FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Singh, A Ling, GY Suhasini, AN Zhang, P Yamamoto, M Navas-Acien, A Cosgrove, G Tuder, RM Kensler, TW Watson, WH Biswal, S AF Singh, Anju Ling, Guoyu Suhasini, Avvaru N. Zhang, Ping Yamamoto, Masayuki Navas-Acien, Ana Cosgrove, Gregory Tuder, Rubin M. Kensler, Thomas W. Watson, Walter H. Biswal, Shyam TI Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Srx1; Nrf2; Oxidative stress; Antioxidant response element; Chronic obstructive pulmonary disease; Emphysema; Free radicals ID OBSTRUCTIVE PULMONARY-DISEASE; CYSTEINE-SULFINIC ACID; NRF2 ENHANCES SUSCEPTIBILITY; ANTIOXIDANT RESPONSE ELEMENT; PLANAR AROMATIC-COMPOUNDS; YA SUBUNIT GENE; TRANSCRIPTION FACTORS; INDUCIBLE EXPRESSION; DIESEL EXHAUST; CELL-SURVIVAL AB Oxidative stress results in protein oxidation and is involved in the pathogenesis of lung diseases such as chronic obstructive pulmonary disorder (COPD). Sulfiredoxin-1 (Srx1) catalyzes the reduction of cysteine sulfinic acid to sulfenic acid in oxidized proteins and protects them from inactivation. This study examined the mechanism of transcriptional regulation of Srx1 and its possible protective role during oxidative stress associated with COPD. Nrf2, a transcription factor known to influence susceptibility to pulmonary diseases, upregulates Srx1 expression during oxidative stress caused by cigarette smoke exposure in the lungs of mice. Disruption of Nrf2 signaling by genetic knockout in mice or RNAi in cells downregulated the expression of Srx1. In silico analysis of the 5'-promoter-flanking region of Srx1 identified multiple antioxidant-response elements (AREs) that are highly conserved. Reporter and chromatin-immunoprecipitation assays demonstrated that ARE1 at -228 is critical for the Nrf2-mediated response. Attenuation of Srx1 expression with RNAi potentiated the toxicity of hydrogen peroxide (H(2)O(2)), whereas overexpression of Srx1 protected against H(2)O(2)-mediated cell death in vitro. Immunoblot analysis revealed dramatic decreases in Srx1 expression in lungs from patients with COPD relative to nonemphysematous lungs together with a decline in Nrf2 protein. Thus, Srx1, a key Nrf2-regulated gene, contributes to protection against oxidative injury in the lung. (C) 2008 Elsevier Inc. All rights reserved. C1 [Singh, Anju; Ling, Guoyu; Zhang, Ping; Yamamoto, Masayuki; Navas-Acien, Ana; Kensler, Thomas W.; Watson, Walter H.; Biswal, Shyam] Johns Hopkins Univ, Dept Environm Hlth Sci, John Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Suhasini, Avvaru N.] NIA, NIH, Baltimore, MD 21224 USA. [Yamamoto, Masayuki] Tohoku Univ, Grad Sch Med, Aoba Ku, Sendai, Miyagi 9808575, Japan. [Yamamoto, Masayuki] ERATO, Environm Response Project, Aoba Ku, Sendai, Miyagi 9808575, Japan. [Cosgrove, Gregory] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [Cosgrove, Gregory; Tuder, Rubin M.] Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. [Kensler, Thomas W.; Biswal, Shyam] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21205 USA. RP Biswal, S (reprint author), Johns Hopkins Univ, Dept Environm Hlth Sci, John Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM sbiswal@jhsph.edu RI Yamamoto, Masayuki/A-4873-2010; Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NIH [R01 HL081205, P50 HL084945, P50 CA058184, P50 ES015903, P30ES03819]; Flight Attendant Medical Research Institute FX This work was supported by NIH Grants R01 HL081205 (S.B.), SCCOR P50 HL084945, P50 CA058184, P50 ES015903 and P30ES03819 and a Young Clinical Innovator Award (S.B., AN) and a Young Clinical Scientist Award to Anju Singh from the Flight Attendant Medical Research Institute. We thank james Watkins III for providing frozen COPD tissues. NR 53 TC 68 Z9 74 U1 1 U2 2 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 FEB 1 PY 2009 VL 46 IS 3 BP 376 EP 386 DI 10.1016/j.freeradbiomed.2008.10.026 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 395LJ UT WOS:000262525300006 PM 19027064 ER PT J AU Flores, J AF Flores, Jorge TI Seeking new pathways for HIV vaccine discovery SO FUTURE MICROBIOLOGY LA English DT Editorial Material ID INFECTION; GENOME; TRIAL; HOSTS C1 NIAID, Vaccine Res Program, Div AIDS, NIH, Bethesda, MD 20892 USA. RP Flores, J (reprint author), NIAID, Vaccine Res Program, Div AIDS, NIH, Bethesda, MD 20892 USA. EM jflores@niad.nih.gov NR 18 TC 5 Z9 5 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 1746-0913 J9 FUTURE MICROBIOL JI Future Microbiol. PD FEB PY 2009 VL 4 IS 1 BP 1 EP 7 DI 10.2217/17460913.4.1.1 PG 7 WC Microbiology SC Microbiology GA 412VO UT WOS:000263752500001 PM 19207094 ER PT J AU Everhart, JE Ruhl, CE AF Everhart, James E. Ruhl, Constance E. TI Burden of Digestive Diseases in the United States Part I: Overall and Upper Gastrointestinal Diseases SO GASTROENTEROLOGY LA English DT Review C1 [Everhart, James E.] NIDDK, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. Social & Sci Syst Inc, Silver Spring, MD USA. RP Everhart, JE (reprint author), NIDDK, Div Digest Dis & Nutr, 2 Democracy Plaza,Room 655,6707 Democracy Blvd,MS, Bethesda, MD 20892 USA. EM JE17G@NIH.GOV FU HHS [N267200612918C, N267200700001G] FX Supported by HHS contracts N267200612918C and N267200700001G. NR 11 TC 163 Z9 172 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2009 VL 136 IS 2 BP 376 EP 386 DI 10.1053/j.gastro.2008.12.015 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 401UK UT WOS:000262967700005 PM 19124023 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, Constance E. Everhart, James E. TI Elevated Serum Alanine Aminotransferase and gamma-Glutamyltransferase and Mortality in the United States Population SO GASTROENTEROLOGY LA English DT Article ID ALL-CAUSE MORTALITY; MIDDLE-AGED MEN; C-REACTIVE PROTEIN; METABOLIC SYNDROME; RISK-FACTORS; FOLLOW-UP; CARDIOVASCULAR-DISEASE; FATTY LIVER; CONSTRUCTION WORKERS; CAFFEINE CONSUMPTION AB Background & Aims: Elevated serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activities are markers of liver injury, but may also be associated with other diseases and death. In a prospective, national, population-based sample, we examined whether elevated ALT and GGT were associated with increased risk of all-cause and disease-specific mortality. Methods: Death certificate-based 12-year mortality was analyzed among 14,950 adult participants in the third US National Health and Nutrition Examination Survey, 1988-1994, who were negative for markers of viral hepatitis B and C. Abnormal ALT was defined as > 30 U/L in men or > 19 U/L in women, and abnormal GGT as > 51 U/L in men or > 33 U/L in women. Results: Cumulative mortality was 13.9% from all causes, including 4.2% from cardiovascular disease, 4.2% from neoplasms, 0.44% from diabetes, and 0.13% from liver disease. In multivariate-adjusted analyses, elevated ALT was not associated with all-cause mortality (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.88-1.6). ALT elevation was associated with deaths from liver disease (HR, 8.2; 95% CI, 2.1-31.9), but not from cardiovascular disease (HR, 0.90; 95% CI, 0.56-1.4), neoplasms (HR, 1.0; 95% Cl, 0.65-1.5), or diabetes (HR, 2.4; 95% CI, 0.65-9.1). All-cause mortality increased with elevated GGT (HR, 1.5; 95% CI, 1.2-1.8), as did mortality from liver disease (HR, 13.0; 95% CI, 2.4-71.5), neoplasms (HR, 1.5; 95% CI, 1.01-2.2), and diabetes (HR, 3.3; 95% CI, 1.4-7.6), but not from cardiovascular disease (HR, 1.3; 95% Cl, 0.80-2.0). Conclusions: In the US population, elevated GGT was associated with mortality from all causes, liver disease, cancer, and diabetes, while ALT was associated only with liver disease mortality. C1 [Ruhl, Constance E.] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Everhart, James E.] NIDDK, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM cruhl@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [HHSN267200700001G] FX Supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN267200700001G). NR 61 TC 147 Z9 147 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2009 VL 136 IS 2 BP 477 EP 485 DI 10.1053/j.gastro.2008.10.052 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 401UK UT WOS:000262967700019 PM 19100265 ER PT J AU Kuzin, A Kundu, M Ekatomatis, A Brody, T Odenwald, WF AF Kuzin, Alexander Kundu, Mukta Ekatomatis, Antonios Brody, Thomas Odenwald, Ward F. TI Conserved sequence block clustering and flanking inter-cluster flexibility delineate enhancers that regulate nerfin-1 expression during Drosophila CNS development SO GENE EXPRESSION PATTERNS LA English DT Article DE Enhancers; Drosophila; Nervous system development; EvoPrinter; phylogenetic footprinting; Nerfin-1; Transcription factor; Embryonic expression; Larval expression ID DEVELOPING NERVOUS-SYSTEM; FINGER TRANSCRIPTION FACTOR; COMPARATIVE GENOMICS; ELEMENT VECTORS; CELL FATE; GENES; IDENTIFICATION; KRUPPEL; DNA; SPECIFICITY AB We have identified clusters of conserved sequences constituting discrete modular enhancers within the Drosophila nerfin-1 locus. nerfin-1 encodes a Zn-finger transcription factor that directs pioneer interneuron axon guidance. nerfin-1 mRNA is detected in many early delaminating neuroblasts, ganglion mother cells and transiently in nascent neurons. The comparative genomics analysis program EvoPrinter revealed conserved sequence blocks both upstream and downstream of the transcribed region. By using the aligning regions of different drosophilids as the reference DNA, EvoPrinter detects Sequence length flexibility between clusters of conserved sequences and thus facilitates differentiation between closely associated modular enhancers. Expression analysis of enhancer-reporter transgenes identified enhancers that drive expression in different regions of the developing embryonic and adult nervous system, including subsets of embryonic CNS neuroblasts, GMCs, neurons and PNS neurons. In Summary, EvoPrinter facilitates the discovery and analysis of enhancers that control crucial aspects of nerfin-1 expression. Published by Elsevier B.V. C1 [Kuzin, Alexander; Kundu, Mukta; Ekatomatis, Antonios; Brody, Thomas; Odenwald, Ward F.] NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD 20892 USA. RP Kuzin, A (reprint author), NINDS, Neural Cell Fate Determinants Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Alex.Kuzin@ninds.nih.gov; ward@codon.nih.gov FU NIH; NINDS FX We thank Jermaine Ross and members of the NINDS central sequencing facility for their technical support and acknowledge the editorial expertise of Judith Brody. This research was supported by the Intramural Research Program of the NIH, NINDS. NR 35 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD FEB PY 2009 VL 9 IS 2 BP 65 EP 72 DI 10.1016/j.gep.2008.10.005 PG 8 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 405IW UT WOS:000263217500001 PM 19056518 ER PT J AU Shimada, M Wang, HB Kondo, A Xu, XP Yoshida, A Shinoda, K Ura, T Mizuguchi, H Klinman, D Luo, JL Bai, H Okuda, K AF Shimada, M. Wang, H. -B Kondo, A. Xu, X. -P Yoshida, A. Shinoda, K. Ura, T. Mizuguchi, H. Klinman, D. Luo, J. -L Bai, H. Okuda, K. TI Effect of therapeutic immunization using Ad5/35 and MVA vectors on SIV infection of rhesus monkeys undergoing antiretroviral therapy SO GENE THERAPY LA English DT Article DE vaccine; virus vector; SIV; monkey model; therapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; MEMORY T-CELLS; TREATMENT INTERRUPTIONS; PROTECTIVE IMMUNITY; VIRAL SUPPRESSION; HIV-1 INFECTION; VACCINE VECTORS; SIMIAN AIDS; VIREMIA; REPLICATION AB Antiretroviral therapy (ART) effectively slows the progression of AIDS. However, drug resistance and/or toxicity can limit the utility of ART in many patients. In this study, we assessed whether a viral vector-based vaccine can be used as a therapeutic vaccine in simian immunodeficiency virus (SIV)-infected monkeys. The effect of vaccinating SIVmac239-infected rhesus monkeys with an SIV gag and gp120-expressing adenovirus (Ad) vector vaccine and a modified vaccinia Ankara (MVA) vaccine was explored while being treated with ART. Rhesus monkeys were intravenously infected with 10 and 1000 TCID(50) (50% tissue culture infectious dose) of SIVmac239. Two months after SIV infection, the monkeys received a 4-month treatment with ART. Some of the monkeys were immunized with adenovirus-based vaccine and MVA-based vaccine with 2 months interval during ART. Viral load, CD4 count and SIV-specific immune responses were observed for 7 months after interruption of ART. The vaccinated animals had higher (i) CD4 counts, (ii) SIV-specific cell-mediated immune responses and (iii) anti-SIV-neutralizing antibody (Ab) titers than monkeys treated with ART alone. More importantly, the vaccination significantly reduced the SIV RNA load from animals infected with a low dose of SIV (10 TCID(50)). The anti-SIV cell-mediated and humoral responses induced by the vaccination was inversely correlated with a reduction in SIV viral load and positively correlated with an increase in CD4(+) T cell counts. These results suggest that vaccination can improve antiviral cell-mediated and humoral immunity, which may contribute to controlling viral replication. C1 [Shimada, M.; Kondo, A.; Yoshida, A.; Shinoda, K.; Ura, T.; Okuda, K.] Yokohama City Univ, Grad Sch Med, Dept Mol Biodef Res, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. [Wang, H. -B; Xu, X. -P; Luo, J. -L; Bai, H.] Hisun Pharmaceut Co, Taizhou, Zhejiang, Peoples R China. [Mizuguchi, H.] Natl Inst Biomed Innovat, Lab Gene Transfer & Regulat, Osaka, Japan. [Klinman, D.] NCI, NIH, Frederick, MD 21701 USA. RP Shimada, M (reprint author), Yokohama City Univ, Grad Sch Med, Dept Mol Biodef Res, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan. EM mshimada@yokohama-cu.ac.jp FU Ministry of Education, Science, Sports and Culture of Japan; Strategic Research Project of Yokohama City University Japan; Research Foundation for Advanced Medical Research Center; Japanese National Institute of Biomedical Innovation [05-1] FX We thank NIH Tetramer Core Facility (Atlanta, GA, USA) for the tetramer; Gilead Sciences Inc. (Foster City, CA, USA) for (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA); Drs Chuan Qin, Hong Gao and Li-San Pan (Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences) for animal care and treatment. This work was partially supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan; a grant for the Strategic Research Project of Yokohama City University, Japan; a grant from the Research Foundation for Advanced Medical Research Center and a grant from the Japanese National Institute of Biomedical Innovation (No. 05-1). NR 46 TC 14 Z9 14 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD FEB PY 2009 VL 16 IS 2 BP 218 EP 228 DI 10.1038/gt.2008.152 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 414VH UT WOS:000263892800007 PM 18923453 ER PT J AU Crusio, WE Goldowitz, D Holmes, A Wolfer, D AF Crusio, W. E. Goldowitz, D. Holmes, A. Wolfer, D. TI Standards for the publication of mouse mutant studies SO GENES BRAIN AND BEHAVIOR LA English DT Article ID C57BL/6J INBRED MICE; NEUROANATOMICAL DIVERGENCE; KNOCKOUT MICE; STRAIN 129; GENE; SUBSTRAINS; BEHAVIOR; NOMENCLATURE; SEROTONIN C1 [Crusio, W. E.] Univ Bordeaux, Ctr Neurosci Integrat & Cognit, CNRS UMR 5228, F-33405 Talence, France. [Goldowitz, D.] Univ British Columbia, Ctr Mol Med & Therapeut, Child & Family Res Inst, Dept Med Genet, Vancouver, BC V5Z 1M9, Canada. [Holmes, A.] