proteins with diverse allosteric responses as well as oxidative and nitrosative redox side reactions. Intra, and inter-molecular cross-linking may in some instances also determine the interactions between HBOCs and normal oxidative inactivation and clearance mechanisms. Oxygen and oxidative reactions of normal and several cross-linked Hbs as well as their interactions with endogenous plasma protein (haptoglobin) and cellular receptor pathways (macrophage CD163) differ significantly. Therefore, safety and efficacy may be addressed by designing HBOCs with modifications that limit hypertension, minimize heme destabilization and take into account endogenous Hb removal mechanisms to optimize exposure times for a given indication. Published by Elsevier B.V. C1 [Buehler, Paul W.; Alayash, Abdu I.] US FDA, LBVB, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), NIH Campus 8800 Rockville Pike,Bldg 29,Rm 112, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov NR 17 TC 31 Z9 31 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD OCT PY 2008 VL 1784 IS 10 SI SI BP 1378 EP 1381 DI 10.1016/j.bbapap.2007.12.009 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 363MH UT WOS:000260270900003 PM 18206989 ER PT J AU Wickner, RB Shewmaker, F Kryndushkin, D Edskes, HK AF Wickner, Reed B. Shewmaker, Frank Kryndushkin, Dmitry Edskes, Herman K. TI Protein inheritance (prions) based on parallel in-register beta-sheet amyloid structures SO BIOESSAYS LA English DT Review ID HET-S PRION; SOLID-STATE NMR; UREIDOSUCCINIC ACID UPTAKE; SACCHAROMYCES-CEREVISIAE; YEAST PRION; HETEROKARYON INCOMPATIBILITY; TRANSLATION TERMINATION; PEPTIDE CONFORMATION; PODOSPORA-ANSERINA; MAMMALIAN PRIONS AB Most prions (infectious proteins) are self-propagating amyloids (filamentous protein multimers), and have been found in both mammals and fungal species. The prions [URE3] and [PSI+] of yeast are disease agents of Saccharomyces cerevisiae while [Het-s] of Podospora anserina may serve a normal cellular function. The parallel in-register beta-sheet structure shown by prion amyloids makes possible a templating action at the end of filaments which explains the faithful transmission of variant differences in these molecules. This property of self-reproduction, in turn, allows these proteins to act as de facto genes, encoding heritable information. BioEssays 30:955-964, 2008. (C) 2008 Wiley Periodicals, Inc. C1 [Wickner, Reed B.; Shewmaker, Frank; Kryndushkin, Dmitry; Edskes, Herman K.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural NIH HHS [ZIA DK024950-04] NR 111 TC 48 Z9 50 U1 1 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD OCT PY 2008 VL 30 IS 10 BP 955 EP 964 DI 10.1002/bies.20821 PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 359AX UT WOS:000259959700007 PM 18798523 ER PT J AU McIntosh, S Sierra, E Dozier, A Diaz, S Quinones, Z Primack, A Chadwick, G Ossip-Klein, DJ AF McIntosh, Scott Sierra, Essie Dozier, Ann Diaz, Sergio Quinones, Zahira Primack, Aron Chadwick, Gary Ossip-Klein, Deborah J. TI Ethical review issues in collaborative research between us and low-middle income country partners: A case example SO BIOETHICS LA English DT Review DE collaborative research; ethical review; case example; tobacco control ID CLINICAL-RESEARCH; HEALTH RESEARCH; WORLD AB The current ethical structure for collaborative international health research stems largely from developed countries' standards of proper ethical practices. The result is that ethical committees in developing countries are required to adhere to standards that might impose practices that conflict with local culture and unintended interpretations of ethics, treatments, and research. This paper presents a case example of a joint international research project that successfully established inclusive ethical review processes as well as other groundwork and components necessary for the conduct of human behavior research and research capacity building in the host country. C1 [Sierra, Essie; Diaz, Sergio; Quinones, Zahira; Primack, Aron] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Univ Rochester, Clin & Translat Res Inst, Rochester, NY 14627 USA. [Primack, Aron] Uniformed Serv Univ Hlth Sci, Int Hlth Program, Bethesda, MD 20814 USA. [Ossip-Klein, Deborah J.] Univ Rochester, Div Social & Behav Med, Med Ctr, Rochester, NY 14627 USA. [Ossip-Klein, Deborah J.] Univ Rochester, Smoking Res Program, Med Ctr, Rochester, NY 14627 USA. RP McIntosh, S (reprint author), Univ Rochester Community & Prevent Med, POB 278969, Rochester, NY 14627 USA. EM scott_mcintosh@urmc.rochester.edu RI Dozier, Ann/A-7427-2009 FU FIC NIH HHS [R01 TW005945] NR 21 TC 10 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-9702 J9 BIOETHICS JI Bioethics PD OCT PY 2008 VL 22 IS 8 BP 414 EP 422 DI 10.1111/j.1467-8519.2008.00662.x PG 9 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 345UU UT WOS:000259023400003 PM 18554278 ER PT J AU Telzer, EH Mogg, K Bradley, BP Mai, XQ Ernst, M Pine, DS Monk, CS AF Telzer, Eva H. Mogg, Karin Bradley, Brendan P. Mai, Xiaoqin Ernst, Monique Pine, Daniel S. Monk, Christopher S. TI Relationship between trait anxiety, prefrontal cortex, and attention bias to angry faces in children and adolescents SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Functional MRI; Trait anxiety; Prefrontal cortex; Attention ID EVENT-RELATED FMRI; GENERALIZED-ANXIETY; COGNITIVE CONTROL; EMOTIONAL FACES; THREATENING FACES; PROCESSING BIAS; DISORDER; STIMULI; MODULATION; DEPRESSION AB Using event-related functional magnetic resonance imaging (fMRI) with a visual-probe task that assesses attention to threat, we investigated the cognitive and neurophysiological correlates of trait anxiety in youth. During fMRI acquisition, 16 healthy children and adolescents viewed angry-neutral face pairs and responded to a probe that was on the same (angry-congruent) or opposite (angry-incongruent) side as the angry face. Attention bias scores were calculated by subtracting participants' mean reaction time for angry-congruent trials from angry-incongruent trials. Trait anxiety was positively associated with attention bias towards angry faces. Neurophysiologically, trait anxiety was positively associated with right dorsolateral prefrontal cortex (PFC) activation on a contrast of trials that reflect the attention bias for angry faces (i.e. angry-incongruent versus angry-congruent trials). Trait anxiety was also positively associated with right ventrolateral PFC activation on trials with face stimuli (vesus baseline), irrespective of their emotional content. (C) 2008 Elsevier B.V. All rights reserved. C1 [Telzer, Eva H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Sch Psychol, Southampton, Hants, England. [Monk, Christopher S.] Univ Michigan, Ctr Human Growth & Dev, Dept Psychol, Ann Arbor, MI 48109 USA. [Ernst, Monique; Pine, Daniel S.] NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bethesda, MD 20892 USA. [Monk, Christopher S.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Telzer, EH (reprint author), Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. EM ehtelzer@ucla.edu RI Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; OI Mogg, Karin/0000-0002-2738-7378; Bradley, Brendan/0000-0003-2801-4271 FU NIMH; [K22 MH068017] FX This research was supported in part by K22 MH068017 to C.S.M. and the NIMH intramural research program. The authors gratefully acknowledge Harvey Iwamoto for programming and computer support, Ken Towbin, MD and Alan Zametkin, MD for medical oversight, and Robert Cox, PhD, Gang Chen, PhD, and Ziad Saad, PhD for statistical and technical advice. NR 57 TC 72 Z9 74 U1 16 U2 40 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD OCT PY 2008 VL 79 IS 2 BP 216 EP 222 DI 10.1016/j.biopsycho.2008.05.004 PG 7 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 363RC UT WOS:000260283400011 PM 18599179 ER PT J AU Alexander, SA Kerr, ME Balzer, J Horowitz, M Kassam, A Kim, Y Hoffman, L Conley, YP AF Alexander, Sheila A. Kerr, Mary E. Balzer, Jeffrey Horowitz, Michael Kassam, Amin Kim, Yookyung Hoffman, Leslie Conley, Yvette P. TI Cerebrospinal fluid apolipoprotein E, calcium and cerebral vasospasm after subarachnoid hemorrhage SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE subarachnoid hemorrhage; cerebral vasospasm; apolipoprotein E; calcium; cerebrospinal fluid ID SMOOTH-MUSCLE CELLS; E POLYMORPHISM; E GENOTYPE; INJURY; NERVE; OXYHEMOGLOBIN; MACROPHAGES; ASTROCYTES; TIRILAZAD; ANEURYSM AB Intracellular calcium (Ca++) regulation of cerebral vessels is impaired after subarachnoid hemorrhage (SAH), making secondary pathways, such as that involving apolipoprotein E, potentially more influential. To evaluate cerebrospinal fluid (CSF) apolipoprotein E and Ca++ levels as biomarkers of cerebral vasospasm, we examined changes in levels over time and apolipoprotein E (APOE) epsilon 4 allele presence after SAH in individuals with and without vasospasm. We hypothesized that individuals with low apolipoprotein E levels, increased Ca++ levels and/or at least one copy of the APOE epsilon 4 allele would have vasospasm. Daily samples from 50 participants, aged 18-75, with SAH were used to quantify apolipoprotein E and Ca++ levels. Vasospasm was verified using cerebral angiogram and/or elevated transcranial Dopplers in combination with clinical neurologic deterioration. Overall apolipoprotein E levels were higher in individuals with the APOE epsilon 4 allele (p = .02) or angiographic vasospasm (p = .01), but there were no differences between individuals with and without symptomatic vasospasm. There were no significant changes in apolipoprotein E levels over time. Individuals with the epsilon 4 allele had lower Ca++ levels (p = .02) with trends suggesting a different pattern of change over time (p = .07). CSF Ca++ levels were lower in individuals with symptomatic vasospasm (p < .01). Change in apolipoprotein E and Ca++ levels (p = .006) correlated over time regardless of genotype or vasospasm status. These findings suggest that apolipoprotein E and Ca++ may be interacting after SAH, but this interaction does not appear to influence vasospasm. C1 [Alexander, Sheila A.; Hoffman, Leslie; Conley, Yvette P.] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15260 USA. [Kerr, Mary E.] NINR, NIH, Bethesda, MD 20892 USA. [Balzer, Jeffrey; Horowitz, Michael; Kassam, Amin] Univ Pittsburgh, Med Ctr, Dept Neurol Surg, Pittsburgh, PA 15260 USA. RP Alexander, SA (reprint author), 336 Victoria Bldg,3500 Victoria St, Pittsburgh, PA 15261 USA. EM salexand@pitt.edu FU American Nurses Foundation/John Merck Foundation; American Association of Neuroscience Nurses; Sigma Theta Tau; Leslie Hoffman Acute Care Research Award; National Institutes of Health [R01 NR04339] FX Dr. Kerr's contributions to this article occurred in association with her previous faculty appointment at the University of Pittsburgh and do not necessarily represent the views of the National Institutes of Health or the U.S. government. Sources of support: American Nurses Foundation/John Merck Foundation; American Association of Neuroscience Nurses; Sigma Theta Tau, Eta Chapter; Leslie Hoffman Acute Care Research Award; National Institutes of Health (R01 NR04339, Leslie Hoffman - Principal Investigator). NR 41 TC 5 Z9 6 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 J9 BIOL RES NURS JI Biol. Res. Nurs. PD OCT PY 2008 VL 10 IS 2 BP 102 EP 112 DI 10.1177/1099800408321722 PG 11 WC Nursing SC Nursing GA 353VI UT WOS:000259596200004 PM 18829593 ER PT J AU Sundin, M Lindblom, A Orvell, C Barrett, AJ Sundberg, B Watz, E Wikman, A Broliden, K Le Blanc, K AF Sundin, Mikael Lindblom, Anna Orvell, Claes Barrett, A. John Sundberg, Berit Watz, Emma Wikman, Agneta Broliden, Kristina Le Blanc, Katarina TI Persistence of human parvovirus B19 in multipotent mesenchymal stromal cells expressing the erythrocyte P antigen: Implications for transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE transplantation; hematopoietic; cell therapy; virus ID VERSUS-HOST-DISEASE; STEM-CELLS; BONE-MARROW; B19 INFECTION; CELLULAR CORECEPTOR; CLINICAL-ASPECTS; IN-VITRO; DNA; VIRUS; REPLICATION AB Multipotent mesenchymal stromal cells (MSCs) are used to improve the outcome of hematopoietic stem cell transplantation (HCST) and in regenerative medicine. MSCs may harbor persistent viruses that may compromise their clinical benefit, however. Retrospectively screened, I of 20 MSCs from healthy donors contained parvovirus B 19 (B 19) DNA. MSCs express the B 19 receptor (P antigen/globoside) and a co-receptor (Ku 80) and can transmit B 19 to bone marrow cells in vitro, suggesting that the virus can persist in the marrow stroma of healthy individuals. Two patients undergoing HSCT received the B19-positive MSCs as treatment for graft-versus-host disease; neither developed viremia nor symptomatic B 19 infection. These findings demonstrate for the first time that persistent B 19 in MSCs can infect hematopoietic stem cells and underscore the importance of monitoring B 19 transmission by MSC products. C1 [Sundin, Mikael; Sundberg, Berit; Watz, Emma; Wikman, Agneta; Le Blanc, Katarina] Karolinska Inst, Div Clin Immunol & Transfus Med, SE-14186 Stockholm, Sweden. [Orvell, Claes] Karolinska Inst, Dept Lab Med, Div Clin Virol, SE-14186 Stockholm, Sweden. [Orvell, Claes] Karolinska Univ Hosp Huddinge, Lab Clin Virol, Stockholm, Sweden. [Le Blanc, Katarina] Karolinska Univ Hosp Huddinge, Hematol Ctr, Stockholm, Sweden. [Lindblom, Anna; Broliden, Kristina] Karolinska Inst, Karolinska Univ Hosp Solna, Dept Med, Infect Dis Unit, SE-14186 Stockholm, Sweden. [Barrett, A. John] NIH, Allogene Stem Cell Transplantat Sect, Hematol Branch, Bethesda, MD 20892 USA. RP Sundin, M (reprint author), Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol, F79, SE-14186 Stockholm, Sweden. EM mikael.sundin@ki.se RI Sundin, Mikael/E-5942-2013 OI Sundin, Mikael/0000-0002-9871-0961 FU Swedish Cancer Society; Swedish Research Council; Tobias Foundation; Cancer Society in Stockholm; wedish Society of Medicine; Stockholm County Council; Sven and Ebba-Christina Hagbergs Foundation; Children's Cancer Foundation; Signe och Olof Wallenius stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne and the Claes Hogman SAGMAN scholarship/Fenwal Blood Technologies Inc; Karolinska Institutet FX The authors thank the Swedish Cancer Society, the Swedish Research Council, the Tobias Foundation, the Cancer Society in Stockholm, the Swedish Society of Medicine, the Stockholm County Council, the Sven and Ebba-Christina Hagbergs Foundation (K.L.B.), the Children's Cancer Foundation (K.B. and K.L.B.), Signe och Olof Wallenius stiftelse, Stiftelsen Sigurd och Elsa Goljes Minne and the Claes Hogman SAGMAN scholarship/Fenwal Blood Technologies Inc (M.S.), and the Karolinska Institutet (M.S., K.L.B., and K.B.) for unrestricted financial support. NR 35 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2008 VL 14 IS 10 BP 1172 EP 1179 DI 10.1016/j.bbmt.2008.08.003 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 354WF UT WOS:000259669100012 PM 18804048 ER PT J AU Westfall, PH Troendle, JF AF Westfall, Peter H. Troendle, James F. TI Multiple Testing with Minimal Assumptions SO BIOMETRICAL JOURNAL LA English DT Article; Proceedings Paper CT 5th International Conference on Multiple Comparison Procedures (MCP 2007) CY JUL 09-11, 2007 CL Vienna, AUSTRIA DE Bootstrap; Exchangeability; Permutation; Resampling; Subset pivotality AB Resampling-based multiple testing methods that control the Familywise Error Rate in the strong sense are presented. It is shown that no assumptions whatsoever on the data-generating process are required to obtain a reasonably powerful and flexible class of multiple testing procedures. Improvements are obtained with mild assumptions. The methods are applicable to gene expression data in particular, but more generally to any multivariate, multiple group data that may be character or numeric. The role of the disputed "subset pivotality" condition is clarified. C1 [Westfall, Peter H.] Texas Tech Univ, Lubbock, TX 79409 USA. [Troendle, James F.] NIH, Bethesda, MD 20892 USA. RP Westfall, PH (reprint author), Texas Tech Univ, Lubbock, TX 79409 USA. EM peter.westfall@ttu.edu FU Intramural NIH HHS [Z99 HL999999] NR 16 TC 41 Z9 41 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD OCT PY 2008 VL 50 IS 5 SI SI BP 745 EP 755 DI 10.1002/bimj.200710456 PG 11 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 369MH UT WOS:000260698100012 PM 18932134 ER PT J AU Morieux, P Stables, JP Kohn, H AF Morieux, Pierre Stables, James P. Kohn, Harold TI Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE amino acid N-benzylamides; aziridine ring opening; anticonvulsants; diethoxytriphenylphosphorane; structure-activity relationship ID ANTIEPILEPTIC DRUG DEVELOPMENT; AMINO-ACID ANTICONVULSANTS; RING-OPENING REACTION; 2-AZIRIDINECARBOXYLIC ACID; LACOSAMIDE; AZIRIDINE; PROGRAM; CHAINS AB Lacosamide has been submitted for regulatory approval in the United States and Europe for the treatment of epilepsy. Previous synthetic methods did not permit the elaboration of the structure-activity relationship (SAR) for the 3-oxy site in lacosamide. We report an expedient five-step stereospecific synthesis for N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide analogs beginning with D-serine methyl ester. The procedure incorporated alkyl (e. g. methyl, primary, secondary, and tertiary) and aryl groups at this position. The SAR for the 3-oxy site showed maximal activity in animal seizure models for small 3-alkoxy substituents. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Morieux, Pierre; Kohn, Harold] Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Stables, James P.] NINDS, Epilepsy Branch, NIH, Rockville, MD 20852 USA. [Kohn, Harold] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Kohn, H (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Campus Box 7360, Chapel Hill, NC 27599 USA. EM harold_kohn@unc.edu FU National Institutes of Health; National Institute of Neurological Disorders and Stroke. [RO1NS054112, F31NS060358] FX The authors thank the NINDS and the Anticonvulsant Screening Program (ASP) at the National Institutes of Health for supporting the pharmacological studies via the ASP's contract site at the University of Utah with Drs. H. Wolfe, S. White, M. Franklin, and K. Wilcox. The project described was supported by Grants RO1NS054112 (H. K.), and F31NS060358 (P. M.) from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. NR 20 TC 29 Z9 33 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD OCT 1 PY 2008 VL 16 IS 19 BP 8968 EP 8975 DI 10.1016/j.bmc.2008.08.055 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 353LG UT WOS:000259568500025 PM 18789868 ER PT J AU Cao, JJ Kopajtic, T Katz, JL Newman, AH AF Cao, Jianjing Kopajtic, Theresa Katz, Jonathan L. Newman, Amy Hauck TI Dual DAT/sigma 1 receptor ligands based on 3-(4-(3-(bis(4-fluorophenyl) amino) propyl) piperazin-1-yl)-1-phenylpropan-1-ol SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE dopamine transport inhibitors; sigma receptors; cocaine; rimcazole; GBR 12909 ID DOPAMINE TRANSPORTER; RIMCAZOLE ANALOGS; MONOAMINE TRANSPORTERS; SIGMA(1) RECEPTOR; COCAINE; INHIBITORS; AFFINITY; BINDING; DESIGN; PROBES AB Ester analogs of (+/-) 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol were synthesized and evaluated for binding at DAT, SERT, NET, and sigma 1 receptors, and compared to GBR 12909 and several known sigma 1 receptor ligands. Most of these compounds demonstrated high affinity (K(i) = 4.3-51 nM) and selectivity for the DAT among the monoamine transporters. S- and R-1-(4-(3(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-2-ol were also prepared wherein modest enantioselectivity was demonstrated at the DAT. However, no enantioselectivity at sigma 1 receptors was observed and most of the ester analogs of the more active S- enantiomer showed comparable binding affinities at both DAT and sigma 1 receptors with a maximal 16-fold DAT/sigma 1 selectivity. Published by Elsevier Ltd. C1 [Cao, Jianjing; Newman, Amy Hauck] Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kopajtic, Theresa; Katz, Jonathan L.] Natl Inst Drug Abuse, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov FU NIDA Intramural Research Program FX The research reported herein was supported by funds from the NIDA Intramural Research Program. NR 19 TC 9 Z9 9 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 1 PY 2008 VL 18 IS 19 BP 5238 EP 5241 DI 10.1016/j.bmcl.2008.08.065 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 350BG UT WOS:000259326800018 PM 18774292 ER PT J AU Dewkar, GK Peddi, S Mosier, PD Roth, BL Westkaemper, RB AF Dewkar, Gajanan K. Peddi, Srinivas Mosier, Philip D. Roth, Bryan L. Westkaemper, Richard B. TI Methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives exhibit differential binding affinities at the 5-HT(2A) receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE 5-HT(2A); AMDA; homology model ID PROTEIN-COUPLED RECEPTORS; SEROTONIN RECEPTOR; GENETIC ALGORITHM; 9-(AMINOMETHYL)-9,10-DIHYDROANTHRACENE; RESIDUES; MODELS; SERIES AB The effects of methoxy-substitution at the 1-, 2-, 3-, and 4-positions of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on h5-HT(2A) receptor affinity were determined. Racemic mixtures of these compounds were found to show the following affinity trend: 3-MeO > 4-MeO > 1-MeO similar to 2-MeO. Comparison of the effects of these substitutions, with the aid of computational molecular modeling techniques, suggest that the various positional and stereochemical isomers of the methoxy-substituted AMDA compounds interact differently with the h5-HT(2A) receptor. It is predicted that for the compounds with higher affinities, the methoxy oxygen atom is able to interact with hydrogen bond-donating sidechains within alternative h5-HT(2A) receptor binding sites, whereas the lower-affinity isomers lack this ability. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Dewkar, Gajanan K.; Peddi, Srinivas; Mosier, Philip D.; Westkaemper, Richard B.] Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Lineberger Canc Ctr,Neurosci Program, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Med Chem, Lineberger Canc Ctr,Neurosci Program, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Med Chem, Lineberger Canc Ctr,NIMH Psychoact Drug Screening, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Lineberger Canc Ctr,NIMH Psychoact Drug Screening, Chapel Hill, NC 27599 USA. RP Westkaemper, RB (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, 410 N 12th St,POB 980540, Richmond, VA 23298 USA. EM rbwestka@vcu.edu RI Roth, Bryan/F-3928-2010 FU United States Public Health Service [R01-MH57969, R01-MH57635, K02-MH01366, R01-MH61887, U19-MH82441]; NIMH Psychoactive Drug Screening Program FX This work was supported by United States Public Health Service Grant R01-MH57969 (RBW), R01-MH57635 (BLR), K02-MH01366 (BLR) and R01-MH61887 (BLR), U19-MH82441 (BLR) and the NIMH Psychoactive Drug Screening Program (BLR). NR 21 TC 2 Z9 3 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 1 PY 2008 VL 18 IS 19 BP 5268 EP 5271 DI 10.1016/j.bmcl.2008.08.059 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 350BG UT WOS:000259326800026 PM 18774714 ER PT J AU Alter, HJ Klein, HG AF Alter, Harvey J. Klein, Harvey G. TI The hazards of blood transfusion in historical perspective SO BLOOD LA English DT Review ID VERSUS-HOST-DISEASE; NON-B-HEPATITIS; ACUTE LUNG INJURY; WEST-NILE-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-DEFICIENCY SYNDROME; NON-A-HEPATITIS; VIRAL-HEPATITIS; UNITED-STATES; POSTTRANSFUSION HEPATITIS AB The beginning of the modern era of blood transfusion coincided with World War II and the resultant need for massive blood replacement. Soon thereafter, the hazards of transfusion, particularly hepatitis and hemolytic transfusion reactions, became increasingly evident. The past half century has seen the near eradication of transfusion-associated hepatitis as well as the emergence of multiple new pathogens, most notably HIV. Specific donor screening assays and other interventions have minimized, but not eliminated, infectious disease transmission. Other transfusion hazards persist, including human error resulting in the inadvertent transfusion of incompatible blood, acute and delayed transfusion reactions, transfusion- related acute lung injury (TRALI), transfusion- associated graft- versus- host disease (TA-GVHD), and transfusion- induced immunomodulation. These infectious and noninfectious hazards are reviewed briefly in the context of their historical evolution. C1 [Alter, Harvey J.; Klein, Harvey G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Alter, HJ (reprint author), NIH, Dept Transfus Med, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov NR 88 TC 121 Z9 126 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2008 VL 112 IS 7 BP 2617 EP 2626 DI 10.1182/blood-2008-07-077370 PG 10 WC Hematology SC Hematology GA 351CR UT WOS:000259402600013 PM 18809775 ER PT J AU Gladwin, MT Kim-Shapiro, DB AF Gladwin, Mark T. Kim-Shapiro, Daniel B. TI The functional nitrite reductase activity of the heme-globins SO BLOOD LA English DT Review ID RED-BLOOD-CELLS; DEPENDENT HYPOXIC VASODILATION; NO-CENTER-DOT; S-NITROSOHEMOGLOBIN; ISCHEMIA-REPERFUSION; HEMOGLOBIN-S; MITOCHONDRIAL RESPIRATION; PHYSIOLOGICAL CONDITIONS; RELAXING FACTOR; OXIDE FORMATION AB Hemoglobin and myoglobin are among the most extensively studied proteins, and nitrite is one of the most studied small molecules. Recently, multiple physiologic studies have surprisingly revealed that nitrite represents a biologic reservoir of NO that can regulate hypoxic vasodilation, cellular respiration, and signaling. These studies suggest a vital role for deoxyhemoglobin- and deoxymyoglobin-dependent nitrite reduction. Biophysical and chemical analysis of the nitrite-deoxyhemoglobin reaction has revealed unexpected chemistries between nitrite and deoxyhemoglobin that may contribute to and facilitate hypoxic NO generation and signaling. The first is that hemoglobin is an allosterically regulated nitrite reductase, such that oxygen binding increases the rate of nitrite conversion to NO, a process termed R-state catalysis. The second chemical property is oxidative denitrosylation, a process by which the NO formed in the deoxyhemoglobin-nitrite reaction that binds to other deoxyhemes can be released due to heme oxidation, releasing free NO. Third, the reaction undergoes a nitrite reductase/anhydrase redox cycle that catalyzes the anaerobic conversion of 2 molecules of nitrite into dinitrogen trioxide (N2O3), an uncharged molecule that may be exported from the erythrocyte. We will review these reactions in the biologic framework of hypoxic signaling in blood and the heart. C1 [Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, Dept Crit Care Med, Ctr Clin,NIH, Bethesda, MD 20892 USA. [Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. RP Gladwin, MT (reprint author), NHLBI, Pulm & Vasc Med Branch, Dept Crit Care Med, Ctr Clin,NIH, Bldg 10 CRC,Rm 5-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@nih.gov; shapiro@wfu.edu FU National Institutes of Health (NIH, Bethedsa) [HL058091, HL078706]; Division of Intramural Research of the National Heart, Lung, and Blood Institute (Bethesda, MD) FX This work was supported by National Institutes of Health (NIH, Bethesda, MD) grants HL058091 and HL078706 and by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (Bethesda, MD). NR 133 TC 135 Z9 141 U1 1 U2 16 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2008 VL 112 IS 7 BP 2636 EP 2647 DI 10.1182/blood-2008-01-115261 PG 12 WC Hematology SC Hematology GA 351CR UT WOS:000259402600016 PM 18596228 ER PT J AU Habermann, TM Wang, SS Maurer, MJ Morton, LM Lynch, CF Ansell, SM Hartge, P Severson, RK Rothman, N Davis, S Geyer, SM Cozen, W Chanock, SJ Cerhan, JR AF Habermann, Thomas M. Wang, Sophia S. Maurer, Matthew J. Morton, Lindsay M. Lynch, Charles F. Ansell, Stephen M. Hartge, Patricia Severson, Richard K. Rothman, Nathaniel Davis, Scott Geyer, Susan M. Cozen, Wendy Chanock, Stephen J. Cerhan, James R. TI Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; PROMOTER POLYMORPHISM; ELDERLY-PATIENTS; INTERLEUKIN-10; RISK; EXPRESSION; CYTOKINE; CHOP; CHEMOTHERAPY; ASSOCIATION AB To evaluate the hypothesis that host germ line variation in immune genes is associated with overall survival in diffuse large B-cell lymphoma (DLBCL), we genotyped 73 single nucleotide polymorphisms (SNPs) from 44 candidate genes in 365 DLBCL patients diagnosed from 1998 to 2000. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of SNPs with survival after adjusting for clinical factors. During follow-up, 96 (26%) patients died, and the median follow-up was 57 months for surviving patients. The observed survival of this cohort was consistent with populationbased estimates conditioned on surviving 12 months. An IL10 haplotype (global P = .03) and SNPs in IL8RB (rs1126580; HRAG/GG = 2.11; CI, 1.28-3.50), IL1A (rs1800587; HRCT/TT = 1.90; CI, 1.26-2.87), TNF (rs1800629; HRAG/GG = 1.44; CI, 0.95-2.18), and IL4R (rs2107356; HRCC/CT = 1.97; CI, 1.01-3.83) were the strongest predictors of overall survival. A risk score that combined the latter 4 SNPs with clinical factors was strongly associated with survival in a Cox model (P = 6.0 x 10(-11)). Kaplan-Meier 5- year survival estimates for low, intermediate-low, intermediate- high, and high-risk patients were 94%, 79%, 60%, and 48%, respectively. These data support a role for germ line variation in immune genes, particularly genes associated with a proinflammatory state, as predictors of late survival in DLBCL. C1 [Cerhan, James R.] Mayo Clin, Coll Med, Div Epidemiol, Rochester, MN 55905 USA. [Wang, Sophia S.; Morton, Lindsay M.; Hartge, Patricia; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Iowa City, IA USA. [Severson, Richard K.] Wayne State Univ, Detroit, MI USA. [Davis, Scott] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Cozen, Wendy] Univ So Calif, Los Angeles, CA USA. RP Cerhan, JR (reprint author), Mayo Clin, Coll Med, Div Epidemiol, 200 1st St SW, Rochester, MN 55905 USA. EM cerhan.james@mayo.edu RI Geyer, Susan/E-3112-2011; Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Cerhan, James/0000-0002-7482-178X FU National Institutes of Health (Bethesda, MD) [R01 CA96704, P50 CA97274]; National Cancer Institute Intramural Program; SEER [N01-PC67 010, N01-PC-67 008, N01-PC-67 009, N01-PC-65 064, N02-PC-71 105] FX The authors thank Peter Hui and Cristine Allmer for programming assistance and Sondra Buehler for assistance in manuscript preparation.; This work was supported by National Institutes of Health (Bethesda, MD) grants R01 CA96704 and P50 CA97274; National Cancer Institute Intramural Program; and SEER contracts N01-PC67 010, N01-PC-67 008, N01-PC-67 009, N01-PC-65 064, and N02-PC-71 105. NR 50 TC 51 Z9 52 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2008 VL 112 IS 7 BP 2694 EP 2702 DI 10.1182/blood-2007-09-111658 PG 9 WC Hematology SC Hematology GA 351CR UT WOS:000259402600023 PM 18633131 ER PT J AU Brenchley, JM Paiardini, M Knox, KS Asher, AI Cervasi, B Asher, TE Scheinberg, P Price, DA Hage, CA Kholi, LM Khoruts, A Frank, I Else, J Schacker, T Silvestri, G Douek, DC AF Brenchley, Jason M. Paiardini, Mirko Knox, Kenneth S. Asher, Ava I. Cervasi, Barbara Asher, Tedi E. Scheinberg, Phillip Price, David A. Hage, Chadi A. Kholi, Lisa M. Khoruts, Alexander Frank, Ian Else, James Schacker, Timothy Silvestri, Guido Douek, Daniel C. TI Differential Th17CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections SO BLOOD LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; TYPE-1 INFECTION; GASTROINTESTINAL-TRACT; IMMUNE ACTIVATION; HIV-1 INFECTION; SOOTY MANGABEYS; LYMPHOID-TISSUE; IN-VIVO; INFLAMMATION AB Acute HIV infection is characterized by massive loss of CD4 T cells from the gastrointestinal (GI) tract. Th17 cells are critical in the defense against microbes, particularly at mucosal surfaces. Here we analyzed Th17 cells in the blood, GI tract, and broncheoalveolar lavage of HIV-infected and uninfected humans, and SIV-infected and uninfected sooty mangabeys. We found that (1) human Th17 cells are specific for extracellular bacterial and fungal antigens, but not common viral antigens; (2) Th17 cells are infected by HIV in vivo, but not preferentially so; (3) CD4 T cells in blood of HIV-infected patients are skewed away from a Th17 phenotype toward a Th1 phenotype with cellular maturation; (4) there is significant loss of Th17 cells in the GI tract of HIV-infected patients; (5) Th17 cells are not preferentially lost from the broncheoalveolar lavage of HIV-infected patients; and (6) SIV-infected sooty mangabeys maintain healthy frequencies of Th17 cells in the blood and GI tract. These observations further elucidate the immunodeficiency of HIV disease and may provide a mechanistic basis for the mucosal barrier breakdown that characterizes HIV infection. Finally, these data may help account for the nonprogressive nature of nonpathogenic SIV infection in sooty mangabeys. C1 [Brenchley, Jason M.; Asher, Ava I.; Asher, Tedi E.; Scheinberg, Phillip; Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, VRC, NIH, Bethesda, MD 20892 USA. [Paiardini, Mirko; Cervasi, Barbara; Frank, Ian; Silvestri, Guido] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Knox, Kenneth S.; Hage, Chadi A.; Kholi, Lisa M.] Indiana Univ, Div Pulm & Crit Care Med, Indianapolis, IN 46204 USA. [Knox, Kenneth S.; Hage, Chadi A.] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. [Price, David A.] Cardiff Univ, Dept Med Biochem & Immunol, Cardiff Sch Med, Cardiff, S Glam, Wales. [Khoruts, Alexander; Schacker, Timothy] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Else, James] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. RP Brenchley, JM (reprint author), NIAID, Human Immunol Sect, VRC, NIH, Room 301,Bldg 4,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov; ddouek@nih.gov RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Scheinberg, Phillip/0000-0002-9047-4538 FU NIH [R01 AI052755, AI066998, R01 AI54232, K24 AI056986, R01 DE-12934, K08HL04545-05, R01 HL083468]; Yerkes Primate Center [RR-00165]; W.W. Smith Charitable Trust; NIAID FX The authors thank Beth Zwickl, Mitchell Goldman, and Jeff Waltz for patient referral, and the Indiana University General Clinical Research Center for patient care.; This work was supported by NIH grants R01 AI052755 and AI066998, the Yerkes Primate Center (RR-00165), and the W.W. Smith Charitable Trust (G.S.); NIH grants R01 AI54232, K24 AI056986, and R01 DE-12934 (T.W.S.); and NIH grants K08HL04545-05 and R01 HL083468 (K.S.K.). D.A.P. is a Medical Research Council (UK) Senior Clinical Fellow. This work was supported in part by the intramural program of NIAID, NIH. NR 53 TC 337 Z9 351 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2008 VL 112 IS 7 BP 2826 EP 2835 DI 10.1182/blood-2008-05-159301 PG 10 WC Hematology SC Hematology GA 351CR UT WOS:000259402600039 PM 18664624 ER PT J AU Chu, YW Schmitz, S Choudhury, B Telford, W Kapoor, V Garfield, S Howe, D Gress, RE AF Chu, Yu-Waye Schmitz, Sabrina Choudhury, Baishakhi Telford, William Kapoor, Veena Garfield, Susan Howe, David Gress, Ronald E. TI Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion SO BLOOD LA English DT Article ID GROWTH-FACTOR-I; BONE-MARROW-TRANSPLANTATION; HEMATOPOIETIC STEM-CELLS; HUMAN T-LYMPHOCYTES; IMMUNE RECONSTITUTION; FACTOR SYSTEM; EXPRESSION; HORMONE; RECEPTOR; DIFFERENTIATION AB Insulin-like growth factor 1 (IGF-1) enhances thymopoiesis but given the broad distribution of IGF-1 receptors (IGF-1Rs), its mechanism of action has remained unclear. To identify points of thymic regulation by IGF-1, we examined its effects on T-cell precursors, thymocytes, and thymic epithelial cells (TECs) in normal and genetically altered mice. In thymus-intact but not thymectomized mice, IGF-1 administration increased peripheral naive and recent thymic emigrant (RTE) populations, demonstrating its effect on cell production, not peripheral expansion. IGF-1 administration increased bone marrow LSK (lineage(-), Sca-1(+), c-kit(+)) precursor proliferation and peripheral LSK populations, increased thymocyte populations in a sequential wave of expansion, and proportionately expanded TEC sub-populations and enhanced their chemokine expression. To separate IGF-1's effects on thymocytes and TECs, we generated mice lacking IGF-1R on thymocytes and T cells. Thymocyte and RTE numbers were decreased in these mice, but IGF-1 treatment produced comparable thymocyte numbers to similarly treated wild-type mice. We additionally separated thymic- from LSK-specific effects by demonstrating that IGF-1 increased thymocyte numbers despite impaired early thymic progenitor (ETP) importation in PSGL-1KO mice. These results indicate the critical point thymic function regulation by IGF-1 involves TEC expansion regulating thymocyte precursor entry and facilitating thymocyte development. C1 [Chu, Yu-Waye; Schmitz, Sabrina; Choudhury, Baishakhi; Telford, William; Kapoor, Veena; Howe, David; Gress, Ronald E.] NIH, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Garfield, Susan] NIH, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Chu, YW (reprint author), NIH, Expt Immunol Branch, Ctr Canc Res, Bldg 10CRC Rm 3-3288,10 Ctr Dr, Bethesda, MD 20892 USA. EM chuy@mail.nih.gov FU National Cancer Institute FX The authors thank Frances Hakim for critical review of the paper and Nyana Singh for technical assistance.; This work was entirely supported by intramural funding through the National Cancer Institute. NR 51 TC 39 Z9 40 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2008 VL 112 IS 7 BP 2836 EP 2846 DI 10.1182/blood-2008-04-149435 PG 11 WC Hematology SC Hematology GA 351CR UT WOS:000259402600040 PM 18658030 ER PT J AU Whittaker, GC Burshtyn, DN Orr, SJ Quigley, L Hodge, DL Pascal, R Zhang, WG McVicar, DW AF Whittaker, Gillian C. Burshtyn, Deborah N. Orr, Selinda J. Quigley, Laura Hodge, Deborah L. Pascal, Ronique Zhang, Weiguo McVicar, Daniel W. TI Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire SO BLOOD LA English DT Article ID PROTEIN-TYROSINE KINASES; NK CELLS; PHOSPHOLIPASE C-GAMMA-2; FUNCTIONAL-ANALYSIS; HLA-B; LAT; RECEPTOR; RECOGNITION; PHOSPHORYLATION; ZAP-70 AB The linker for activation of T cells (LAT) and the linker for activation of B cells (LAB/NTAL/LAT2) are integral proteins in receptor coupling to downstream events. Both proteins are expressed in natural killer (NK) cells and LAT is phosphorylated during target cell interactions or ligation of the immunoreceptor tyrosine-based activation motif (ITAM)-coupled CD16. Regardless, Lat(-/-) mice exhibit normal natural and antibody-mediated killing. Here we place both LAT and LAB in the DAP12 pathway of NK cells. Moreover, we unveil a LAT-independent pathway that requires expression of Syk. Mice lacking either LAT or LAB have a skewed Ly49 repertoire, and activated NK cells from Lat(-/-) mice have reduced responses to the ITAM-coupled receptor NK1.1. In contrast, resting Lat(-/-) NK cells show intact NK1.1 responses, whereas NK cells without LAB are hyperactive. Elimination of both adaptors severely reduces NK1.1 signaling under both conditions. Together these data show that NK ITAMs preferentially use a signaling cassette regulated by interplay between LAT and LAB. Activation by interleukin-2 causes a shift to greater dependency on LAT due to suppression of Syk signaling. The overlapping use of multiple adaptors permits fine-tuning of NK-cell ITAM responses over the course of an immune response. C1 [Whittaker, Gillian C.; Orr, Selinda J.; Quigley, Laura; Hodge, Deborah L.; Pascal, Ronique; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Burshtyn, Deborah N.] Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB, Canada. [Zhang, Weiguo] Duke Univ, Med Ctr, Dept Immunol, Durham, NC USA. RP McVicar, DW (reprint author), NCI, Canc & Inflammat Program, Bldg 560,Room 31-46, Frederick, MD 21702 USA. EM mcvicard@mail.nih.gov RI McVicar, Daniel/G-1970-2015; OI Orr, Selinda/0000-0001-8539-7825 FU National Cancer Institute FX The 721.221 were from R. DeMars and the 721.221-Cw4 were from J. Gumperz and P. Parham. HP-3E4 was from M. LopezBotet. LAT-/- mice were kindly provided by Dr C. Summers and Dr L. Samelson.; This project has been funded in whole or in part with federal funds from the National Cancer Institute Intramural Research Program (Bethesda, MD).; The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 44 TC 10 Z9 11 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2008 VL 112 IS 7 BP 2869 EP 2877 DI 10.1182/blood-2007-11-121590 PG 9 WC Hematology SC Hematology GA 351CR UT WOS:000259402600043 PM 18645037 ER PT J AU Bi, YM Kilts, T Griffin, A Hefferan, T Syed-Picard, F Chiedi, A Young, M Marian, E AF Bi, Yanming Kilts, Tina Griffin, Alfred Hefferan, Theresa Syed-Picard, Fatima Chiedi, Amanda Young, Marian Marian, E. TI Biglycan (Bgn) and fibromodulin (Fmod) modulate bone mass by regulating osteoclast differentiation through bone marrow stromal cells SO BONE LA English DT Meeting Abstract CT International Conference on Osteoporosis and Bone Research CY OCT 22-25, 2008 CL Beijing, PEOPLES R CHINA SP Chinese Med Assoc, Int Bone & Mineral Soc, Int Chinese Hard Tissue Soc C1 [Bi, Yanming; Kilts, Tina; Griffin, Alfred; Syed-Picard, Fatima; Chiedi, Amanda; Young, Marian; Marian, E.] NIDCR, CSDB, NIH, Bethesda, MD USA. [Hefferan, Theresa] Mayo Clin, Rochester, MN USA. NR 0 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 8756-3282 J9 BONE JI Bone PD OCT PY 2008 VL 43 SU 1 BP S58 EP S58 DI 10.1016/j.bone.2008.08.058 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 360TT UT WOS:000260081500122 ER PT J AU Cizza, G AF Cizza, Giovanni TI Low bone mass in premenopausal women with major depression. For the power study group SO BONE LA English DT Meeting Abstract CT International Conference on Osteoporosis and Bone Research CY OCT 22-25, 2008 CL Beijing, PEOPLES R CHINA SP Chinese Med Assoc, Int Bone & Mineral Soc, Int Chinese Hard Tissue Soc C1 [Cizza, Giovanni] NIDDK, NIH, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD OCT PY 2008 VL 43 SU 1 BP S50 EP S50 DI 10.1016/j.bone.2008.08.034 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 360TT UT WOS:000260081500098 ER PT J AU Shi, XM Ou, GM Hamrick, M Ding, KH Yang, SY Gonzalez, F Kream, B Isales, C AF Shi, Xing-Ming Ou, Guomin Hamrick, Mark Ding, Kehong Yang, Shang-You Gonzalez, Frank Kream, Barbara Isales, Carlos TI Targeted disruption of PPAR gamma in bone marrow stromal cells reveals its role in aging-induced bone loss SO BONE LA English DT Meeting Abstract CT International Conference on Osteoporosis and Bone Research CY OCT 22-25, 2008 CL Beijing, PEOPLES R CHINA SP Chinese Med Assoc, Int Bone & Mineral Soc, Int Chinese Hard Tissue Soc C1 [Shi, Xing-Ming; Ou, Guomin; Hamrick, Mark; Ding, Kehong; Isales, Carlos] Med Coll Georgia, Augusta, GA 30912 USA. [Yang, Shang-You] Wayne State Univ, Detroit, MI USA. [Gonzalez, Frank] Natl Canc Inst, Bethesday, MD USA. [Kream, Barbara] Univ Connecticut, Ctr Hlth, Farmington, CT USA. RI Isales, Carlos/J-9902-2013; Hamrick, Mark/K-1131-2016 OI Isales, Carlos/0000-0002-4480-3484; NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD OCT PY 2008 VL 43 SU 1 BP S40 EP S40 DI 10.1016/j.bone.2008.08.009 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 360TT UT WOS:000260081500073 ER PT J AU Voon, V Krack, P Lang, AE Lozano, AM Dujardin, K Schupbach, M D'Ambrosia, J Thobois, S Tamma, F Herzog, J Speelman, JD Samanta, J Kubu, C Rossignol, H Poon, YY Saint-Cyr, JA Ardouin, C Moro, E AF Voon, Valerie Krack, Paul Lang, Anthony E. Lozano, Andres M. Dujardin, Kathy Schuepbach, Michael D'Ambrosia, James Thobois, Stephane Tamma, Filippo Herzog, Jan Speelman, Johannes D. Samanta, Johan Kubu, Cynthia Rossignol, Helene Poon, Yu-Yan Saint-Cyr, Jean A. Ardouin, Claire Moro, Elena TI A multicentre study on suicide outcomes following subthalamic stimulation for Parkinsons disease SO BRAIN LA English DT Article DE suicide; deep brain stimulation; Parkinson's disease; depression; subthalamic stimulation ID DEEP-BRAIN-STIMULATION; NUCLEUS STIMULATION; MOVEMENT-DISORDERS; RISK-FACTORS; DEPRESSION; RESPONSES; ISSUES AB Subthalamic nucleus deep brain stimulation improves motor symptoms and quality of life in advanced Parkinsons disease. As after other life-altering surgeries, suicides have been reported following deep brain stimulation for movement disorders. We sought to determine the suicide rate following subthalamic nucleus deep brain stimulation for Parkinsons disease by conducting an international multicentre retrospective survey of movement disorder and surgical centres. We further sought to determine factors associated with suicide attempts through a nested case-control study. In the survey of suicide rate, 55/75 centres participated. The completed suicide percentage was 0.45% (24/5311) and attempted suicide percentage was 0.90% (48/5311). Observed suicide rates in the first postoperative year (263/100 000/year) (0.26%) were higher than the lowest and the highest expected age-, gender- and country-adjusted World Health Organization suicide rates (Standardized Mortality Ratio for suicide: SMR 12.63-15.64; P < 0.001) and remained elevated at the fourth postoperative year (38/100 000/year) (0.04%) (SMR 1.81-2.31; P < 0.05). The excess number of deaths was 13 for the first postoperative year and one for the fourth postoperative year. In the case-control study of associated factors, 10 centres participated. Twenty-seven attempted suicides and nine completed suicides were compared with 70 controls. Postoperative depression (P < 0.001), being single (P = 0.007) and a previous history of impulse control disorders or compulsive medication use (P = 0.005) were independent associated factors accounting for 51% of the variance for attempted suicide risk. Attempted suicides were also associated (P < 0.05) with being younger, younger Parkinsons disease onset and a previous suicide attempt. Completed suicides were associated with postoperative depression (P < 0.001). Postoperative depression remained a significant factor associated with attempted and completed suicides after correction for multiple comparisons using the stringent Bonferroni correction. Mortality in the first year following subthalamic nucleus deep brain stimulation has been reported at 0.4%. Suicide is thus one of the most important potentially preventable risks for mortality following subthalamic nucleus deep brain stimulation for Parkinsons disease. Postoperative depression should be carefully assessed and treated. A multidisciplinary assessment and follow-up is recommended. C1 [Voon, Valerie; D'Ambrosia, James] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Voon, Valerie; Lang, Anthony E.; Lozano, Andres M.; Saint-Cyr, Jean A.; Moro, Elena] Univ Toronto, UHN, Toronto, ON, Canada. [Krack, Paul; Rossignol, Helene; Ardouin, Claire] Univ Grenoble 1, Grenoble, France. [Dujardin, Kathy] Lille Univ Hosp, Lille, France. [Schuepbach, Michael] Hop La Pitie Salpetriere, INSERM, Paris, France. [Thobois, Stephane] Univ Lyon 1, Hosp Neurol Pierre Wertheimer, F-69365 Lyon, France. [Tamma, Filippo] Osped San Paolo, Neurol Clin, Milan, Italy. [Herzog, Jan] Univ Kiel, Kiel, Germany. [Speelman, Johannes D.