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, Rockville, MD 20852 USA. [Wolfer, D.] Univ Zurich, Inst Anat, Zurich, Switzerland. [Wolfer, D.] ETH, Inst Human Movement Sci & Sport, Zurich, Switzerland. RP Crusio, WE (reprint author), Univ Bordeaux, Ctr Neurosci Integrat & Cognit, CNRS UMR 5228, Bat B2,Ave Fac, F-33405 Talence, France. EM wim_crusio@yahoo.com RI Crusio, Wim/A-7070-2008; Wolfer, David/B-3293-2016 OI Crusio, Wim/0000-0001-6638-202X; Wolfer, David/0000-0002-5957-1401 NR 25 TC 59 Z9 59 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD FEB PY 2009 VL 8 IS 1 BP 1 EP 4 DI 10.1111/j.1601-183X.2008.00438.x PG 4 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 400SD UT WOS:000262888000001 PM 18778401 ER PT J AU Enoch, MA Waheed, JF Harris, CR Albaugh, B Goldman, D AF Enoch, M. -A. Waheed, J. F. Harris, C. R. Albaugh, B. Goldman, D. TI COMT Val158Met and cognition: main effects and interaction with educational attainment SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Anxiety; attention; COMT Val158Met; education; long-term memory; resilience; WAIS-R; working memory ID CATECHOL-O-METHYLTRANSFERASE; VAL(158)MET GENOTYPE; PREFRONTAL CORTEX; EXECUTIVE FUNCTION; POLYMORPHISM; GENE; ANXIETY; SCHIZOPHRENIA; ASSOCIATION; PERFORMANCE AB Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. Catechol-O-methyltransferase (COMT) Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient prefrontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the Wechsler Adult Intelligence Scale-Revised (WAIS-R) to 328 community-derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5-18). We found significant genotypic effects on WAIS-R measures of long-term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers' scores improved markedly with increasing yrs ed, whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11-12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps because of emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity. C1 [Enoch, M. -A.; Waheed, J. F.; Harris, C. R.; Goldman, D.] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Albaugh, B.] Ctr Human Behav Studies Inc, Weatherford, OK USA. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism; NIH; Office of Research on Minority Health FX We thank Pei-Hong Shen and Longina Akhtar for technical assistance. This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and in part by the Office of Research on Minority Health. NR 35 TC 24 Z9 25 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD FEB PY 2009 VL 8 IS 1 BP 36 EP 42 DI 10.1111/j.1601-183X.2008.00441.x PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 400SD UT WOS:000262888000005 PM 19076243 ER PT J AU Nyholt, DR Gillespie, NG Merikangas, KR Treloar, SA Martin, NG Montgomery, GW AF Nyholt, Dale R. Gillespie, Nathan G. Merikangas, Kathleen R. Treloar, Susan A. Martin, Nicholas G. Montgomery, Grant W. TI Common Genetic Influences Underlie Comorbidity of Migraine and Endometriosis SO GENETIC EPIDEMIOLOGY LA English DT Article DE heritability; headache; women; hormones; pain; comorbid ID TENSION-TYPE HEADACHE; GENERAL-POPULATION; ORAL-CONTRACEPTIVES; MENSTRUAL MIGRAINE; FAMILIAL RISK; DOUBLE-BLIND; LATENT CLASS; TWIN SAMPLE; LIFE-STYLE; PREVALENCE AB We examined the co-occurrence of migraine and endometriosis within the largest known collection of families containing multiple women with surgically confirmed endometriosis and in an independent sample of 815 monozygotic and 457 dizygotic female twin pairs. Within the endometriosis families, a significantly increased risk of migrainous headache was observed in women with endometriosis compared to women without endometriosis (odds ratio [OR] 1.57, 95% confidence interval [CI]: 1.12-2.21, P = 0.009). Bivariate heritability analyses indicated no evidence for common environmental factors influencing either migraine or endometriosis but significant genetic components for both traits, with heritability estimates of 69 and 49%, respectively. Importantly, a significant additive genetic correlation (r(G) = 0.27, 95% CI: 0.06-0.47) and bivariate heritability (h(2) = 0.17, 95% CI: 0.08-0.27) was observed between migraine and endometriosis. Controlling for the personality trait neuroticism made little impact on this association. These results confirm the previously reported comorbidity between migraine and endometriosis and indicate common genetic influences completely explain their co-occurrence within individuals. Given pharmacological treatments for endometriosis typically target hormonal pathways and a number of findings provide support for a relationship between hormonal variations and migraine, hormone-related genes and pathways are highly plausible candidates for both migraine and endometriosis. Therefore, taking into account the status of both migraine and endometriosis may provide a novel opportunity to identify the genes underlying them. Finally, we propose that the analysis of such genetically correlated comorbid traits can increase power to detect genetic risk loci through the use of more specific, homogenous and heritable phenotypes. Genet. Epidemiol. 33:105-113, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Nyholt, Dale R.] PO Royal Brisbane Hosp, Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4029, Australia. [Gillespie, Nathan G.] VCU, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Merikangas, Kathleen R.] NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Montgomery, Grant W.] Queensland Inst Med Res, Mol Epidemiol Lab, Brisbane, Qld 4006, Australia. RP Nyholt, DR (reprint author), PO Royal Brisbane Hosp, Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4029, Australia. EM daleN@qimr.edu.au RI Nyholt, Dale/C-8384-2013; Gillespie, Nathan/D-6029-2013; Montgomery, Grant/B-7148-2008; OI Montgomery, Grant/0000-0002-4140-8139; Martin, Nicholas/0000-0003-4069-8020 FU NHMRC RD Wright [339462]; NHMRC [4339430]; Mayne Bequest Fund (The University of Queensland, Brisbane, Australia); Australian Gynaecological Endoscopy Society; Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC); Cerylid Biosciences (Melbourne); Neville and Shirley Hawkins; Western Australian Endometriosis Support Association; Endometriosis Association FX We thank Dr Daniel T. O'Connor for assistance with recruitment and confirmation of endometriosis diagnoses, Barbara Haddon for coordinating the endometriosis study recruitment and Clare Redfern for coordinating the collection of migraine data in endometriosis families. DRN is supported by an NHMRC RD Wright Fellowship (#339462). This research was supported in part by NHMRC Project Grant (4339430). The 1993-1994 Gynaecological Health Study was funded by the Mayne Bequest Fund (The University of Queensland, Brisbane, Australia) and the Australian Gynaecological Endoscopy Society. The Australian endometriosis study recruitment was funded by Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), by Cerylid Biosciences (Melbourne), and by donations from Neville and Shirley Hawkins, the Western Australian Endometriosis Support Association and the Endometriosis Association. NR 79 TC 15 Z9 15 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2009 VL 33 IS 2 BP 105 EP 113 DI 10.1002/gepi.20361 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 401UN UT WOS:000262968000002 PM 18636479 ER PT J AU Vermeulen, SH Shi, M Weinberg, CR Umbach, DM AF Vermeulen, Sita H. Shi, Min Weinberg, Clarice R. Umbach, David M. TI A Hybrid Design: Case-Parent Triads Supplemented by Control-Mother Dyads SO GENETIC EPIDEMIOLOGY LA English DT Article DE genetic relative risk; maternal effect; single nucleotide polymorphism (SNP); association studies; family-based design; population-based design; Poisson regression; early-onset disease ID TRANSMISSION DISEQUILIBRIUM TEST; ASSOCIATION; DISEASE; GENES; RISK AB Hybrid designs arose from an effort to combine the benefits of family-based and population-based study designs. A recently proposed hybrid approach augments case-parent triads with population-based control-parent triads, genotyping everyone except the control offspring. Including parents of controls substantially improves statistical efficiency for testing and estimating both offspring and maternal genetic relative risk parameters relative to using case-parent triads alone. Moreover, it allows testing of required assumptions. Nevertheless, control fathers can be hard to recruit, whereas control offspring and their mothers may be readily available. Consequently, we propose an alternative hybrid design where offspring-mother pairs, instead of parents, serve as population-based controls. We compare the power of our proposed method with several competitors and show that it performs well in various scenarios, though it is slightly less powerful than the hybrid design that uses control parents. We describe approaches for checking whether population stratification will bias inferences that use controls and whether the mating-symmetry assumption holds. Surprisingly, if mating symmetry is violated, even though mating-type parameters cannot be directly estimated using control-mother dyads alone, and maternal effects cannot be estimated using case-parent triads alone, combining both sources of data allows estimation of all the parameters. This hybrid design can also be used to study environmental influences on disease risk and gene-by-environment interactions. Genet. Epidemiol. 33:136-144, 2009. Published 2008 Wiley-Liss, Inc. C1 [Shi, Min; Weinberg, Clarice R.; Umbach, David M.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. [Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol, Biostat & HTA, NL-6525 ED Nijmegen, Netherlands. RP Umbach, DM (reprint author), NIEHS, Biostat Branch, Mail Drop A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM umbach@niehs.nih.gov RI Vermeulen, H.H.M./L-4716-2015 FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [NIH Z01-ES040007]; Ter Meulen Fund FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (NIH Z01-ES040007) and by the Ter Meulen Fund. We thank Drs. Abee Boyles and Gregg Dinse for their helpful comments. NR 13 TC 13 Z9 15 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2009 VL 33 IS 2 BP 136 EP 144 DI 10.1002/gepi.20365 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 401UN UT WOS:000262968000005 PM 18759250 ER PT J AU Sidransky, E Pastores, GM Mori, M AF Sidransky, Ellen Pastores, Gregory M. Mori, Motomi TI Dosing enzyme replacement therapy for Gaucher disease: older, but are we wiser? SO GENETICS IN MEDICINE LA English DT Editorial Material C1 [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Pastores, Gregory M.] NYU, Dept Neurol, Sch Med, New York, NY 10016 USA. [Pastores, Gregory M.] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Mori, Motomi] Oregon Hlth & Sci Univ, OHSU Canc Inst, Portland, OR 97201 USA. [Mori, Motomi] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Portland, OR 97201 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room IA213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 0 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD FEB PY 2009 VL 11 IS 2 BP 90 EP 91 DI 10.1097/GIM.0b013e3181928f6a PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 411QB UT WOS:000263663300004 PM 19265747 ER PT J AU Persaud-Sawin, DA Banach, L Harry, GJ AF Persaud-Sawin, Dixie-Ann Banach, Lynna Harry, Gaylla Jean TI Raft Aggregation with Specific Receptor Recruitment Is Required for Microglial Phagocytosis of A beta(42) SO GLIA LA English DT Article DE microglia; phagocytosis; rafts; CD36 ID AMYLOID-BETA-PEPTIDE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TRAUMATIC BRAIN-INJURY; GPI-ANCHORED PROTEINS; RED-BLOOD-CELLS; ALZHEIMERS-DISEASE; LIPID RAFTS; SCAVENGER RECEPTOR; REGGIE/FLOTILLIN PROTEINS; MACROPHAGE PHAGOCYTOSIS AB Microglial phagocytosis contributes to the maintenance of brain homeostasis. Mechanisms involved, however, remain unclear. Using A beta 42 solely as a stimulant, we provide novel insight into regulation of microglial phagocytosis by rafts. We demonstrate the existence of an A beta 42 threshold level of 250 pg/mL, above which microglial phagocytic function is impaired. Low levels of A beta 42 facilitate fluorescent bead uptake, whereas phagocytosis is inhibited when A beta 42 accumulates. We also show that region-specific raft clustering occurs before microglial phagocytosis. Low A beta 42 levels stimulated this type of raft aggregation, but high A beta 42 levels inhibited it. Additionally, treatment with high A beta 42 concentrations caused a redistribution of the raft structural. protein flotillin1 from low to higher density fractions along a sucrose gradient. This suggests a loss of raft structural integrity. Certain non-steroidal anti-inflammatory drugs, e.g., the cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs, celecoxib, raise A beta 42 levels. We demonstrated that prolonged celecoxib exposure can disrupt rafts in a manner similar to that seen in an elevated A beta 42 environment: abnormal raft aggregation and Flot1 distribution. This resulted in aberrant receptor recruitment to rafts and impaired receptor-mediated phagocytosis by microglial cells. Specifically, recruitment of the scavenger receptor CD36 to rafts during active phagocytosis was affected. Thus, we propose