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Samanta, Johan] Univ Arizona, Phoenix, AZ USA. [Kubu, Cynthia] Cleveland Clin Fdn, Cleveland, OH 44195 USA. RP Voon, V (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, 10 Ctr Dr,Bldg 10,Rm 5S213, Bethesda, MD 20892 USA. EM voonv@ninds.nih.gov RI Dujardin, Kathy/H-5037-2011 OI Dujardin, Kathy/0000-0002-0110-574X NR 32 TC 214 Z9 218 U1 1 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD OCT PY 2008 VL 131 BP 2720 EP 2728 DI 10.1093/brain/awn214 PN 10 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 365BQ UT WOS:000260381300018 PM 18941146 ER PT J AU Miniussi, C Cappa, SF Cohen, LG Floel, A Fregni, F Nitsche, MA Oliveri, M Pascua-Leone, A Paulus, W Priori, A Walsh, V AF Miniussi, Carlo Cappa, Stefano F. Cohen, Leonardo G. Floel, Agnes Fregni, Felipe Nitsche, Michael A. Oliveri, Massimiliano Pascua-Leone, Alvaro Paulus, Walter Priori, Alberto Walsh, Vincent TI Efficacy of repetitive transcranial magnetic stimulation/transcranial direct current stimulation in cognitive neurorehabititation SO BRAIN STIMULATION LA English DT Review DE cognitive deficits; cognitive rehabilitation; memory; attention; language; repetitive transcranial magnetic stimulation; transcranial direct current stimulation ID HUMAN MOTOR CORTEX; NONINVASIVE BRAIN-STIMULATION; PRIMARY PROGRESSIVE APHASIA; CONCURRENT TMS-FMRI; PREFRONTAL CORTEX; WORKING-MEMORY; LANGUAGE FUNCTION; EPISODIC MEMORY; CORTICAL EXCITABILITY; ALZHEIMERS-DISEASE AB Cognitive deficits are a common consequence of neurologic disease, in particular, of traumatic brain injury, stroke, and neurodegenerative disorders, and there is evidence that specific cognitive training may be effective in cognitive rehabilitation. Several investigations emphasize the fact that interacting With cortical activity, by means of cortical stimulation, can positively affect the short-term cognitive performance and improve the rehabilitation potential of neurologic patients. In this respect, preliminary evidence suggests that cortical stimulation may play a role in treating aphasia, unilateral neglect, and other cognitive disorders. Several possible mechanisms can account for the effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) on cognitive performance. They all reflect the potential of these methods to improve the Subject's ability to relearn or to acquire new strategies for carrying out behavioral tasks. The responsible mechanisms remain Unclear but they are most likely related to the activation of impeded pathways or inhibition of maladaptive responses. Modifications of the brain activity may assist relearning by facilitating local activity or by suppressing interfering activity from other brain areas. Notwithstanding the promise of these preliminary findings. to date no systematic application of these methods to neurorehabilitation research has been reported. Considering the potential benefit of these interventions, further Studies taking into consideration large patient populations, long treatment periods. or the combination of different rehabilitation strategies are needed. Brain stimulation is indeed an exciting Opportunity in the field Of cognitive neurorehabilitation, which clearly in need Of further research. (c) 2008 Elsevier Inc. All rights reserved. C1 [Miniussi, Carlo] Univ Brescia, Natl Inst Neurosci, Dept Biomed Sci & Biotechnol, I-25123 Brescia, Italy. [Miniussi, Carlo] IRCCS San Giovanni Dio Fatebenefratelli, Cognit Neurosci Sect, Brescia, Italy. [Cappa, Stefano F.] Univ Vita Salute San Raffaele, Natl Inst Neurosci, Dept Neurosci, Milan, Italy. [Cappa, Stefano F.] Ist Sci San Raffaele, I-20132 Milan, Italy. [Cohen, Leonardo G.] NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. [Cohen, Leonardo G.] NINDS, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. [Floel, Agnes] Univ Munster, Dept Neurol, D-4400 Munster, Germany. [Floel, Agnes] Univ Munster, IZKF, Munster, Germany. [Fregni, Felipe; Pascua-Leone, Alvaro] Beth Israel Deaconess Med Ctr, Dept Neurol, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Fregni, Felipe; Pascua-Leone, Alvaro] Harvard Univ, Sch Med, Boston, MA USA. [Nitsche, Michael A.; Paulus, Walter] Univ Gottingen, Dept Clin Neurophysiol, Gottingen, Germany. [Oliveri, Massimiliano] Univ Palermo, Dept Psychol, Rome, Italy. [Oliveri, Massimiliano] Fdn Sania Lucia IRCCS, Rome, Italy. [Priori, Alberto] Univ Milan, Clin Ctr Neuronanotechnol & Nettrostimulat, Dept Neurol Sci, Milan, Italy. [Priori, Alberto] IRCCS Osped Maggiore Policlin, Milan, Italy. [Walsh, Vincent] UCL, Inst Cognit Neurosci, London, England. [Walsh, Vincent] UCL, Dept Psychol, London, England. RP Miniussi, C (reprint author), Univ Brescia, Natl Inst Neurosci, Dept Biomed Sci & Biotechnol, Viale Europa 11, I-25123 Brescia, Italy. EM miniussi@med.unibs.it RI Miniussi, Carlo/E-7602-2010; Nitsche, Michael/B-6755-2012; Floel, Agnes/A-9426-2017; Paulus, Walter/A-3544-2009 OI Miniussi, Carlo/0000-0002-5436-4745; Paulus, Walter/0000-0001-5549-8377 NR 118 TC 107 Z9 111 U1 11 U2 77 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD OCT PY 2008 VL 1 IS 4 BP 326 EP 336 DI 10.1016/j.brs.2008.07.002 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 398FC UT WOS:000262717000002 PM 20633391 ER PT J AU Reis, J Robertson, EM Krakauer, JW Rothwell, J Marshall, L Gertoff, C Wassermann, EM Pascual-Leone, A Hummel, F Celnik, PA Classen, J Floel, A Ziemann, U Paulus, W Siebner, HR Born, J Cohen, LG AF Reis, Janine Robertson, Edwin M. Krakauer, John W. Rothwell, John Marshall, Lisa Gertoff, Christian Wassermann, Eric M. Pascual-Leone, Alvaro Hummel, Friedhelm Celnik, Pablo A. Classen, Joseph Floel, Agnes Ziemann, Ulf Paulus, Walter Siebner, Hartwig R. Born, Jan Cohen, Leonardo G. TI Consensus: Can transcranial direct current stimulation and transcranial magnetic stimulation enhance motor learning and memory formation? SO BRAIN STIMULATION LA English DT Article DE transcranial magnetic stimulation; transcranial direct current stimulation; stroke; learning; motor ID ADULT SQUIRREL-MONKEYS; LOW-FREQUENCY RTMS; PRISM ADAPTATION; TIME-COURSE; MOVEMENT REPRESENTATIONS; CORTICAL STIMULATION; CORTEX EXCITABILITY; FINGER MOVEMENTS; CONSOLIDATION; SLEEP AB Noninvasive brain stimulation has developed as a promising tool for cognitive neuroscientists. Transcranial magnetic (TMS) and direct current (tDCS) stimulation allow researchers to purposefully enhance or decrease excitability in focal areas of the brain. The purpose of this article is to review information on the use of TMS and tDCS as research tools to facilitate motor memory formation, motor performance, and motor learning in healthy Volunteers. Studies implemented so far have mostly focused on the ability of TMS and tDCS to elicit relatively short-lasting motor improvements and the mechanisms Underlying these changes have been only partially investigated. Despite limitations. including the scarcity of data, work that has been already accomplished raises the exciting hypothesis that currently available noninvasive transcranial stimulation techniques could modulate motor learning and memory formation in healthy humans and potentially in patients with neurologic and psychiatric disorders. (C) 2008 Elsevier Inc. All rights reserved. C1 [Reis, Janine; Cohen, Leonardo G.] NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. [Robertson, Edwin M.; Pascual-Leone, Alvaro] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Krakauer, John W.] Columbia Univ, Dept Neurol, Motor Performance Lab, New York, NY USA. [Rothwell, John] Inst Neurol, London WC1N 3BG, England. [Marshall, Lisa; Born, Jan] Med Univ Lubeck, Dept Neurol & Clin Neuroendocrinol, D-23538 Lubeck, Germany. [Gertoff, Christian; Hummel, Friedhelm] Univ Hamburg, Dept Neurol, Hamburg, Germany. [Wassermann, Eric M.] NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. [Celnik, Pablo A.] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD USA. [Classen, Joseph] Univ Wurzburg, Dept Neurol, Human Cort Physiol & Motor Control Lab, D-8700 Wurzburg, Germany. [Floel, Agnes] Univ Munster, Dept Neurol, D-4400 Munster, Germany. [Floel, Agnes] IZKF Munster, Munster, Germany. [Ziemann, Ulf] Univ Frankfurt, Dept Neurol, Frankfurt, Germany. [Paulus, Walter] Univ Gottingen, Dept Clin Neurophysiol, Gottingen, Germany. [Siebner, Hartwig R.] Univ Kiel, Dept Neurol, Brain Mapping Lab, D-2300 Kiel, Germany. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Westwood, Sam/P-7000-2015; Siebner, Hartwig/G-4052-2016; Born, Jan/K-2596-2016; Floel, Agnes/A-9426-2017; Paulus, Walter/A-3544-2009; OI Paulus, Walter/0000-0001-5549-8377; Rothwell, John/0000-0003-1367-6467 NR 84 TC 114 Z9 119 U1 3 U2 52 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD OCT PY 2008 VL 1 IS 4 BP 363 EP 369 DI 10.1016/j.brs.2008.08.001 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 398FC UT WOS:000262717000005 PM 20633394 ER PT J AU Hummel, FC Ceinik, P Pascual-Leone, A Fregni, F Byblow, WD Buetefisch, CM Rothwell, J Cohen, LG Gertoff, C AF Hummel, Friedhelm C. Ceinik, Pablo Pascual-Leone, Alvero Fregni, Felipe Byblow, Winston D. Buetefisch, Cathrin M. Rothwell, John Cohen, Leonardo G. Gertoff, Christian TI Controversy: Noninvasive and invasive cortical stimulation show efficacy in treating stroke patients SO BRAIN STIMULATION LA English DT Review DE stroke; plasticity; recovery; rehabilitation ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; VENTRAL PREMOTOR CORTEX; RANDOMIZED CLINICAL-TRIAL; THETA-BURST STIMULATION; UNAFFECTED HEMISPHERE; DOUBLE-BLIND; BRAIN-STIMULATION; SUBACUTE STROKE; CORTICOMOTOR EXCITABILITY AB Stroke is the leading cause of disability in the adult Population of western industrialized Countries. Despite significant improvements of acute stroke care, two thirds of stroke survivors have to cope with persisting neurologic deficits. Adjuvant brain stimulation is a novel approach to improving the treatment of residual deficits after stroke. Transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS). and epidural electrical stimulation have been used in first trials on small cohorts of stroke patients. Effect sizes in the order of 8% to 30% Of functional improvement have been reported. but a publication bias toward presenting "promising" but not negative results is likely. Many questions regarding underlying mechanisms, optimal stimulation parameters, combination with other types of interventions, among others, are open. This review addresses six controversies related to the experimental application of brain stimulation techniques to stroke patients. Cortical stimulation after stroke will need to be individually tailored and a thorough patient stratification according to type and extent of clinical deficit. lesion location, lesion size. comorbidities, time in the recovery process. and perhaps also age and gender will be necessary. There is consensus that cortical stimulation in stroke patients is still experimental and should only be applied in the frame of scientific studies. (C) 2008 Elsevier Inc. All rights reserved. C1 [Hummel, Friedhelm C.; Gertoff, Christian] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Brain Imaging & Neurostimulat Lab, D-20246 Hamburg, Germany. [Ceinik, Pablo] Johns Hopkins Univ, Dept Neurol, Dept Phys Med & Rehabil, Baltimore, MD 21218 USA. [Pascual-Leone, Alvero; Fregni, Felipe] Harvard Univ, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA USA. [Pascual-Leone, Alvero; Fregni, Felipe] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Byblow, Winston D.] Univ Auckland, Movement Neurosci Lab, Dept Sport & Exercise Sci, Auckland 1, New Zealand. [Rothwell, John] W Virginia Univ, Dept Physiol, Dept Neurol, Morgantown, WV 26506 USA. [Cohen, Leonardo G.] NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. [Cohen, Leonardo G.] NINDS, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. RP Gertoff, C (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Brain Imaging & Neurostimulat Lab, Martinistr 52, D-20246 Hamburg, Germany. EM gerloff@uke.uni-hamburg.de RI Byblow, Winston/D-3579-2009; OI Rothwell, John/0000-0003-1367-6467 NR 127 TC 57 Z9 59 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD OCT PY 2008 VL 1 IS 4 BP 370 EP 382 DI 10.1016/j.brs.2008.09.003 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 398FC UT WOS:000262717000006 PM 20633395 ER PT J AU Miller, SA Coelho, SG Zmudzka, BZ Bushar, HF Yamaguchi, Y Hearing, VJ Beer, JZ AF Miller, S. A. Coelho, S. G. Zmudzka, B. Z. Bushar, H. F. Yamaguchi, Y. Hearing, V. J. Beer, J. Z. TI Dynamics of pigmentation induction by repeated ultraviolet exposures: dose, dose interval and ultraviolet spectrum dependence SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article DE melanogenesis; pigmentation; repeated exposures; ultraviolet radiation ID SKIN COLOR; TIME-COURSE; RADIATION; ERYTHEMA; MELANIN AB Background The dynamics of ultraviolet (UV)-induced melanogenesis have been well characterized for single UV exposures. However, our knowledge of the effects of repeated UV exposures on the development of new pigmentation is limited. Objectives To characterize the dynamics and dose dependence of pigmentation induction by repeated UV exposures using two different UV sources. Methods A total of 40 healthy subjects participated in the study: 21 were exposed to a 5% UVB/95% UVA source and 19 were exposed to a 2% UVB/98% UVA source. Skin phototypes 2-3 were represented. Subjects were exposed one to three times per week. The minimal erythemal dose and minimal melanogenic dose of all subjects were determined, and both visual and instrumental observations of the development of pigmentation and erythema were recorded. Results Dark-brown pigmentation could be produced by a cumulative UV dose of 4200 J m(-2) given as 10 exposures over 5 weeks. However, comparable pigmentation could also be induced by a cumulative dose of 2900 J m(-2) given as eight exposures over 4 weeks. The lowest cumulative dose of 1900 J m(-2) given over 4 weeks produced moderate pigmentation. The 2% UVB source led to earlier and darker pigmentation than the 5% UVB source did for equally erythemogenic doses. Conclusions These observations show that the dynamics of melanogenesis induced by repeated exposures depends on UV dose, dose interval and emission spectrum. They also indicate that increasing the UV dose above a certain level of cumulative exposure does not significantly increase the level of UV-induced pigmentation. C1 [Miller, S. A.; Zmudzka, B. Z.; Bushar, H. F.; Beer, J. Z.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Coelho, S. G.; Yamaguchi, Y.; Hearing, V. J.] NIH, NCI, Cell Biol Lab, Bethesda, MD 20852 USA. RP Miller, SA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. EM sharona.miller@fda.hhs.gov FU U. S. FDA Office of Women's Health; National Cancer Institute; National Institutes of Health FX This research was supported by the U. S. FDA Office of Women's Health, and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The authors wish to express their sincere appreciation to Dr Katalin S. Korossey for her dermatological support and numerous valuable suggestions, and to Judith Kniskern, RN for her excellent handling of the human subjects and records. NR 26 TC 18 Z9 18 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD OCT PY 2008 VL 159 IS 4 BP 921 EP 930 DI 10.1111/j.1365-2133.2008.08708.x PG 10 WC Dermatology SC Dermatology GA 349UB UT WOS:000259307700020 PM 18616777 ER PT J AU O'Connor, OA Portlock, C Moskowitz, C Straus, D Hamlin, P Stubblefield, M Dumetrescu, O Colevas, AD Grant, B Zelenetz, A AF O'Connor, Owen A. Portlock, Carol Moskowitz, Craig Straus, David Hamlin, Paul Stubblefield, Michael Dumetrescu, Otila Colevas, A. Dimitrios Grant, Barbara Zelenetz, Andrew TI A multicentre phase II clinical experience with the novel aza-epothilone Ixabepilone (BMS247550) in patients with relapsed or refractory indolent non-Hodgkin lymphoma and mantle cell lymphoma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Ixabepilone; epothilones; indolent non-Hodgkin lymphoma; mantle cell lymphoma ID MICROTUBULE-STABILIZING AGENTS; PROTEASOME INHIBITOR BORTEZOMIB; HUMAN TUMOR XENOGRAFTS; DESOXYEPOTHILONE-B; PACLITAXEL TAXOL(R); DRUG-RESISTANCE; DAILY SCHEDULE; BMS-247550; TRIAL; CANCER AB The epothilones represent a novel group of microtubule stabilization agents that appear to retain activity even in chemotherapy-resistant cell lines and animal models. Because of their ability to overcome chemotherapy resistance, we conducted a phase II study of Ixabepilone in patients with indolent non-Hodgkin lymphoma and mantle cell lymphoma (MCL). Ixabepilone was given at a dose of 25 mg/m(2) weekly for three of four consecutive weeks. Patients were required to have received <= 4 prior chemotherapy regimens, with an interval of at least one month since the last treatment, 3 months from prior rituximab, and 7 d from prior steroids, an absolute neutrophil count > 1 x 10(9)/l and a platelet count > 50 x 10(9)/l. Dose reductions were allowed. The overall response rate in assessable patients was 27% in this otherwise heavily treated population. One patient with chemotherapy-refractory follicular lymphoma attained a complete remission that lasted approximately 8 months. Three responses were also seen in refractory MCL and one in small lymphocytic lymphoma. The duration of response ranged from 2 to 8 months. Major toxicities included fatigue, myelosuppression and neuropathy. These data suggest that Ixabepilone has activity in chemotherapy-refractory lymphoma. C1 [O'Connor, Owen A.; Portlock, Carol; Moskowitz, Craig; Straus, David; Hamlin, Paul; Zelenetz, Andrew] Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Oncol, Lymphoma Serv, New York, NY 10021 USA. [Stubblefield, Michael] Mem Sloan Kettering Canc Ctr, Dept Rehabil Med, New York, NY 10021 USA. [Dumetrescu, Otila] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Colevas, A. Dimitrios] NCI, Canc Therapy & Evaluat Program, Bethesda, MD 20892 USA. [Grant, Barbara] Univ Vermont, Vermont Reg Canc Ctr, Burlington, VT USA. RP O'Connor, OA (reprint author), Columbia Univ, Lymphoma Serv, Lymphoid Dev & Malignancy Program, Herbert Irving Comprehens Canc Ctr, 1130 St Nicholas Ave,Rm 216, New York, NY 10032 USA. EM oo2130@columbia.edu OI Zelenetz, Andrew/0000-0003-1403-6883 FU Leukemia and Lymphoma Society; NCI Phase II [UO1 CA 69913]; Vermont Cancer Center [P30CA22435] FX OAO is the recipient of the Leukemia and Lymphoma Society Scholar in Research Award. This work was supported under a NCI Phase II Grant (UO1 CA 69913) and the Vermont Cancer Center Support Grant P30CA22435. NR 36 TC 12 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2008 VL 143 IS 2 BP 201 EP 209 DI 10.1111/j.1365-2141.2008.07271.x PG 9 WC Hematology SC Hematology GA 352OF UT WOS:000259505900005 PM 18691173 ER PT J AU Borges, G Benjet, C Medina-Mora, ME Orozco, R Wang, PS AF Borges, G. Benjet, C. Medina-Mora, M. E. Orozco, R. Wang, P. S. TI Treatment of mental disorders for adolescents in Mexico City SO BULLETIN OF THE WORLD HEALTH ORGANIZATION LA English DT Article ID NATIONAL COMORBIDITY SURVEY; HEALTH-SERVICE USE; PRIMARY-CARE PATIENTS; UNMET NEED; TREATMENT GUIDELINES; COLLABORATIVE CARE; SURVEY REPLICATION; UNITED-STATES; HELP-SEEKING; DEPRESSION AB Objective This study describes the prevalence, adequacy and correlates of 12-month mental health service use among participants in the Mexican Adolescent Mental Health Survey. Methods The authors conducted face-to-face household surveys of a probability sample of 3005 adolescents aged 12-17 years residing in the Mexico City metropolitan area during 2005. The prevalence of mental health disorders and the use of services were assessed with the computer-assisted adolescent version of the World Mental Health Composite International Diagnostic Interview. Correlates of service use and adequate treatment were identified in logistic regression analyses that took into account the complex sample design and weighting process. Findings Less than