that maintaining raft integrity is crucial for determining microglial phagocytic outcomes and disease progression. (C) 2008 Wiley-Liss, Inc. C1 [Persaud-Sawin, Dixie-Ann] NIEHS, Neurobiol Lab, Neurotoxicol Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Persaud-Sawin, DA (reprint author), NIEHS, Neurobiol Lab, Neurotoxicol Grp, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM sawind@niehs.nih.gov FU Division of Intramural Research of NIEHS (NIH) [1Z01ES101623-05]; NTEHS Chemistry Contract [10015-42-05] FX Grant sponsor: Division of Intramural Research of NIEHS (NIH); Grant number: #1Z01ES101623-05; Grant sponsor: NTEHS Chemistry Contract; Grant number: #10015-42-05. NR 100 TC 11 Z9 12 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD FEB PY 2009 VL 57 IS 3 BP 320 EP 335 DI 10.1002/glia.20759 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 392BF UT WOS:000262277200008 PM 18756527 ER PT J AU Hagen, KGT Zhang, LP Tian, E Zhang, Y AF Hagen, Kelly G. Ten Zhang, Liping Tian, E. Zhang, Ying TI Glycobiology on the fly: Developmental and mechanistic insights from Drosophila SO GLYCOBIOLOGY LA English DT Review ID POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; HEPARAN-SULFATE PROTEOGLYCANS; THROMBOSPONDIN TYPE-1 REPEATS; CAENORHABDITIS-ELEGANS; PROTEIN O-FUCOSYL-TRANSFERASE-1; FUNCTIONAL-CHARACTERIZATION; UDP-GALNAC; GLYCOSPHINGOLIPID BIOSYNTHESIS; LIGAND-BINDING; MODIFIES NOTCH AB Drosophila melanogaster offers many unique advantages for deciphering the complexities of glycan biosynthesis and function. The completion of the Drosophila genome sequencing project as well as the comprehensive catalogue of existing mutations and phenotypes have lead to a prolific database where many of the genes involved in glycan synthesis, assembly, modification, and recognition have been identified and characterized. Recent biochemical and molecular studies have elucidated the structure of the glycans present in Drosophila. Powerful genetic approaches have uncovered a number of critical biological roles for glycans during development that impact on our understanding of their function during mammalian development. Here, we summarize key recent findings and provide evidence for the usefulness of this model organism in unraveling the complexities of glycobiology across many species. C1 [Hagen, Kelly G. Ten; Zhang, Liping; Tian, E.] NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD 20892 USA. [Zhang, Ying] Univ Virginia, Old Med Sch, Dept Neurol, Charlottesville, VA 22903 USA. RP Hagen, KGT (reprint author), NIDCR, Dev Glycobiol Unit, NIH, Bldg 30,Room 426,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM Kelly.Tenhagen@nih.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health FX We would like to thank the many members of the community who have contributed to the work mentioned herein. We would like to thank Drs. Lawrence A. Tabak, Jaya Raman, Yu Guan, and Hazuki Miwa for carefully reading this manuscript. This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 91 TC 2 Z9 2 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD FEB PY 2009 VL 19 IS 2 BP 102 EP 111 DI 10.1093/glycob/cwn096 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 388CD UT WOS:000261997000001 ER PT J AU Wentzensen, N Sherman, ME Schiffman, M Wang, SS AF Wentzensen, Nicolas Sherman, Mark E. Schiffman, Mark Wang, Sophia S. TI Utility of methylation markers in cervical cancer early detection: Appraisal of the state-of-the-science SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Cervical cancer; Biomarker; Methylation; HPV; CIN ID HUMAN-PAPILLOMAVIRUS DNA; TUMOR-SUPPRESSOR GENES; PROMOTER HYPERMETHYLATION; ABERRANT METHYLATION; PROTEIN EXPRESSION; HUMAN MALIGNANCIES; P16 METHYLATION; UTERINE CERVIX; CELL-LINES; NEOPLASIA AB Objective. We wanted to identify the most promising methylation marker candidates for cervical cancer early detection. Methods. A systematic literature review was performed in Medline and weighted average frequencies for methylated genes stratified by tissue source and methods used were computed. Results. 51 Studies were identified analyzing 68 different genes for methylation in 4376 specimens across all stages of cervical carcinogenesis. 15 genes, DAPK1, RASSF1, CDH1, CDKN2A, MGMT, RARB, APC, FHIT, MLH1, TIMP3, GSTP1, CADM1, CDH13, HIC1, and TERT have been analyzed in 5 or more studies. The published data on these genes is highly heterogeneous; 7 genes (CDH1, FHIT, TERT, CDH13, MGMT, TIMP3, and HIC1) had a reported range of methylation frequencies in cervical cancers of greater than 60% between studies. Stratification by analysis method did not resolve the heterogeneity. Three markers, DAPK1, CADM1, and RARB, showed elevated methylation in cervical cancers consistently across studies. Conclusions. There is currently no methylation marker that can be readily translated for use in cervical cancer screening or triage settings. Large, well-conducted methylation profiling Studies of cervical carcinogenesis could yield new candidates that are more specific for HPV-related carcinogenesis. New candidate markers need to be thoroughly validated in highly standardized assays. Published by Elsevier Inc. C1 [Wentzensen, Nicolas; Sherman, Mark E.; Schiffman, Mark; Wang, Sophia S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20854 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5012, Rockville, MD 20854 USA. EM wentzenn@mail.nih.gov FU Intramural NIH HHS [Z01 CP010124-12] NR 62 TC 135 Z9 146 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 BP 293 EP 299 DI 10.1016/j.ygyno.2008.10.012 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 404JS UT WOS:000263148400002 PM 19054549 ER PT J AU Bosquet, JG Calcei, J Wei, JS Garcia-Closas, M Sherman, ME Hewitt, S Vockley, J Gerhard, D Teng, D Khan, J Chanock, SJ AF Bosquet, J. Gonzalez Calcei, J. Wei, J. S. Garcia-Closas, M. Sherman, M. E. Hewitt, S. Vockley, J. Gerhard, D. Teng, D. Khan, J. Chanock, S. J. TI Scanning of somatic mutations by high-resolution DNA melting analysis in gynecologic tumors SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Bosquet, J. Gonzalez; Calcei, J.; Chanock, S. J.] Natl Canc Inst, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Wei, J. S.; Khan, J.] Natl Canc Inst, Adv Technol Ctr, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD USA. [Sherman, M. E.] Natl Canc Inst, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Hewitt, S.] Natl Canc Inst, Tissue Array Res Program, Bethesda, MD USA. [Vockley, J.; Gerhard, D.] Natl Canc Inst, Off Canc Genom, Bethesda, MD USA. [Teng, D.] Idaho Technol, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 231 BP S117 EP S118 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200230 ER PT J AU Davidson, B Elstrand, MB Kleinberg, L Kohn, EC Trope, C AF Davidson, B. Elstrand, M. Bunkholt Kleinberg, L. Kohn, E. C. Trope, C. TI Expression and clinical role of antiapoptotic proteins of the bag, heat shock, and Bcl-2 families in effusions, primary tumors and solid metastases in ovarian carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Davidson, B.; Kleinberg, L.] Univ Hosp, Rikshosp, Dept Pathol, Norwegian Radium Hosp, Oslo, Norway. [Elstrand, M. Bunkholt; Trope, C.] Univ Hosp, Rikshosp, Dept Obstet & Gynecol, Norwegian Radium Hosp, Oslo, Norway. [Kohn, E. C.] NCI, Mol Signaling Sect, Med Oncol Branch, Canc Res Ctr,NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 252 BP S129 EP S129 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200251 ER PT J AU Kinney, W Fetterman, B Akhtar, I Husain, M Gold, MA Guido, R Castle, PE AF Kinney, W. Fetterman, B. Akhtar, I. Husain, M. Gold, M. A. Guido, R. Castle, P. E. TI Age-appropriate use of human papillomavirus vaccines in the United States SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Kinney, W.] Kaiser Permanente No Calif, Div Gynecol Oncol, Sacramento, CA USA. [Fetterman, B.] Kaiser Permanente No Calif, Reg Lab, Berkeley, CA USA. [Akhtar, I.] Univ Mississippi, Dept Pathol, Jackson, MS 39216 USA. [Husain, M.] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Gold, M. A.] Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Guido, R.] Magee Womens Hosp, Dept Obstet & Gynecol & Reprod Sci, Pittsburgh, PA USA. [Castle, P. E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 64 BP S34 EP S35 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200065 ER PT J AU Kuo, DY Blank, SV Kim, M Caputo, TA Pothuri, B Hershman, D Goldman, NA Ivy, P Runowicz, CD Muggia, F Goldberg, GL Einstein, MH AF Kuo, D. Y. Blank, S. V. Kim, M. Caputo, T. A. Pothuri, B. Hershman, D. Goldman, N. A. Ivy, P. Runowicz, C. D. Muggia, F. Goldberg, G. L. Einstein, M. H. TI Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: A New York Cancer Consortium study SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Kuo, D. Y.; Goldberg, G. L.; Einstein, M. H.] Albert Einstein Coll Med, Div Gynecol Oncol, Dept Obstet & Gynecol & Womens Hlth, Montefiore Med Ctr, Bronx, NY 10467 USA. [Kuo, D. Y.; Kim, M.; Goldberg, G. L.; Einstein, M. H.] Ctr Canc, Bronx, NY USA. [Blank, S. V.; Pothuri, B.] NYU, Dept Obstet & Gynecol, Div Gynecol Oncol, Sch Med, New York, NY 10016 USA. [Kim, M.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Caputo, T. A.] Cornell Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, New York Presbyterian Weill Med Coll, New York, NY 10021 USA. [Hershman, D.] Columbia Univ, Dept Med, New York Presbyterian Hosp, New York, NY USA. [Goldman, N. A.] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, New York, NY 10003 USA. [Ivy, P.] NCI, CTEP, Invest Drug Branch, Bethesda, MD 20892 USA. [Runowicz, C. D.] Univ Connecticut, Ctr Hlth, Dept Obstet & Gynecol, Carole & Ray Neag Comprehens Canc Ctr, Farmington, CT USA. [Muggia, F.] NYU, Sch Med, Dept Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 27 BP S15 EP S15 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200028 ER PT J AU Lin, YG Merritt, WM Spannuth, WA Nick, AM Stone, RL Tsinberg, P Coleman, RL Birrer, MJ Bischoff, F Sood, AK AF Lin, Y. G. Merritt, W. M. Spannuth, W. A. Nick, A. M. Stone, R. L. Tsinberg, P. Coleman, R. L. Birrer, M. J. Bischoff, F. Sood, A. K. TI Rare circulating tumor cells can be reliably and efficiently detected using a novel microfluidies and micro-electromechanical systems (MEMS)-based rare cell recovery platform: Preclinical and clinical data SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Lin, Y. G.; Merritt, W. M.; Spannuth, W. A.; Nick, A. M.; Stone, R. L.; Coleman, R. L.; Sood, A. K.] Univ Texas MD Anderson Canc Ctr, Div Gynecol Oncol, Dept Obstet & Gynaecol, Houston, TX 77030 USA. [Tsinberg, P.; Bischoff, F.] Biocept Inc, San Diego, CA USA. [Birrer, M. J.] NCI, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 230 BP S117 EP S117 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200229 ER PT J AU Matthews, KS Noker, P Tian, B Grimes, S Fulton, R Schweikart, K Harris, R Aurigemma, R Wang, M Curiel, DT Alvarez, RD AF Matthews, K. S. Noker, P. Tian, B. Grimes, S. Fulton, R. Schweikart, K. Harris, R. Aurigemma, R. Wang, M. Curiel, D. T. Alvarez, R. D. TI Identifying the safety profile of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in anticipation of a phase I clinical trial in patients with recurrent ovarian cancer and other selected gynecologic cancers SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Matthews, K. S.] Univ Alabama, Dept Gynecol Oncol, Birmingham, AL USA. [Noker, P.; Tian, B.; Grimes, S.; Fulton, R.] So Res Inst, Birmingham, AL 35255 USA. [Schweikart, K.] NCI, Toxicol Pharmacol Branch, Bethesda, MD 20892 USA. [Harris, R.] SAIC Frederick, Biopharmaceut Dev Program, Frederick, MD USA. [Aurigemma, R.] NCI, Biol Resources Branch, Bethesda, MD 20892 USA. [Wang, M.; Curiel, D. T.] Univ Alabama, Dept Human Gene Therapy, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 219 BP S111 EP S112 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200218 ER PT J AU Sood, AK Mangala, LS Han, H Lu, C Ali-Fehmi, R Stone, R Munkarah, A Spannuth, W Nick, AM Lee, J Shahzad, M Guven, E Coleman, RL Denkbas, E Birrer, MJ Lopez-Berestein, G AF Sood, A. K. Mangala, L. S. Han, H. Lu, C. Ali-Fehmi, R. Stone, R. Munkarah, A. Spannuth, W. Nick, A. M. Lee, J. Shahzad, M. Guven, E. Coleman, R. L. Denkbas, E. Birrer, M. J. Lopez-Berestein, G. TI In vivo angiogenic gene silencing using chitosan nanoparticles in ovarian carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Sood, A. K.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Sood, A. K.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Ali-Fehmi, R.] Wayne State Univ, Dept Pathol, Sch Med, Detroit, MI 48202 USA. [Munkarah, A.] Wayne State Univ, Sch Med, Dept Gynecol Oncol, Detroit, MI USA. [Guven, E.] Hacettepe Univ, Dept Nanotechnol & Nanomed, Ankara, Turkey. [Birrer, M. J.] NCI, Dept Cell & Canc Biol, Bethesda, MD 20892 USA. [Lopez-Berestein, G.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 268 BP S136 EP S137 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200267 ER PT J AU Stone, RL Nick, AM Spannuth, WA Bonome, T Lutgendorf, S DeGeest, K Merritt, W Lin, YG Gershenson, DM Coleman, RL Birrer, MJ Sood, AK AF Stone, R. L. Nick, A. M. Spannuth, W. A. Bonome, T. Lutgendorf, S. DeGeest, K. Merritt, W. Lin, Y. G. Gershenson, D. M. Coleman, R. L. Birrer, M. J. Sood, A. K. TI Focal adhesion kinase is a new focus for antiangiogenesis therapy in ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Stone, R. L.; Nick, A. M.; Spannuth, W. A.; Merritt, W.; Lin, Y. G.; Gershenson, D. M.; Coleman, R. L.; Sood, A. K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Bonome, T.; Birrer, M. J.] NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Lutgendorf, S.; DeGeest, K.] Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA 52242 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 55 BP S30 EP S31 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200056 ER PT J AU Tanner, E Olshen, AB Bonome, T Shih, KK Dao, F Bogomolniy, F Chi, DS Birrer, MJ Boyd, J Levine, DA AF Tanner, E. Olshen, A. B. Bonome, T. Shih, K. K. Dao, F. Bogomolniy, F. Chi, D. S. Birrer, M. J. Boyd, J. Levine, D. A. TI Gene expression profiling of advanced ovarian cancers to predict the need for maximal surgical effort SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Tanner, E.; Olshen, A. B.; Shih, K. K.; Dao, F.; Bogomolniy, F.; Chi, D. S.; Levine, D. A.] Mem Sloan Kettering Canc Ctr, Dept Gynecol Surg, New York, NY 10021 USA. [Bonome, T.; Birrer, M. J.] NCI, Rockville, MD USA. [Boyd, J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2009 VL 112 IS 2 MA 257 BP S131 EP S132 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 419OY UT WOS:000264230200256 ER PT J AU Ron, E AF Ron, Elaine TI OVERESTIMATION OF THYROID CANCER INCIDENCE AFTER CHERNOBYL Reply SO HEALTH PHYSICS LA English DT Letter ID ACCIDENT; DISEASES; COHORT; RISK C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Ron, E (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM eron@mail.nih.gov NR 4 TC 2 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2009 VL 96 IS 2 BP 186 EP 187 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 396LH UT WOS:000262592700010 ER PT J AU Nahavandi, M Nichols, JP Hassan, M Gandjbakhche, A Kato, GJ AF Nahavandi, M. Nichols, J. P. Hassan, M. Gandjbakhche, A. Kato, G. J. TI Near-infrared spectra absorbance of blood from sickle cell patients and normal individuals SO HEMATOLOGY LA English DT Article DE Near-infrared spectroscopy; sickle cell disease; hemoglobin; cerebral oxygen saturation ID CEREBRAL OXIMETRY; BRAIN OXYGENATION; DISEASE; TRANSPLANTATION AB Limited data are available regarding the physicochemical dynamics of tissue hypoxia in sickle cell disease. Studies using near-infrared spectroscopy (NIRS) have reported that patients with sickle cell disease (SCD) have lower cerebral oxygen saturation values (rSO(2)) than normal individuals. The reason SCD patients have subnormal rSO(2) values is not known. It may be related to the degree of anaemia, sickle haemoglobin, disease complications and the possibility of SCD different NIRS absorbance spectra than normal. This study compared NIRS absorbance spectra of blood with adult haemoglobin AA, sickle haemoglobin SS, and AS. Venous blood was collected from SCD (SS and AS) and non-SCD patients (AA). Whole blood, cell free haemoglobin samples were scanned through the wavelength range of 600-1000 nm. The results showed no different NIRS spectra absorbance between the haemoglobin's AA, SS. It thus appears that lower brain oxygen saturation in sickle cell anaemia patients is related to impaired oxygen carrying capacity or delivery by sickle haemoglobin. C1 [Nahavandi, M.] NHLBI, Pulm & Vasc Med Branch, NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Hassan, M.; Gandjbakhche, A.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Nahavandi, M (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. EM nahavandim@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU National Heart, Lung and Blood Institute; National Institute of Child Health and Human Development; Clinical Center at the National Institute of Health, Bethesda, MD, USA FX This research was supported by intramural funding from the National Heart, Lung and Blood Institute, National Institute of Child Health and Human Development, and the Clinical Center at the National Institute of Health, Bethesda, MD, USA. NR 12 TC 10 Z9 10 U1 1 U2 5 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1024-5332 J9 HEMATOLOGY JI Hematology PD FEB PY 2009 VL 14 IS 1 BP 46 EP 48 DI 10.1179/102453309X385133 PG 3 WC Hematology SC Hematology GA 473AE UT WOS:000268174500007 PM 19154664 ER PT J AU Gottwein, JM Scheel, TKH Jensen, TB Lademann, JB Prentoe, JC Knudsen, ML Hoegh, AM Bukh, J AF Gottwein, Judith M. Scheel, Troels K. H. Jensen, Tanja B. Lademann, Jacob B. Prentoe, Jannick C. Knudsen, Maria L. Hoegh, Anne M. Bukh, Jens TI Development and Characterization of Hepatitis C Virus Genotype 1-7 Cell Culture Systems: Role of CD81 and Scavenger Receptor Class B Type I and Effect of Antiviral Drugs SO HEPATOLOGY LA English DT Article ID CORE PROTEIN; INFECTIOUS VIRUS; MAJOR GENOTYPES; STEATOSIS; NEUTRALIZATION; CHOLESTEROL; AMANTADINE; MUTATIONS; ASSAY; 5A AB Six major hepatitis C virus (HCV) genotypes and numerous subtypes have been described and recently a seventh major genotype was discovered. Genotypes show significant molecular and clinical differences, such as differential response to combination therapy with interferon-a and ribavirin. Recently, HCV research has been accelerated by cell culture systems based on the unique growth capacity of strain JFH1 (genotype 2a). By development of JFH1-based intergenotypic recombinants containing Core, envelope protein 1 and 2 (El, E2), p7, and nonstructural protein 2 (NS2) of genotype 6a and 7a strains, as well as subtype 1b and 2b strains, we have completed a panel of culture systems for all major HCV genotypes. Efficient growth in Huh7.5 cells depended on adaptive mutations for HK6a/JFH1 (6a/2a, in E1 and E2) and J4/JFH1 (1b/2a, in NS2 and NS3); viability of J8/JFH1 (2b/2a) and QC69/JFH1 (7a/2a) did not require adaptation. To facilitate comparative studies, we generated virus stocks of genotype 1-7 recombinants with infectivity titers of 10(3.7) to 10(5.2) 50% tissue culture infectious dose/mL and HCV RNA titers of 10(7.0) to 10(7.9) IU/mL. Huh7.5 cultures infected with genotype 1-6 viruses had similar spread kinetics, intracellular Core, NS5A, and lipid amounts, and colocalization of Core and NS5A with lipids. Treatment with interferon-alpha 2b but not ribavirin or amantadine showed a significant antiviral effect. Infection with all genotypes could be blocked by specific antibodies against the putative coreceptors CD81 and scavenger receptor class B type I in a dose-dependent manner. Finally, neutralizing antibodies in selected chronic phase HCV sera had differential effects against genotype 1-7 viruses. Conclusion: We completed and characterized a panel of JTH1-based cell culture systems of all seven major HCV genotypes and important subtypes and used these viruses in comparative studies of antivirals, HCV receptor interaction, and neutralizing antibodies. (HEPATOLOGY 2009;49:364-377.) C1 [Gottwein, Judith M.; Scheel, Troels K. H.; Jensen, Tanja B.; Lademann, Jacob B.; Prentoe, Jannick C.; Knudsen, Maria L.; Bukh, Jens] Copenhagen Univ Hosp, Copenhagen Hepatitis C Program, Dept Infect Dis, DK-2650 Hvidovre, Denmark. [Gottwein, Judith M.; Scheel, Troels K. H.; Jensen, Tanja B.; Lademann, Jacob B.; Prentoe, Jannick C.; Knudsen, Maria L.; Bukh, Jens] Copenhagen Univ Hosp, Copenhagen Hepatitis C Program, Clin Res Ctr, DK-2650 Hvidovre, Denmark. [Gottwein, Judith M.; Scheel, Troels K. H.; Jensen, Tanja B.; Lademann, Jacob B.; Prentoe, Jannick C.; Knudsen, Maria L.; Bukh, Jens] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Fac Hlth Sci, DK-1168 Copenhagen, Denmark. [Hoegh, Anne M.] Copenhagen Univ Hosp, Dept Clin Microbiol, Hvidovre, Denmark. [Bukh, Jens] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), Copenhagen Univ Hosp, Copenhagen Hepatitis C Program, Dept Infect Dis, Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. EM jbukh@niaid.nih.gov OI Prentoe, Jannick/0000-0003-2203-9478; Scheel, Troels/0000-0003-1545-4067 FU Copenhagen University Hospital, Hvidovre; Novo Nordisk Foundation; Lundbeck Foundation; Danish Medical Research Council; Danish Cancer Society FX This study was supported by Copenhagen University Hospital, Hvidovre (support to J. M. G., T K. H. S., T B.J., J B. L., and J. B.); Novo Nordisk Foundation (support to J G. and J. B.); Lundbeck Foundation (support to J.B.); The Danish Medical Research Council (support to J. B.); and The Danish Cancer Society (support to J B.). NR 25 TC 215 Z9 223 U1 0 U2 13 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2009 VL 49 IS 2 BP 364 EP 377 DI 10.1002/hep.22673 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 401EW UT WOS:000262923300008 PM 19148942 ER PT J AU Zhu, F Park, EM Liu, BG Xia, XJ Fischer, SM Hu, YL AF Zhu, Feng Park, Eunmi Liu, Bigang Xia, Xiaojun Fischer, Susan M. Hu, Yinling TI Critical role of I kappa B kinase alpha in embryonic skin development and skin carcinogenesis SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE I kappa B kinase alpha (IKK alpha); Embryonic skin development; Skin carcinogenesis; Nuclear factor-kappaB (NF-kappa B) ID SQUAMOUS-CELL CARCINOMAS; H3 LYSINE-9 METHYLATION; HELIX-LOOP-HELIX; IKK-ALPHA; HISTONE H3; DNA METHYLATION; MICE LACKING; EPIGENETIC INACTIVATION; TUMOR PROGRESSION; ACTIVATION AB I kappa B kinase alpha (IKK alpha), IKK beta, and IKK gamma/NEMO form the IKK complex, which is essential for NF-kappa B activation. However, genetic studies have shown that the role of IKK alpha is distinct from that of IKK alpha or IKK gamma in the development of the mouse embryonic skin. Loss of IKK alpha has been shown to cause epidermal hyperplasia, prevent keratinocyte terminal differentiation, and impair the formation of the skin, resulting in the deaths of IKK alpha-deficient (Ikk alpha(-/-)) mice soon after birth. Recent experimental data from several laboratories have revealed that IKK alpha functions as a tumor suppressor in human squamous cell carcinomas (SCCs) of skin, lungs, and head and neck. Chemical carcinogenesis studies using mice have shown that reduction in IKK alpha expression increases the number and size of Ras-initiated skin tumors and promotes their progression, indicating that reduced IKK alpha expression provides a selective growth advantage that cooperates with Ras activity to promote skin carcinogenesis. In this review, we will summarize these findings from our and other studies on the role that IKK alpha plays in development of the mouse embryonic skin and skin carcinogenesis. C1 [Hu, Yinling] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. [Zhu, Feng; Park, Eunmi; Liu, Bigang; Xia, Xiaojun; Fischer, Susan M.; Hu, Yinling] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA. RP Hu, YL (reprint author), NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. EM huy2@mail.nih.gov FU National Cancer Institute grants [CA102510, CA117314, CA105345, CA16672]; National Institute of Environmental Health Sciences Center [ES07784] FX The studies reviewed in this article were supported by National Cancer Institute grants CA102510 and CA117314 (to Y.H.), CA105345 (to S.M.F.), and CA16672 (M. D. Anderson Cancer Center Core Grant), and by the National Institute of Environmental Health Sciences Center Grant ES07784. NR 51 TC 16 Z9 16 U1 0 U2 1 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD FEB PY 2009 VL 24 IS 2 BP 265 EP 271 PG 7 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 383TR UT WOS:000261696900013 PM 19085841 ER PT J AU Valcour, V Yeh, TM Bartt, R Clifford, D Gerschenson, M Evans, SR Cohen, BA Ebenezer, GJ Hauer, P Millar, L Gould, M Tran, P Shikuma, C Souza, S McArthur, JC AF Valcour, V. Yeh, T-M Bartt, R. Clifford, D. Gerschenson, M. Evans, S. R. Cohen, B. A. Ebenezer, G. J. Hauer, P. Millar, L. Gould, M. Tran, P. Shikuma, C. Souza, S. McArthur, J. C. CA AIDS Clinical Trials Grp ACTG 5157 Protocol Team TI Acetyl-L-carnitine and nucleoside reverse transcriptase inhibitor-associated neuropathy in HIV infection SO HIV MEDICINE LA English DT Article DE fat; HIV; mitochondria; neuropathy ID ANTIRETROVIRAL TOXIC NEUROPATHY; BLOOD MONONUCLEAR-CELLS; PERIPHERAL NEUROPATHY; RISK-FACTORS; MITOCHONDRIAL TOXICITY; NATURAL-HISTORY; MANAGEMENT; ANALOGS; AIDS; DNA AB Objectives Antiretroviral toxic neuropathy (ATN) is associated with dideoxynucleoside reverse transcriptase inhibitor use in patients infected with HIV, possibly as a result of mitochondrial toxicity. Acetyl-L-carnitine (ALC) has been linked to symptomatic improvement in ATN. We present an open-label single-arm pilot study to evaluate changes in intra-epidermal nerve fibre (IENF) density and mitochondrial DNA ( mtDNA) copies/cell among subjects treated with 3000 mg ALC daily. Methods Punch skin biopsies were examined at baseline and after 24 weeks of therapy. Participants reported neuropathic symptoms using the Gracely Pain Intensity Score. Neurological examinations were completed. Results Twenty-one subjects completed the study. ALC was generally well tolerated. The IENF density did not change in cases completing 24 weeks of ALC therapy, with median (90% confidence interval) IENF changes of - 1.70 (- 3.50, infinity) (P=0.98) and 2.15 (- 0.10, infinity) (P=0.11) for the distal leg and proximal thigh, respectively. Fat mtDNA copies/cell did not change with therapy. Improvements in neuropathic pain (P < 0.01), paresthesias ( P=0.01), and symptoms of numbness ( P < 0.01) were noted. Similarly, improvement was noted on the Gracely Pain Intensity Score. Conclusions ALC therapy coincided with improvements in subjective measures of pain in this open-label single-arm study. However, changes were not observed in objective measures of IENF density or mtDNA levels, providing little objective support for use of ALC in this setting. C1 [Valcour, V.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Valcour, V.; Gerschenson, M.; Shikuma, C.; Souza, S.] Univ Hawaii, John A Burns Sch Med, Hawaii AIDS Clin Res Program, Honolulu, HI 96822 USA. [Yeh, T-M; Evans, S. R.] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Bartt, R.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Bartt, R.] Cook Cty Hosp, Chicago, IL 60612 USA. [Clifford, D.; Gould, M.] Washington Univ, Sch Med, St Louis, MO USA. [Cohen, B. A.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Ebenezer, G. J.; Hauer, P.; McArthur, J. C.] Johns Hopkins Univ, Baltimore, MD USA. [Millar, L.] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Tran, P.] NIAID, Pharmaceut Affairs Branch, Div Aids, NIH, Bethesda, MD 20892 USA. RP Valcour, V (reprint author), Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, 350 Parnassus Ave,Suite 706, San Francisco, CA 94143 USA. EM Vvalcour@hawaii.edu FU NCRR NIH HHS [RR025005]; NIAID NIH HHS [3U01AI046376-05S4, AI 069471, AI069434, AI069465, AI069471, AI069495, AI069556-02, AI25915-(15-20), AI34853, AI38855, AI38858, AI46370, AI68634, AI68636, U01 AI034853, U01 AI038855, U01 AI038858, U01 AI068634, U01 AI068636, U01 AI069471, U01 AI069495, U01 AI069495-03, UM1 AI068634, UM1 AI068636, UM1 AI069471, UM1 AI069495]; NIMH NIH HHS [MH075673]; NIMHD NIH HHS [MD000173, P20 MD000173]; NINDS NIH HHS [NS0322228, NS032228-10, NS32228, NS44807, R01 NS032228, U01 NS032228, U01 NS032228-12]; PHS HHS [5 U01 A1069415-02] NR 29 TC 15 Z9 15 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-2662 J9 HIV MED JI HIV Med. PD FEB PY 2009 VL 10 IS 2 BP 103 EP 110 DI 10.1111/j.1468-1293.2008.00658.x PG 8 WC Infectious Diseases SC Infectious Diseases GA 397DB UT WOS:000262641200006 PM 19200173 ER PT J AU Keil, A Sabatinelli, D Ding, MZ Lang, PJ Ihssen, N Heim, S AF Keil, Andreas Sabatinelli, Dean Ding, Mingzhou Lang, Peter J. Ihssen, Niklas Heim, Sabine TI Re-entrant Projections Modulate Visual Cortex in Affective Perception: Evidence From Granger Causality Analysis SO HUMAN BRAIN MAPPING LA English DT Article DE affective arousal; electroencephalography; emotion; Granger causality; steady-state potentials ID MOTIVATED ATTENTION; BRAIN POTENTIALS; CORTICAL AREAS; FEAR; ACTIVATION; MECHANISMS; EEG; CONNECTIONS; RESPONSES; NETWORKS AB Re-entrant modulation of visual cortex has been suggested as a critical process for enhancing perception of emotionally arousing visual stimuli. This study explores how the time information inherent in large-scale electrocortical measures can be used to examine the functional relationships among the structures involved in emotional perception. Granger causality analysis was conducted on steady-state visual evoked potentials elicited by emotionally arousing pictures flickering at a rate of 10 Hz. This procedure allows one to examine the direction of neural connections. Participants viewed pictures that varied in emotional content, depicting people in neutral contexts, erotica, or interpersonal attack scenes. Results demonstrated increased Coupling between visual and cortical areas when viewing emotionally arousing content. Specifically, intraparietal to inferotemporal and precuneus to calcarine connections were stronger for emotionally arousing picture content. Thus, we provide evidence for re-entrant signal flow during emotional perception, which originates from higher tiers and enters lower tiers of visual cortex. Hum Brain Mapp 30:532-540, 2009. (C) 2007 Wiley-Liss, Inc. C1 [Keil, Andreas; Sabatinelli, Dean; Lang, Peter J.] Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32611 USA. [Ding, Mingzhou] Univ Florida, Dept Biomed Engn, Gainesville, FL 32611 USA. [Ihssen, Niklas; Heim, Sabine] Univ Konstanz, Dept Psychol, Constance, Germany. RP Keil, A (reprint author), Univ Florida, Dept Psychol, POB 112766, Gainesville, FL 32611 USA. EM akeil@ufl.edu RI Ihssen, Niklas/B-6324-2012; Keil, Andreas/F-9427-2011; OI Ihssen, Niklas/0000-0001-8386-1524; Keil, Andreas/0000-0002-4064-1924; sabatinelli, dean/0000-0001-7409-8504 FU Deutsche Forschungsgemeinschaft; National Institute of Mental Health (NIMH); Center for the Study of Emotion and Attention (CSEA); University of Florida [P50-MH52384] FX Deutsche Forschungsgemeinschaft; Contract grant sponsor: National Institute of Mental Health (NIMH) (Behavioral Science grant to the Center for the Study of Emotion and Attention (CSEA), University of Florida); Contract grant number: P50-MH52384. NR 51 TC 69 Z9 69 U1 2 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD FEB PY 2009 VL 30 IS 2 BP 532 EP 540 DI 10.1002/hbm.20521 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 405NZ UT WOS:000263232800016 PM 18095279 ER PT J AU Portier, C AF Portier, C. TI Toxicological decision-making on hazards and risks - status quo and way forward SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article; Proceedings Paper CT 1st International Forum Towards Evidence-Based Toxicology CY OCT 15-15, 2007 CL Como, ITALY C1 Natl Inst Environm Hlth Sci, Off Risk Assessment Res, Res Triangle Pk, NC 27709 USA. RP Portier, C (reprint author), Natl Inst Environm Hlth Sci, Off Risk Assessment Res, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 3 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0960-3271 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD FEB-MAR PY 2009 VL 28 IS 2-3 BP 123 EP 125 DI 10.1177/0960327109105768 PG 3 WC Toxicology SC Toxicology GA 489IM UT WOS:000269413700013 PM 19713376 ER PT J AU Cullinane, AR Straatman-Iwanowska, A Seo, JK Ko, JS Song, KS Gizewska, M Gruszfeld, D Gliwicz, D Tuysuz, B Erdemir, G Sougrat, R Wakabayashi, Y Hinds, R Barnicoat, A Mandel, H Chitayat, D Fischler, B Garcia-Cazorla, A Knisely, AS Kelly, DA Maher, ER Gissen, P AF Cullinane, Andrew R. Straatman-Iwanowska, Anna Seo, Jeong K. Ko, Jae S. Song, Kyung S. Gizewska, Maria Gruszfeld, Dariusz Gliwicz, Dorota Tuysuz, Beyhan Erdemir, Gulin Sougrat, Rachid Wakabayashi, Yoshiyuki Hinds, Rupert Barnicoat, Angela Mandel, Hanna Chitayat, David Fischler, Bjorn Garcia-Cazorla, Angels Knisely, A. S. Kelly, Deirdre A. Maher, Eamonn R. Gissen, Paul TI Molecular Investigations to Improve Diagnostic Accuracy in Patients With ARC Syndrome SO HUMAN MUTATION LA English DT Article DE arthrogryposis; renal tubular dysfunction; neonatal cholestasis; ARC; vesicular trafficking defect ID RENAL DYSFUNCTION; ARTHROGRYPOSIS; CHOLESTASIS; VPS33B; MUTATION AB Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a >50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in similar to 25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC. (C) 2008 Wiley-Liss, Inc. C1 [Gissen, Paul] Univ Birmingham, Sch Med, Inst Biomed Res W, Dept Med & Mol Genet, Birmingham B15 2TT, W Midlands, England. [Seo, Jeong K.; Ko, Jae S.] Seoul Natl Univ, Coll Med, Dept Pediat, Seoul, South Korea. [Song, Kyung S.] YongDong Severance Hosp, Dept Lab Med, Seoul, South Korea. [Gizewska, Maria] Pomeranian Med Univ, Dept Paediat 2, Szczecin, Poland. [Gruszfeld, Dariusz] Childrens Mem Hlth Inst Warsaw, Dept Neonatol, Warsaw, Poland. [Gliwicz, Dorota] Childrens Mem Hlth Inst, Dept Gastroenterol Hepatol & Immunol, Warsaw, Poland. [Tuysuz, Beyhan] Istanbul Univ, Dept Pediat Genet, Cerrahpasa Med Fac, Istanbul, Turkey. [Erdemir, Gulin] Uludag Univ, Fac Med, Dept Pediat Gastroenterol Hepatol & Nutr, Gorukle, Bursa, Turkey. [Sougrat, Rachid; Wakabayashi, Yoshiyuki] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD USA. [Hinds, Rupert; Knisely, A. S.] Kings Coll Hosp, Inst Liver Studies, London, England. [Barnicoat, Angela] Great Ormond St Hosp Sick Children, Dept Genet, London WC1N 3JH, England. [Mandel, Hanna] Technion Israel Inst Technol, Rambam Med Ctr, Fac Med, Meyer Childrens Hosp,Metab Unit, Haifa, Israel. [Chitayat, David] Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON M5S 1A1, Canada. [Fischler, Bjorn] Karolinska Univ Hosp, Childrens Hosp, Huddinge, Sweden. [Garcia-Cazorla, Angels] Inst Salud Carlos III, Ctr Biomed Res & Rare Dis CIBER ER, Madrid, Spain. [Garcia-Cazorla, Angels] Hosp St Joan de Deu, Barcelona, Spain. [Kelly, Deirdre A.] Birmingham Childrens Hosp, Liver Unit, Birmingham, W Midlands, England. [Maher, Eamonn R.] Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Gissen, Paul] Birmingham Childrens Hosp, Metab Unit, Birmingham, W Midlands, England. RP Gissen, P (reprint author), Univ Birmingham, Sch Med, Inst Biomed Res W, Dept Med & Mol Genet, Wolfson Dr, Birmingham B15 2TT, W Midlands, England. EM p.gissen@bham.ac.uk RI Gissen, Paul/A-4352-2010; Seo, Jeong Kee/J-5512-2012; Gizewska, Maria/B-3020-2015; OI Gissen, Paul/0000-0002-9712-6122; Sougrat, Rachid/0000-0001-6476-1886 FU Children's Liver Disease Foundation (CLDF); ARC syndrome association; Children Living with Inherited Metabolic Diseases (CLIMB); Intramural Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Birmingham Children's Hospital Research Foundation (BCHRF) FX PG is a GSK Clinician Scientist. Authors thank all the families and clinicians who contributed to this research. Authors also wish to thank Children's Liver Disease Foundation (CLDF), ARC syndrome association, Children Living with Inherited Metabolic Diseases (CLIMB), the Intramural Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health and Birmingham Children's Hospital Research Foundation (BCHRF) for their generous support. NR 10 TC 11 Z9 13 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD FEB PY 2009 VL 30 IS 2 BP E330 EP E337 DI 10.1002/humu.20900 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 626PQ UT WOS:000279979200003 PM 18853461 ER PT J AU Zhu, JL Basso, O Obel, C Bech, BH Nohr, EA Shrestha, A Olsen, J AF Zhu, Jin Liang Basso, Olga Obel, Carsten Bech, Bodil Hammer Nohr, Ellen Aagaard Shrestha, Anshu Olsen, Jorn TI Parental infertility and sexual maturation in children SO HUMAN REPRODUCTION LA English DT Article ID ASSISTED REPRODUCTIVE TECHNOLOGY; SECULAR TREND; SEMEN QUALITY; DENMARK; HEALTH; AGE; HYPOSPADIAS; MENARCHE; PUBERTY; BOYS AB The reproductive health of children born of infertile couples may be affected by infertility treatment or factors associated with infertility. We examined sexual maturation in children of parents with infertility. We used data from a follow-up of 3382 girls and 2810 boys born between 1984 and 1987 in the Aalborg-Odense Birth Cohort. We had mothers' report of time to pregnancy (TTP) and infertility treatment (at the time, mostly hormonal) from the pregnancy questionnaire administered in 1984-1987, and the children's report of their own sexual maturation from the follow-up questionnaire administered in 2005, when they were between 18 and 21 years old. Many reported age only in year when they had the events related to sexual maturation, and for each event, we imputed the month based on the median month at each year of age among those reporting both years and months. In girls, the mean age at menarche was 13.3 years and, in boys, the mean age at appearance of acne, voice break, regular shaving and first nocturnal emission were 14.5, 14.5, 17.2 and 14.7 years, respectively. We saw no significant differences in age at these events among children born of either fertile (with TTP of 0-12 months and no treatment), untreated infertile (with TTP of more than 12 months and no treatment) or treated infertile couples (with a history of examination or treatment for infertility). Our data suggest no significant association between parental infertility or hormonal treatment and timing of sexual maturation in the offspring. C1 [Zhu, Jin Liang; Obel, Carsten; Bech, Bodil Hammer; Nohr, Ellen Aagaard; Olsen, Jorn] Univ Aarhus, Inst Publ Hlth, Dept Epidemiol, Danish Epidemiol Sci Ctr, DK-8000 Aarhus C, Denmark. [Basso, Olga] NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. [Obel, Carsten] Aarhus Univ Hosp, Dept Obstet & Gynaecol, Perinatal Epidemiol Res Unit, DK-8200 Aarhus N, Denmark. [Shrestha, Anshu; Olsen, Jorn] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. RP Zhu, JL (reprint author), Univ Aarhus, Inst Publ Hlth, Dept Epidemiol, Danish Epidemiol Sci Ctr, Vennelyst Blvd 6, DK-8000 Aarhus C, Denmark. EM zjl@soci.au.dk RI Basso, Olga/E-5384-2010; Olsen, Jorn/F-8801-2015; Bech, Bodil Hammer/B-9646-2016 OI Basso, Olga/0000-0001-9298-4921; Olsen, Jorn/0000-0001-7462-5140; FU Danish Medical Research Council [271-05-0115]; NIH; National Institute of Environmental Health Sciences [Z01 ES044003] FX This work was supported by a grant from the Danish Medical Research Council (271-05-0115) and, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044003). NR 24 TC 2 Z9 4 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2009 VL 24 IS 2 BP 445 EP 450 DI 10.1093/humrep/den366 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 395JD UT WOS:000262519500025 PM 18840889 ER PT J AU Louis, GMB Dmochowski, J Lynch, C Kostyniak, P McGuinness, BM Vena, JE AF Louis, G. M. Buck Dmochowski, J. Lynch, C. Kostyniak, P. McGuinness, B. M. Vena, J. E. TI Polychlorinated biphenyl serum concentrations, lifestyle and time-to-pregnancy SO HUMAN REPRODUCTION LA English DT Article ID MENSTRUAL-CYCLE; FERTILE WINDOW; ALCOHOL INTAKE; ANGLER COHORT; WAITING TIME; FECUNDABILITY; CONSUMPTION; EXPOSURE; INFERTILITY; FECUNDITY AB Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied. Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings-025EFestrogenic, anti-estrogenic and other-025EFand entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs). Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI < 0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00). These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health. C1 [Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Rockville, MD 20852 USA. [Dmochowski, J.] Univ N Carolina, Dept Math & Stat, Charlotte, NC 28223 USA. [Lynch, C.] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Kostyniak, P.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Toxicol, Buffalo, NY 14214 USA. [McGuinness, B. M.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. [Vena, J. E.