one in seven respondents with psychiatric disorders used any mental health services during the previous year. Respondents with substance-use disorders reported the highest prevalence of service use and those with anxiety disorders the lowest. Approximately one in every two respondents receiving any services obtained treatment that could be considered minimally adequate. Conclusion We found large unmet needs for mental health services among adolescents with psychiatric disorders in Mexico City. Improvements in the mental health care of Mexican youth are urgently needed. Bulletin of the World Health Organization 2008;86:757-764. C1 [Borges, G.; Benjet, C.; Medina-Mora, M. E.] Inst Nacl Psiquiatria, Mexico City, DF, Mexico. [Orozco, R.] Secretaria Salud Mexico, Mexico City, DF, Mexico. [Wang, P. S.] NIMH, Bethesda, MD 20892 USA. RP Borges, G (reprint author), Inst Nacl Psiquiatria, Calzada Mexico Xochimilco 101,Col San Lorenzo Hui, Mexico City, DF, Mexico. EM guibor@imp.edu.mx RI Benjet, Corina/D-7363-2012; OI Borges, Guilherme/0000-0002-3269-0507; Benjet, Corina/0000-0002-4569-6094 NR 50 TC 9 Z9 11 U1 0 U2 1 PU WORLD HEALTH ORGANIZATION PI GENEVA 27 PA MARKETING AND DISSEMINATION, CH-1211 GENEVA 27, SWITZERLAND SN 0042-9686 EI 1564-0604 J9 B WORLD HEALTH ORGAN JI Bull. World Health Organ. PD OCT PY 2008 VL 86 IS 10 BP 757 EP 764 DI 10.2471/BLT.07.047696 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 360QA UT WOS:000260071200009 PM 18949212 ER PT J AU Jensen, RI Berna, MJ Bingham, DB Norton, JA AF Jensen, Robert I. Berna, Marc J. Bingham, David B. Norton, Jeffrey A. TI Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management, and controversies SO CANCER LA English DT Review DE pancreatic endocrine tumors; neuroendocrine tumors; Multiple Endocrine Neoplasia type 1; von Hippel-Lindau disease; neurofibromatosis 1; tuberous sclerosis; gastrinomas; insulinomas; Zollinger-Ellison syndrome ID ZOLLINGER-ELLISON-SYNDROME; SOMATOSTATIN-RECEPTOR SCINTIGRAPHY; NEOPLASIA-TYPE-I; HIPPEL-LINDAU-DISEASE; ISLET-CELL TUMORS; POSITRON-EMISSION-TOMOGRAPHY; VON-RECKLINGHAUSENS-DISEASE; GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS; GASTRIC-ACID HYPERSECRETION; TUBEROUS SCLEROSIS COMPLEX AB Pancreatic endocrine tumors (PETs) call Occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1 > VHL > NF-1 > TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and Surgical treatment of PETs in Such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these Uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed. C1 [Jensen, Robert I.; Berna, Marc J.] NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Bingham, David B.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Norton, Jeffrey A.] Stanford Univ, Dept Surg, Stanford, CA 94305 USA. RP Jensen, RI (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM roberj@bdg10.niddk.nih.gov FU National Institutes of Diabetes, Digestive, and Kidney Diseases; National Institutes of Health; [R01 CA 096645-01] FX Supported in part by intramural funds from the National Institutes of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, and R01 CA 096645-01. NR 373 TC 140 Z9 148 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2008 VL 113 IS 7 SI SI BP 1807 EP 1843 DI 10.1002/cncr.23648 PG 37 WC Oncology SC Oncology GA 354TL UT WOS:000259661800011 PM 18798544 ER PT J AU Bondy, ML Scheurer, ME Malmer, B Barnholtz-Sloan, JS Davis, FG Il'Yasova, D Kruchko, C McCarthy, BJ Rajaraman, P Schwartzbaum, JA Sadetzki, S Schlehofer, B Tihan, T Wiemels, JL Wrensch, M Buffler, PA AF Bondy, Melissa L. Scheurer, Michael E. Malmer, Beatrice Barnholtz-Sloan, Jill S. Davis, Faith G. Il'Yasova, Dora Kruchko, Carol McCarthy, Bridget J. Rajaraman, Preetha Schwartzbaum, Judith A. Sadetzki, Siegal Schlehofer, Brigitte Tihan, Tarik Wiemels, Joseph L. Wrensch, Margaret Buffler, Patricia A. CA Brain Tumor Epidemiol Consortium TI Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium SO CANCER LA English DT Review DE glioma; meningioma; epidemiology; genetics ID CENTRAL-NERVOUS-SYSTEM; ATOMIC-BOMB SURVIVORS; REGULATORY T-CELLS; RECURSIVE PARTITIONING ANALYSIS; GROWTH-FACTOR RECEPTOR; MOBILE PHONE USE; COMPARATIVE GENOMIC HYBRIDIZATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; OCCUPATIONAL RISK-FACTORS; MALIGNANT GLIOMA PATIENTS AB Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in Promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently, been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the groups Consensus oil the Current state of scientific findings, and they present a consensus oil research priorities to identify which important areas the science should move to address. C1 [Bondy, Melissa L.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Scheurer, Michael E.] Baylor Coll Med, Dept Pediat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Malmer, Beatrice] Umea Univ, Dept Radiat Sci & Oncol, Umea, Sweden. [Barnholtz-Sloan, Jill S.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Davis, Faith G.; McCarthy, Bridget J.] Univ Illinois, Sch Publ Hlth, Div Epidemiol Biostat, Chicago, IL USA. [Il'Yasova, Dora] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Kruchko, Carol; McCarthy, Bridget J.] Cent Brain Tumor Registry US, Hinsdale, IL USA. [Rajaraman, Preetha] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Schwartzbaum, Judith A.] Ohio State Univ, Sch Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Sadetzki, Siegal] Chaim Sheba Med Ctr, Gertner Inst, Canc & Radiat Epidemiol Unit, IL-52621 Tel Hashomer, Israel. [Schlehofer, Brigitte] German Canc Res Ctr, Environm Epidemiol Unit, D-6900 Heidelberg, Germany. [Tihan, Tarik] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA. [Wiemels, Joseph L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Wrensch, Margaret] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Buffler, Patricia A.] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA. RP Bondy, ML (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, 1155 Pressler St,Unit 1340, Houston, TX 77030 USA. EM mbondy@mdanderson.org RI Barnholtz-Sloan, Jill/A-4817-2011; Ruder, Avima/I-4155-2012; Cardis, Elisabeth/C-3904-2017; OI Ruder, Avima/0000-0003-0419-6664; Scheurer, Michael/0000-0002-8379-6088 FU NCI NIH HHS [R01 CA052689, R01 CA052689-18, R01 CA052689-19] NR 196 TC 297 Z9 307 U1 8 U2 53 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2008 VL 113 IS 7 SI SI BP 1953 EP 1968 DI 10.1002/cncr.23741 PG 16 WC Oncology SC Oncology GA 354TL UT WOS:000259661800019 PM 18798534 ER PT J AU Lowy, DR Solomon, D Hildesheim, A Schiller, JT Schiffman, M AF Lowy, Douglas R. Solomon, Diane Hildesheim, Allan Schiller, John T. Schiffman, Mark TI Human papillomavirus infection and the primary and secondary prevention of cervical cancer SO CANCER LA English DT Review DE cervical intraepithelial lesion; developing world; human papillomavirus assays; Papanicolaou smear; screen-and-treat approach; virus-like particle vaccines ID RANDOMIZED CONTROLLED-TRIAL; ATYPICAL SQUAMOUS-CELLS; 2006 CONSENSUS GUIDELINES; ADENOCARCINOMA IN-SITU; LIQUID-BASED CYTOLOGY; PARTICLE VACCINE; INTRAEPITHELIAL NEOPLASIA; YOUNG-WOMEN; FOLLOW-UP; COLLABORATIVE REANALYSIS AB A wealth of evidence has led to the conclusion that virtually all cases of cervical cancer are attributable to persistent infection by a subset of human papillomavirus (HPV) types, especially HPV type 16 (HPV-16) and HPV-18. These HPV types also cause a proportion of other cancers, including vulvar, vaginal, anal, penile, and oropharyngeal cancers. Although cervical cancer screening, primarily with the Papanicolaou (Pap) smear, has reduced the incidence of this cancer in industrialized countries, cervical cancer remains the second most common Cause of death from cancer in women worldwide, because the developing world has lacked the resources for widespread, high-quality screening. In addition to advances in Pap smear technology, the identification of HPV as the etiologic agent has produced 2 recent advances that may have a major impact on approaches to reduce the incidence of this disease. The first is the development of a preventive vaccine, the current versions of which appear to prevent close to 100% of persistent genital infection and disease caused by HPV-16 and HPV-18; future second-gene ration vaccines may be able to protect against oncogenic infections by a broader array of HPV types. The second is the incorporation of HPV testing into screening programs. In women aged >30 years, HPV testing can identify high-grade cervical intraepithelial neoplasia earlier than Pap smears with acceptable rates of specificity. These results, together with the high sensitivity of HPV testing, suggest that such testing could permit increased intervals for screening. An inexpensive HPV test in development, if successful, may be incorporated as part of an economically friable 'screen-and-treat' approach in the developing world. The manner in which vaccination and screening programs are integrated will need to be considered carefully so that they are efficient in reducing the overall incidence of cervical cancer. C1 [Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Hildesheim, Allan; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bldg 37,Room 4106,MSC 4263, Bethesda, MD 20892 USA. EM lowyd@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU National Cancer Institute FX Funded by the National Cancer Institute. NR 108 TC 66 Z9 68 U1 1 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 1 PY 2008 VL 113 IS 7 SI SI BP 1980 EP 1993 DI 10.1002/cncr.23704 PG 14 WC Oncology SC Oncology GA 354TL UT WOS:000259661800021 PM 18798536 ER EF