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29201 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, 6100 Execut Blvd,Rm 7B03, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU Great Lakes Protection Fund [RM791-3021]; Agency for Toxic Substances and Disease Registry [H751 ATH 298338]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported in part with funding from the Great Lakes Protection Fund (RM791-3021), the Agency for Toxic Substances and Disease Registry (H751 ATH 298338) and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 39 TC 37 Z9 37 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2009 VL 24 IS 2 BP 451 EP 458 DI 10.1093/humrep/den373 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 395JD UT WOS:000262519500026 ER PT J AU Tang, JS Rangayyan, R Yao, JH Yang, YY AF Tang, Jinshan Rangayyan, Raj Yao, Jianhua Yang, Yongyi TI Introduction to the Issue on Digital Image Processing Techniques for Oncology SO IEEE JOURNAL OF SELECTED TOPICS IN SIGNAL PROCESSING LA English DT Editorial Material C1 [Tang, Jinshan] Alcorn State Univ, Dept Adv Technol, Lorman, MS 39096 USA. [Rangayyan, Raj] Univ Calgary, Dept Elect & Comp Engn, Schulich Sch Engn, Calgary, AB T2N 1N4, Canada. [Yao, Jianhua] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Yang, Yongyi] IIT, Dept Elect & Comp Engn, Chicago, IL 60616 USA. RP Tang, JS (reprint author), Alcorn State Univ, Dept Adv Technol, Lorman, MS 39096 USA. EM jtang@alcorn.edu; ranga@enel.ucalgary.ca; JYao@cc.nih.gov; yy@ece.iit.edu NR 0 TC 3 Z9 3 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1932-4553 J9 IEEE J-STSP JI IEEE J. Sel. Top. Signal Process. PD FEB PY 2009 VL 3 IS 1 BP 1 EP 3 DI 10.1109/JSTSP.2009.2013533 PG 3 WC Engineering, Electrical & Electronic SC Engineering GA 437OC UT WOS:000265495800001 ER PT J AU Yao, JH Chen, J Chow, C AF Yao, Jianhua Chen, Jeremy Chow, Catherine TI Breast Tumor Analysis in Dynamic Contrast Enhanced MRI Using Texture Features and Wavelet Transform SO IEEE JOURNAL OF SELECTED TOPICS IN SIGNAL PROCESSING LA English DT Article DE Breast cancer; dynamic contrast enhanced MRI; texture analysis; wavelet transform ID PARAMETERS AB Dynamic contrast enhanced MRI (DCE-MRI) is an emerging imaging protocol in locating, identifying and characterizing breast cancer. However, due to image artifacts in MR, pixel intensity alone cannot accurately characterize the tissue properties. We propose a robust method based on the temporal sequence of textural change and wavelet transform for pixel-by-pixel classification. We first segment the breast region using an active contour model. We then compute textural change on pixel blocks. We apply a three-scale discrete wavelet transform on the texture temporal sequence to further extract frequency features. We employ a progressive feature selection scheme and a committee of support vector machines for the classification. We trained the system on ten cases and tested it on eight independent test cases. Receiver-operating characteristics (ROC) analysis shows that the texture temporal sequence (Az: 0.966 and 0.949 in training and test) is much more effective than the intensity sequence (Az: 0.871 and 0.868 in training and test). The wavelet transform further improves the classification performance (Az: 0.989 and 0.984 in training and test). C1 [Yao, Jianhua; Chen, Jeremy; Chow, Catherine] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM jyao@cc.nih.gov FU National Institutes of Health, Clinical Center FX This work was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center. The Guest Editor coordinating the review of this manuscript and approving it for publication was Dr. Jinshan Tang. NR 28 TC 13 Z9 13 U1 0 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1932-4553 J9 IEEE J-STSP JI IEEE J. Sel. Top. Signal Process. PD FEB PY 2009 VL 3 IS 1 BP 94 EP 100 DI 10.1109/JSTSP.2008.2011110 PG 7 WC Engineering, Electrical & Electronic SC Engineering GA 437OC UT WOS:000265495800011 ER PT J AU Shamir, L Ling, SM Scott, WW Bos, A Orlov, N Macura, TJ Eckley, DM Ferrucci, L Goldberg, IG AF Shamir, Lior Ling, Shari M. Scott, William W., Jr. Bos, Angelo Orlov, Nikita Macura, Tomasz J. Eckley, D. Mark Ferrucci, Luigi Goldberg, Ilya G. TI Knee X-Ray Image Analysis Method for Automated Detection of Osteoarthritis SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Automated detection; image classification; Kellgren-Lawrence (KL) classification; osteoarthritis (OA); X-ray ID QUANTITATIVE-ANALYSIS; CARTILAGE; FEATURES; HIP; INFORMATICS; COMPUTATION; SEVERITY; MOMENTS; BONE AB We describe a method for automated detection of radiographic osteoarthritis (OA) in knee X-ray images. The detection is based on the Kellgren-Lawrence (KL) classification grades, which correspond to the different stages of OA severity. The classifier was built using manually classified X-rays, representing the first four KL grades (normal, doubtful, minimal, and moderate). Image analysis is performed by first identifying a set of image content descriptors and image transforms that are informative for the detection of OA in the X-rays and assigning weights to these image features using Fisher scores. Then, a simple weighted nearest neighbor rule is used in order to predict the KL grade to which a given test X-ray sample belongs. The dataset used in the experiment contained 350 X-ray images classified manually by their KL grades. Experimental results show that moderate OA (KL grade 3) and minimal OA (KL grade 2) can be differentiated from normal cases with accuracy of 91.5% and 80.4%, respectively. Doubtful OA (KL grade 1) was detected automatically with a much lower accuracy of 57%. The source code developed and used in this study is available for free download at www.openmicroscopy.org. C1 [Shamir, Lior; Orlov, Nikita; Macura, Tomasz J.; Eckley, D. Mark; Goldberg, Ilya G.] NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. [Ling, Shari M.; Bos, Angelo; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21225 USA. [Ling, Shari M.] Johns Hopkins Univ, Sch Med, Div Geriatr Med Gerontol & Rheumatol, Baltimore, MD 21205 USA. [Ling, Shari M.] Univ Maryland, College Pk, MD 20742 USA. [Scott, William W., Jr.] Johns Hopkins Sch Med, Ctr Arthritis, Baltimore, MD 21205 USA. [Macura, Tomasz J.] Univ Cambridge Trinity Coll, Comp Lab, Cambridge CB2 1TQ, England. RP Shamir, L (reprint author), NIA, Image Informat & Computat Biol Unit, Genet Lab, NIH, Baltimore, MD 21224 USA. EM shamirl@mail.nih.gov RI Goldberg, Ilya/H-5307-2011; Eckley, Mark/M-3526-2014 OI Goldberg, Ilya/0000-0001-8514-6110; Eckley, Mark/0000-0003-2296-5164 FU Intramural Research Program; National Institute on Aging; National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH). NR 37 TC 31 Z9 32 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD FEB PY 2009 VL 56 IS 2 BP 407 EP 415 DI 10.1109/TBME.2008.2006025 PG 9 WC Engineering, Biomedical SC Engineering GA 435VZ UT WOS:000265372700025 PM 19342330 ER PT J AU Beare, PA Unsworth, N Andoh, M Voth, DE Omsland, A Gilk, SD Williams, KP Sobral, BW Kupko, JJ Porcella, SF Samuel, JE Heinzen, RA AF Beare, Paul A. Unsworth, Nathan Andoh, Masako Voth, Daniel E. Omsland, Anders Gilk, Stacey D. Williams, Kelly P. Sobral, Bruno W. Kupko, John J., III Porcella, Stephen F. Samuel, James E. Heinzen, Robert A. TI Comparative Genomics Reveal Extensive Transposon-Mediated Genomic Plasticity and Diversity among Potential Effector Proteins within the Genus Coxiella SO INFECTION AND IMMUNITY LA English DT Review ID NECROSIS-FACTOR-ALPHA; IV SECRETION SYSTEM; LEGIONELLA-PNEUMOPHILA; Q-FEVER; PHASE-I; MOLECULAR CHARACTERIZATION; CHLAMYDIA-TRACHOMATIS; PHYLOGENETIC ANALYSIS; BACTERIAL PATHOGENS; REPEAT PROTEINS AB Genetically distinct isolates of Coxiella burnetii, the cause of human Q fever, display different phenotypes with respect to in vitro infectivity/cytopathology and pathogenicity for laboratory animals. Moreover, correlations between C. burnetii genomic groups and human disease presentation ( acute versus chronic) have been described, suggesting that isolates have distinct virulence characteristics. To provide a more-complete understanding of C. burnetii's genetic diversity, evolution, and pathogenic potential, we deciphered the whole-genome sequences of the K (Q154) and G (Q212) human chronic endocarditis isolates and the naturally attenuated Dugway (5J108-111) rodent isolate. Cross-genome comparisons that included the previously sequenced Nine Mile (NM) reference isolate (RSA493) revealed both novel gene content and disparate collections of pseudogenes that may contribute to isolate virulence and other phenotypes. While C. burnetii genomes are highly syntenous, recombination between abundant insertion sequence ( IS) elements has resulted in genome plasticity manifested as chromosomal rearrangement of syntenic blocks and DNA insertions/deletions. The numerous IS elements, genomic rearrangements, and pseudogenes of C. burnetii isolates are consistent with genome structures of other bacterial pathogens that have recently emerged from nonpathogens with expanded niches. The observation that the attenuated Dugway isolate has the largest genome with the fewest pseudogenes and IS elements suggests that this isolate's lineage is at an earlier stage of pathoadaptation than the NM, K, and G lineages. C1 [Beare, Paul A.; Voth, Daniel E.; Omsland, Anders; Gilk, Stacey D.; Heinzen, Robert A.] NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Coxiella Pathogenesis Sect, Hamilton, MT 59840 USA. [Kupko, John J., III; Porcella, Stephen F.] NIAID, Rocky Mt Labs, Genom Core Facil, Res Technol Branch, Hamilton, MT 59840 USA. [Unsworth, Nathan; Andoh, Masako; Samuel, James E.] Texas A& M Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. [Williams, Kelly P.; Sobral, Bruno W.] Virginia Polytech Inst & State Univ, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. RP Heinzen, RA (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Coxiella Pathogenesis Sect, 903 S 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU National Institutes of Health; National Institute of Allergy and Infectious Diseases [AI057156] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases ( R. A. H.), and by Public Heath Service grant AI057156 from the National Institute of Allergy and Infectious Diseases ( J. E. S.). NR 113 TC 100 Z9 832 U1 3 U2 21 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2009 VL 77 IS 2 BP 642 EP 656 DI 10.1128/IAI.01141-08 PG 15 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 399CF UT WOS:000262777300009 PM 19047403 ER PT J AU Wipasa, J Xu, HJ Liu, XQ Hirunpetcharat, C Stowers, A Good, MF AF Wipasa, Jiraprapa Xu, Huji Liu, Xueqin Hirunpetcharat, Chakrit Stowers, Anthony Good, Michael F. TI Effect of Plasmodium yoelii Exposure on Vaccination with the 19-Kilodalton Carboxyl Terminus of Merozoite Surface Protein 1 and Vice Versa and Implications for the Application of a Human Malaria Vaccine SO INFECTION AND IMMUNITY LA English DT Article ID PROTECTIVE IMMUNITY; CROSS-REACTIVITY; AOTUS MONKEYS; TH CELLS; FALCIPARUM; FRAGMENT; MICE; IMMUNOGENICITY; ANTIBODIES; INFECTION AB It is well known that exposure to one antigen can modulate the immune responses that develop following exposure to closely related antigens. It is also known that the composition of the repertoire can be skewed to favor epitopes shared between a current infection and a preceding one, a phenomenon referred to as "original antigenic sin." It was of interest, therefore, to investigate the antibody response that develops following exposure to the malaria vaccine candidate homologue Plasmodium yoelii MSP1(19) in mice that had previously experienced malaria infection and vice versa. In this study, preexposure of mice to Plasmodium yoelii elicited native anti-MSP1(19) antibody responses, which could be boosted by vaccination with recombinant MSP1(19). Likewise, infection of MSP1(19)-primed mice with P. yoelii led to an increase of anti-MSP1(19) antibodies. However, this increase was at the expense of antibodies to parasite determinants other than MSP1(19). This change in the balance of antibody specificities significantly affected the ability of mice to withstand a subsequent infection. These data have particular relevance to the possible outcome of malaria vaccination for those situations where the vaccine response is suboptimal and suggest that suboptimal vaccination may in fact render the ultimate acquisition of natural immunity more difficult. C1 [Wipasa, Jiraprapa; Xu, Huji; Liu, Xueqin; Good, Michael F.] PO Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Wipasa, Jiraprapa] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50200, Thailand. [Xu, Huji] Second Mil Med Univ, Changzheng Hosp, Shanghai 200003, Peoples R China. [Hirunpetcharat, Chakrit] Mahidol Univ, Fac Publ Hlth, Dept Microbiol, Bangkok 10400, Thailand. [Stowers, Anthony] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Good, MF (reprint author), PO Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. EM Huji.Xu@qimr.edu.au; Michael.Good@qimr.edu.au FU Australian National Health and Medical Research Council; UNDP/World Bank/ WHO Special Program for Research and Training in Tropical Diseases (TDR); Australian NHMRC RD Wright; China MOST 973 [CB513100]; [NNSF30610103103] FX Research in the authors' laboratories is supported by the Australian National Health and Medical Research Council and the UNDP/World Bank/ WHO Special Program for Research and Training in Tropical Diseases (TDR). H. X. is an Australian NHMRC RD Wright fellow, and his research is also supported by China MOST 973 CB513100 and NNSF30610103103. NR 19 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2009 VL 77 IS 2 BP 817 EP 824 DI 10.1128/IAI.01063-08 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 399CF UT WOS:000262777300029 PM 19015251 ER PT J AU Lu, ZY Kim, W Wilbur, WJ AF Lu, Zhiyong Kim, Won Wilbur, W. John TI Evaluation of query expansion using MeSH in PubMed SO INFORMATION RETRIEVAL LA English DT Article DE Query expansion; TREC genomics; PubMed; MeSH ID AUTOMATIC TEXT RETRIEVAL; SUBJECT-HEADINGS MESH; LANGUAGE AB This paper investigates the effectiveness of using MeSH (R) in PubMed through its automatic query expansion process: Automatic Term Mapping (ATM). We run Boolean searches based on a collection of 55 topics and about 160,000 MEDLINE (R) citations used in the 2006 and 2007 TREC Genomics Tracks. For each topic, we first automatically construct a query by selecting keywords from the question. Next, each query is expanded by ATM, which assigns different search tags to terms in the query. Three search tags: [MeSH Terms], [Text Words], and [All Fields] are chosen to be studied after expansion because they all make use of the MeSH field of indexed MEDLINE citations. Furthermore, we characterize the two different mechanisms by which the MeSH field is used. Retrieval results using MeSH after expansion are compared to those solely based on the words in MEDLINE title and abstracts. The aggregate retrieval performance is assessed using both F-measure and mean rank precision. Experimental results suggest that query expansion using MeSH in PubMed can generally improve retrieval performance, but the improvement may not affect end PubMed users in realistic situations. C1 [Lu, Zhiyong; Kim, Won; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM luzh@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 30 TC 58 Z9 58 U1 3 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-4564 J9 INFORM RETRIEVAL JI Inf. Retr. PD FEB PY 2009 VL 12 IS 1 BP 69 EP 80 DI 10.1007/s10791-008-9074-8 PG 12 WC Computer Science, Information Systems SC Computer Science GA 414CZ UT WOS:000263842800004 PM 19774223 ER PT J AU Dinglasan, RR Devenport, M Florens, L Johnson, JR McHugh, CA Donnelly-Doman, M Carucci, DJ Yates, JR Jacobs-Lorena, M AF Dinglasan, R. R. Devenport, M. Florens, L. Johnson, J. R. McHugh, C. A. Donnelly-Doman, M. Carucci, D. J. Yates, J. R., III Jacobs-Lorena, M. TI The Anopheles gambiae adult midgut peritrophic matrix proteome SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Anopheles gambiae; Peritrophic matrix; Mosquito; Proteome ID BLOCKING MALARIA TRANSMISSION; AEDES-AEGYPTI; PLASMODIUM-GALLINACEUM; IDENTIFICATION TECHNOLOGY; SHOTGUN PROTEOMICS; PARASITE CHITINASE; MEMBRANE-PROTEIN; SERINE-PROTEASE; BLOOD MEAL; MOSQUITO AB Malaria is a devastating disease. For transmission to occur, Plasmodium, the causative agent of malaria, must complete a complex developmental cycle in its mosquito vector. Thus, the mosquito is a potential target for disease control. Plasmodium ookinetes, which develop within the mosquito midgut, must first cross the midgut's peritrophic matrix (PM), a thick extracellular sheath that completely surrounds the blood meal. The PM poses a partial, natural barrier against parasite invasion of the midgut and it is speculated that modifications to the PM may lead to a complete barrier to infection. However, such strategies require thorough characterization of the structure of the PM. Here, we describe for the first time, the complete PM proteome of the main malaria vector, Anopheles gambiae. Altogether, 209 proteins were identified by mass spectrometry. Among them were nine new chitin-binding peritrophic matrix proteins, expanding the list from three to twelve peritrophins. Lastly, we provide a model for the putative interactions among the proteins identified in this study. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Dinglasan, R. R.; Devenport, M.; McHugh, C. A.; Jacobs-Lorena, M.] Johns Hopkins Bloomberg Sch Publ Hlth, Malaria Res Inst, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Florens, L.; Johnson, J. R.; Yates, J. R., III] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Carucci, D. J.] NIH, Grand Challenges Global Hlth Fdn, Bethesda, MD USA. [Donnelly-Doman, M.] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. RP Jacobs-Lorena, M (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Malaria Res Inst, Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM mlorena@jhsph.edu OI Dinglasan, Rhoel/0000-0001-5433-8179; Dinglasan, Rhoel/0000-0001-6563-1506; Florens, Laurence/0000-0002-9310-6650 FU NIAID; NIH [R01AI040971, 5F32AI068212]; Johns Hopkins Malaria Research Institute; Bloomberg Family Foundation FX This work was supported by a grant from the NIAID, NIH (R01AI040971) and by the Johns Hopkins Malaria Research Institute and the Bloomberg Family Foundation. R.R.D. is a NIH Ruth L Kirschstein National Research Service Award Scholar (5F32AI068212). NR 52 TC 56 Z9 59 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD FEB PY 2009 VL 39 IS 2 BP 125 EP 134 DI 10.1016/j.ibmb.2008.10.010 PG 10 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 425AA UT WOS:000264608200007 PM 19038338 ER PT J AU Kobey, RL Hoshizaki, DK Gibbs, AG AF Kobey, R. L. Hoshizaki, D. K. Gibbs, A. G. TI The Effect of Melanization on Desiccation Resistance and Thermotolerance in Drosophila melanogaster SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology CY JAN 03-07, 2009 CL Boston, MA SP Soc Integrat & Comparat Biol C1 Univ Nevada, Las Vegas, NV 89154 USA. NIDDK, NIH, Bethesda, MD 20892 USA. EM kobeyr@unlv.nevada.edu RI Gibbs, Allen/D-6968-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1540-7063 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD FEB PY 2009 VL 49 BP E255 EP E255 PG 1 WC Zoology SC Zoology GA 481KL UT WOS:000268808801018 ER PT J AU Fitzpatrick, JM Fuentes, JM Chalmers, IW Wynn, TA Modolell, M Hoffmann, KF Hesse, M AF Fitzpatrick, Jennifer M. Fuentes, Jose M. Chalmers, Iain W. Wynn, Thomas A. Modolell, Manuel Hoffmann, Karl F. Hesse, Matthias TI Schistosoma mansoni arginase shares functional similarities with human orthologs but depends upon disulphide bridges for enzymatic activity SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Helminth; Metabolism; Enzyme; Evolution; Adaptation; Urea; Trematode; Drug target ID NITRIC-OXIDE SYNTHASE; HYDROXY-L-ARGININE; HELICOBACTER-PYLORI ARGINASE; ALTERNATIVE MACROPHAGE ACTIVATION; MULTIPLE SEQUENCE ALIGNMENT; MAMMARY-GLAND ARGINASE; LIVER ARGINASE; MURINE MACROPHAGES; AMINO-ACIDS; PHYSICOCHEMICAL PROPERTIES AB Schistosome helminths constitute a major health risk for the human population in many tropical areas. We demonstrate for the first time that several developmental stages of the human parasite Schistosoma mansoni express arginase, which is responsible for the hydrolysis Of L-arginine to L-ornithine and urea. Arginase activity by alternatively activated macrophages is an essential component of the mammalian host response in schistosomiasis. However, it has not been previously shown that the parasite also expresses arginase when it is in contact with the mammalian host. After cloning and sequencing the cDNA encoding the parasite enzyme, we found that many structural features of human arginase are well conserved in the parasite ortholog. Subsequently, we discovered that S. mansoni arginase shares many similar molecular, biochemical and functional properties with both human arginase isoforms, Nevertheless, our data also reveal striking differences between human and schistosome arginase. Particularly, we found evidence that schistosome arginase activity depends upon disulphide bonds by cysteines, in contrast to human arginase. In conclusion, we report that S. mansoni arginase is well adapted to the physiological conditions that exist in the human host. (c) 2008 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. C1 [Hesse, Matthias] Cornell Univ, Dept Microbiol & Immunol, Coll Vet Med, Ithaca, NY 14853 USA. [Fitzpatrick, Jennifer M.; Chalmers, Iain W.; Hoffmann, Karl F.] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Fuentes, Jose M.] Univ Extremadura, CIBER Enfermedades Neurodegenerat, Dept Bioquim & Biol Mol & Genet, EU Enfermeria & TO, Caceres, Spain. [Wynn, Thomas A.; Hesse, Matthias] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD USA. [Modolell, Manuel] Max Planck Inst Immunobiol, D-7800 Freiburg, Germany. RP Hesse, M (reprint author), Cornell Univ, Dept Microbiol & Immunol, Coll Vet Med, VMC C5 147, Ithaca, NY 14853 USA. EM mh325@cornell.edu RI Greenberg, Robert/D-1091-2009; Wynn, Thomas/C-2797-2011; Fuentes, Jose/H-9490-2014 OI Fuentes, Jose/0000-0001-6910-2089 FU Uunta de Extremadura [PR106B124]; ISCIII [PR106B124]; Wellcome Trust [RG35177, RG35522] FX We thank Dr. Fred Lewis and his colleagues at the Biomedical Research Institute (Rockville, MD) for providing parasite material used in this study. We further thank Mary Leusink (LPD, Bethesda, MD) and Fae Tompkins (Cornell University, Ithaca, NY) for technical assistance. Funding was provided by grants PR106B124 Uunta de Extremadura) and P1070400 (FIS, ISCIII, MSQ to JM Fuentes and KF Hoffmann is Supported by grants received from the Wellcome Trust (RG35177 and RG35522). NR 96 TC 10 Z9 10 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD FEB PY 2009 VL 39 IS 3 BP 267 EP 279 DI 10.1016/j.ijpara.2008.06.015 PG 13 WC Parasitology SC Parasitology GA 412FQ UT WOS:000263710000001 PM 18723022 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Evolution of genome architecture SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Review DE Positive selection; Purifying selection; Recombination; Operons; Gene clustering ID HUMAN TRANSCRIPTOME MAP; GENE CLUSTERS; NEIGHBORING GENES; PROKARYOTIC GENOMES; SELFISH OPERONS; EXPRESSED GENES; CAENORHABDITIS-ELEGANS; COMPUTATIONAL ANALYSIS; TRANSPOSABLE ELEMENTS; SPLICEOSOMAL INTRONS AB Charles Darwin believed that all traits of organisms have been honed to near perfection by natural selection. The empirical basis underlying Darwin's conclusions consisted of numerous observations made by him and other naturalists on the exquisite adaptations of animals and plants to their natural habitats and on the impressive results of artificial selection. Darwin fully appreciated the importance of heredity but was unaware of the nature and, in fact, the very existence of genomes. A century and a half after the publication of the "Origin", we have the opportunity to draw conclusions from the comparisons of hundreds of genome sequences from all walks of life. These comparisons suggest that the dominant mode of genome evolution is quite different from that of the phenotypic evolution. The genomes of vertebrates, those purported paragons of biological perfection, turned out to be veritable junkyards of selfish genetic elements where only a small fraction of the genetic material is dedicated to encoding biologically relevant information. In sharp contrast, genomes of microbes and viruses are incomparably more compact, with most of the genetic material assigned to distinct biological functions. However, even in these genomes, the specific genome organization (gene order) is poorly conserved. The results of comparative genomics lead to the conclusion that the genome architecture is not a straightforward result of continuous adaptation but rather is determined by the balance between the selection pressure, that is itself dependent on the effective population size and mutation rate, the level of recombination, and the activity of selfish elements. Although genes and, in many cases, multigene regions of genomes possess elaborate architectures that ensure regulation of expression, these arrangements are evolutionarily volatile and typically change substantially even on short evolutionary scales when gene sequences diverge minimally. Thus, the observed genome architectures are, mostly, products of neutral processes or epiphenomena of more general selective processes, such as selection for genome streamlining in successful lineages with large populations. Selection for specific gene arrangements (elements of genome architecture) seems only to modulate the results of these processes. Published by Elsevier Ltd C1 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 DHHS (National Library of Medicine) FX I thank Pavel Novichkov for providing the data for Fig. 3. The author's research is supported by the DHHS (National Library of Medicine) intramural funds. NR 116 TC 76 Z9 78 U1 4 U2 39 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD FEB PY 2009 VL 41 IS 2 BP 298 EP 306 DI 10.1016/j.biocel.2008.09.015 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 399IF UT WOS:000262792900008 PM 18929678 ER PT J AU Meijer, CJLM Berkhof, J Castle, PE Hesselink, AT Franco, EL Ronco, G Arbyn, M Bosch, FX Cuzick, J Dillner, J Heideman, DAM Snijders, PJF AF Meijer, Chris J. L. M. Berkhof, Johannes Castle, Philip E. Hesselink, Albertus T. Franco, Eduardo L. Ronco, Guglielmo Arbyn, Marc Bosch, F. Xavier Cuzick, Jack Dillner, Joakim Heideman, Danielle A. M. Snijders, Peter J. F. TI Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HPV-DNA testing; cervical screening; HPV test guidelines; HPV test requirements; HPV test statistics ID RANDOMIZED CONTROLLED-TRIAL; POLYMERASE-CHAIN-REACTION; RISK HUMAN-PAPILLOMAVIRUS; LIQUID-BASED CYTOLOGY; INTRAEPITHELIAL NEOPLASIA; HYBRID CAPTURE-2; BASE-LINE; HYBRID-CAPTURE-2; RECRUITMENT; MANAGEMENT AB Given the strong etiologic link between high-risk HPV infection and cervical cancer high-risk HPV testing is now being considered as an alternative for cytology-based cervical cancer screening. Many test systems have been developed that can detect the broad spectrum of hrHPV types in one assay. However, for screening purposes the detection of high-risk HPV is not inherently useful unless it is informative for the presence of high-grade cervical intraepithelial neoplasia (CIN 2/3) or cancer. Candidate high-risk HPV tests to be used for screening should reach an optimal balance between clinical sensitivity and specificity for detection of high-grade CIN and cervical cancer to minimize redundant or excessive follow-up procedures for high-risk HPV positive women without cervical lesions. Data from various large screening studies have shown that high-risk HPV testing by hybrid capture 2 and GP5+/6+-PCR yields considerably better results in the detection of CIN 2/3 than cytology. The data from these studies can be used to guide the translation of high-risk HPV testing into clinical practice by setting standards of test performance and characteristics. On the basis of these data we have developed guidelines for high-risk HPV test requirements for primary cervical screening and validation guidelines for candidate HPV assays. (C) 2008 Wiley-Liss, Inc. C1 [Meijer, Chris J. L. M.; Hesselink, Albertus T.; Heideman, Danielle A. M.; Snijders, Peter J. F.] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. [Berkhof, Johannes] Vrije Univ Amsterdam, Med Ctr, Dept Clin Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands. [Castle, Philip E.] NIH, Dept Canc Epidemiol & Genet, Washington, DC USA. [Franco, Eduardo L.] McGill Univ, Div Canc Epidemiol, Montreal, PQ, Canada. [Ronco, Guglielmo] Ctr Prevenz Oncol, Canc Epidemiol Unit, Turin, Italy. [Arbyn, Marc] Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. [Arbyn, Marc] IARC, ECCG European Cooperat Dev & Implementat Canc Scr, Lyon, France. [Bosch, F. Xavier] Hosp Ilobregat, ICO, Serv Epidemiol, Barcelona, Spain. [Cuzick, Jack] Barts & London Queen Marys Sch Med & Dent, London, England. [Dillner, Joakim] Lund Univ, Univ Hosp, Dept Med Microbiol, Malmo, Sweden. [Cuzick, Jack] Canc Res UK, London, England. RP Meijer, CJLM (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Pathol, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM cjlm.meijer@vumc.nl RI Arbyn, Marc/B-6887-2009; BOSCH JOSE, FRANCESC XAVIER/J-6339-2012; OI BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412; Franco, Eduardo/0000-0002-4409-8084 FU Intramural NIH HHS [Z99 CA999999] NR 34 TC 247 Z9 253 U1 1 U2 12 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 FEB 1 PY 2009 VL 124 IS 3 BP 516 EP 520 DI 10.1002/ijc.24010 PG 5 WC Oncology SC Oncology GA 391AS UT WOS:000262205400002 PM 18973271 ER PT J AU Castillejo, A Rothman, N Murta-Nascimento, C Malats, N Garcia-Closas, M Gomez-Martinez, A Lloreta, J Tardon, A Serra, C Garcia-Closas, R Chanock, S Silverman, DT Dosemeci, M Kogevinas, M Carrato, A Soto, JL Real, FX AF Castillejo, Adela Rothman, Nathaniel Murta-Nascimento, Cristiane Malats, Nuria Garcia-Closas, Montserrat Gomez-Martinez, Angeles Lloreta, Josep Tardon, Adonina Serra, Consol Garcia-Closas, Reina Chanock, Stephen Silverman, Debra T. Dosemeci, Mustafa Kogevinas, Manolis Carrato, Alfredo Soto, Jose Luis Real, Francisco X. TI TGFB1 and TGFBR1 polymorphic variants in relationship to bladder cancer risk and prognosis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE urinary bladder cancer; genetic susceptibility; transforming growth factor beta; transforming growth factor-beta receptor; prognosis; survival; recurrence; progression ID GROWTH-FACTOR-BETA; GENE POLYMORPHISMS; TGF-BETA-1 GENE; ASSOCIATION; TGFBR1-ASTERISK-6A; DISEASE; SUSCEPTIBILITY; METAANALYSIS; CARCINOMA AB The transforming growth factor-beta (TGF-beta) signalling pathway plays an important role in tumor development and progression. We aimed at analyzing whether 7 different common variants in genes coding for 2 key members of the TGF-beta signalling pathway (TGFBI and TGFBR1) are associated with bladder cancer risk and prognosis. A total of 1,157 cases with urothelial cell carcinoma of the bladder and 1,157 matched controls where genotyped for 3 single nucleotide polymorphisms (SNPs) in TGFBI (rs1982073, rs1800472, rs1800471) and an additional 3 SNPs and 1 indel polymorphism in TGFBR1 (rs868, rs928180, rs334358 and rs11466445, respectively). In the case-control study, we estimated odds ratios and 95% confidence intervals for each individual genetic variant using unconditional logistic regression adjusting for age, gender, study area and smoking status. Survival analysis was performed using the Kaplan-Meier method and Cox models. The endpoints of interest were tumor relapse, progression and death from bladder cancer. All the SNPs analyzed showed a similar distribution among cases and controls. The distribution of the TGFBR1*6A allele (rs11466445) was also similar among cases and controls, indicating no association with bladder cancer risk. Similarly, none of the haplotypes was significantly associated with bladder cancer risk. Among patients with muscle-invasive tumors, we found a significant association between TGFBR1-rs868 and disease-specific mortality with an allele dosage effect (p-trend = 0.003). In conclusion, the genetic variants analyzed were not associated with an increased risk of bladder cancer. The association of TGFBR1-rs868 with outcome should be validated in independent patient series. (C) 2008 Wiley-Liss, Inc. C1 [Castillejo, Adela; Gomez-Martinez, Angeles; Carrato, Alfredo; Soto, Jose Luis] Hosp Gen Univ Elche, Mol Oncol Grp, Elche, Spain. [Rothman, Nathaniel; Garcia-Closas, Montserrat; Silverman, Debra T.; Dosemeci, Mustafa] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Murta-Nascimento, Cristiane; Malats, Nuria; Kogevinas, Manolis; Real, Francisco X.] IMIM Hosp del Mar, Inst Municipal Invest Med, Programa Recerca Canc, Barcelona, Spain. [Murta-Nascimento, Cristiane; Malats, Nuria; Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Malats, Nuria; Real, Francisco X.] CNIO, Programa Genet Canc Humano, E-28029 Madrid, Spain. [Malats, Nuria; Real, Francisco X.] CNIO, Programa Patol Mol, E-28029 Madrid, Spain. [Lloreta, Josep] Hosp del Mar, Dept Patol, Barcelona, Spain. [Lloreta, Josep; Serra, Consol; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Tardon, Adonina] Univ Oviedo, Dept Epidemiol & Prevent Med, Oviedo, Spain. [Tardon, Adonina; Kogevinas, Manolis] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, Dept Social Med, San Cristobal la Laguna, Spain. [Kogevinas, Manolis] Univ Crete, Iraklion, Greece. [Chanock, Stephen] NCI, Core Genotype Facil, Adv Technol Ctr, Gaithersburg, MD USA. RP Real, FX (reprint author), CNIO, Programa Genet Canc Humano, C Melchor Fernandez Almagro 3, E-28029 Madrid, Spain. EM preal@cnio.es RI Murta-Nascimento, Cristiane/G-3738-2012; Serra, C/E-6879-2014; Lloreta, J/I-2112-2014; Benavides, Fernando/A-5137-2008; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015 OI Serra, C/0000-0001-8337-8356; Lloreta, J/0000-0003-1644-9470; Benavides, Fernando/0000-0003-0747-2660; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Soto, Jose Luis/0000-0003-0234-9188; Real, Francisco X/0000-0001-9501-498X FU Fondo de Investigacion Sanitaria, Spain [00/0745, G03/174, PI051436, PI061614]; Fundacio La Marato de TV3; National Cancer Institute, USA FX Grant sponsor: Fondo de Investigacion Sanitaria, Spain: Grant numbers: 00/0745, G03/174. PI051436, PI061614; Grant sponsors: Fundacio La Marato de TV3, National Cancer Institute. USA. NR 24 TC 29 Z9 31 U1 0 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 FEB 1 PY 2009 VL 124 IS 3 BP 608 EP 613 DI 10.1002/ijc.24013 PG 6 WC Oncology SC Oncology GA 391AS UT WOS:000262205400013 PM 19004027 ER PT J AU Birmann, BM Breen, EC Stuver, S Cranston, B Martinez-Maza, O Falk, KI Okayama, A Hanchard, B Mueller, N Hisada, M AF Birmann, Brenda M. Breen, Elizabeth C. Stuver, Sherri Cranston, Beverly Martinez-Maza, Otoniel Falk, Kerstin I. Okayama, Akihiko Hanchard, Barrie Mueller, Nancy Hisada, Michie TI Population differences in immune marker profiles associated with human T-lymphotropic virus type I infection in Japan and Jamaica SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HTLV-I; epidemiology; natural history; host immunity; viral markers ID MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; CIRCULATING INTERLEUKIN-6 LEVELS; CELL LEUKEMIA ATL; HTLV-I; HEALTHY CARRIERS; PROVIRAL LOAD; CD8(+) CELLS; ANTIBODY; ACTIVATION; PATTERNS AB The natural history of human T-lymphotropic virus type I (HTLV-1) has been shown to differ markedly by geographic area. The differences include contrasting patterns of risk of adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may be due in part to differences in host immune response to infection. To characterize variations in host immunity across populations, we compared serologic immune marker patterns in HTLV-I-endemic populations in Japan and Jamaica. We matched 204 participants with archived blood from the Miyazaki Cohort Study (Japan) and the Food Handlers Study (Jamaica)-i.e., 51 HTLV-I-positive ("carriers") and 51 HTLV-I-negative individuals ("noncarriers") from each population-by age, sex and blood collection year. We compared plasma concentrations of markers of T-cell-mediated (antigen-specific) and nonspecific immunity using regression models and correlation coefficients. Compared to Jamaican HTLV-1 non-carriers, Japanese noncarriers had higher covariate-adjusted mean levels of T-cell activation markers, including antibody to Epstein-Barr virus nuclear antigen-1 (reciprocal titer 27 vs. 7 1, respectively, p = 0.005), soluble interleukin-2 receptor-a (477 vs. 623 pg/mL, p = 0.0008) and soluble CD30 (34 vs. 46 U/mL, p = 0.0001) and lower levels of C-reactive protein (1.1 vs. 0.43 mu g/mL, p = 0.0004). HTLV-1 infection was associated with activated T-cell immunity in Jamaicans but with diminished T-cell immunity in Japanese persons. The observed population differences in background and HTLV-I-related host immunity correspond closely to the divergent natural histories of infection observed among HTLV-1 carriers in Japan and Jamaica and corroborate a role for host immune status in the contrasting patterns of ATL and HAM/TSP risk. (C) 2008 Wiley-Liss, Inc. C1 [Birmann, Brenda M.; Stuver, Sherri; Mueller, Nancy] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Breen, Elizabeth C.; Martinez-Maza, Otoniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Stuver, Sherri] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Cranston, Beverly; Hanchard, Barrie] Univ W Indies, Dept Pathol, Kingston 7, Jamaica. [Falk, Kerstin I.] Karolinska Inst, Ctr Microbiol Preparedness, Swedish Inst Infect Dis Control, Stockholm, Sweden. [Falk, Kerstin I.] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Okayama, Akihiko] Miyazaki Univ, Dept Lab Med, Miyazaki Med Coll, Miyazaki, Japan. [Hisada, Michie] NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Birmann, BM (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM brenda.birmann@channing.harvard.edu RI Martinez-Maza, Otoniel/B-2667-2009; OI Martinez-Maza, Otoniel/0000-0003-1364-0675; Stuver, Sherri/0000-0002-4027-2663 FU Public Health Service [CA115687, CA38450, CA09001]; Intramural Research Program of the National Institutes of Health; National Cancer Institute. Division of Cancer Epidemiology and Genetics FX Grant sponsor: Public Health Service: Grant numbers: CA115687, CA38450, CA09001. Grant sponsors: Intramural Research Program of the National Institutes of Health, National Cancer Institute. Division of Cancer Epidemiology and Genetics. NR 45 TC 12 Z9 12 U1 0 U2 0 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 FEB 1 PY 2009 VL 124 IS 3 BP 614 EP 621 DI 10.1002/ijc.24012 PG 8 WC Oncology SC Oncology GA 391AS UT WOS:000262205400014 PM 18989900 ER PT J AU Patlolla, AK Barnes, C Hackett, D Tchounwou, PB AF Patlolla, Anita K. Barnes, Constance Hackett, Diahanna Tchounwou, Paul B. TI Potassium Dichromate Induced Cytotoxicity, Genotoxicity and Oxidative Stress in Human Liver Carcinoma (HepG(2)) Cells SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE HepG2 cells; cytotoxicity; DNA damage; lipid peroxidation; malondialdehyde; potassium dichromate ID DNA-DAMAGE; HEXAVALENT CHROMIUM; LIPID-PEROXIDATION; CARCINOGENICITY; ANTIOXIDANTS; MECHANISMS; TOXICITY; CR(VI); RATS; MICE AB Chromium is a widespread industrial waste. The soluble hexavalent chromium Cr (VI) is an environmental contaminant widely recognized to act as a carcinogen, mutagen and teratogen towards humans and animals. The fate of chromium in the environment is dependent on its oxidation state. Hexavalent chromium primarily enters the cells and undergoes metabolic reduction to trivalent chromium, resulting in the formation of reactive oxygen species together with oxidative tissue damage and a cascade of cellular events. However, the results from in vitro studies are often conflicting. The aim of this study was to develop a model to establish relationships between cytotoxicity, genotoxicity and oxidative stress, in human liver carcinoma [HepG2] cells exposed to potassium dichromate. HepG2 cells were cultured following standard protocols and exposed to various concentrations [0-50 mu M] of potassium dichromate [K(2)Cr(2)O(7)]. Following exposure to the toxic metal, the MTT assay was performed to assess the cytotoxicity, the thiobarbituric acid test to evaluate the degree of lipid peroxidation as an indicator of oxidative stress and the alkaline comet assay was used to assess DNA damage to study genotoxicity. The results of the study indicated that potassium dichromate was cytotoxic to HepG2 cells. The LD(50) values of 8.83 +/- 0.89 mu g/ml, 6.76 +/- 0.99 mu g/ml, respectively, for cell mortality at 24 and 48 hrs were observed, indicating a dose- and time-dependent response with regard to the cytotoxic effects of potassium dichromate. A statistically significant increase in the concentration of malondialdehyde [MDA], an indicator of lipid peroxidation, was recorded in exposed cells [15.9 - 69.9 mu M] compared to control [13 mu M]. Similarly, a strong dose-response relationship (p<0.05) was also obtained with respect to potassium dichromate induced DNA damage (comet assay) in HepG2 cells exposed [3.16 +/- 0.70 - 24.84 +/- 1.86 microns - mean comet tail length]; [12.4 +/- 1.45% - 76 +/- 1.49% - % tail DNA] to potassium dichromate than control [3.07 +/- 0.26 microns - mean comet tail length]; [2.69 + 0.19% - % Tail DNA], respectively. The results demonstrated that potassium dichromate was highly cytotoxic to HepG2 cells, and its cytotoxicity seems to be mediated by oxidative stress and DNA damage. C1 [Patlolla, Anita K.; Barnes, Constance; Hackett, Diahanna; Tchounwou, Paul B.] Jackson State Univ, Mol Toxicol Res Lab, NIH, Ctr Environm Hlth,CSET, Jackson, MS USA. RP Patlolla, AK (reprint author), Jackson State Univ, Mol Toxicol Res Lab, NIH, Ctr Environm Hlth,CSET, Jackson, MS USA. EM anita.k.patlolla@jsums.edu; constancepb@yahoo.com; diahanna.m.hackett@jsums.edu; paul.b.tchounwou@jsums.edu FU National Institutes of Health [1G12RR13459] FX This research was financially supported by a grant from the National Institutes of Health - (Grant No 1G12RR13459), through the RCMI-Center for Environmental Health at Jackson State University.. The authors thank Dr. Abdul K. Mohamed, Dean Emeritus, and the RCMI external advisory committee members, for their technical support in this project. NR 38 TC 32 Z9 34 U1 0 U2 13 PU MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD FEB PY 2009 VL 6 IS 2 BP 643 EP 653 DI 10.3390/ijerph6020643 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 451BI UT WOS:000266445300017 PM 19440407 ER PT J AU Burton, PR Hansell, AL Fortier, I Manolio, TA Khoury, MJ Little, J Elliott, P AF Burton, Paul R. Hansell, Anna L. Fortier, Isabel Manolio, Teri A. Khoury, Muin J. Little, Julian Elliott, Paul TI Size matters: just how big is BIG? Quantifying realistic sample size requirements for human genome epidemiology SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Human genome epidemiology; biobank; sample size; statistical power; simulation studies; measurement error; reliability; aetiological heterogeneity ID GENE-DISEASE ASSOCIATIONS; FACTOR-H POLYMORPHISM; WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; MACULAR DEGENERATION; COMPLEX DISEASES; COMMON DISEASES; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; PROSTATE-CANCER AB Background Despite earlier doubts, a string of recent successes indicates that if sample sizes are large enough, it is possible-both in theory and in practice-to identify and replicate genetic associations with common complex diseases. But human genome epidemiology is expensive and, from a strategic perspective, it is still unclear what 'large enough' really means. This question has critical implications for governments, funding agencies, bioscientists and the tax-paying public. Difficult strategic decisions with imposing price tags and important opportunity costs must be taken. Methods Conventional power calculations for case-control studies disregard many basic elements of analytic complexity-e. g. errors in clinical assessment, and the impact of unmeasured aetiological determinants-and can seriously underestimate true sample size requirements. This article describes, and applies, a rigorous simulation-based approach to power calculation that deals more comprehensively with analytic complexity and has been implemented on the web as ESPRESSO: (www.p3gobservatory.org/powercalculator.htm). Results Using this approach, the article explores the realistic power profile of stand-alone and nested case-control studies in a variety of settings and provides a robust quantitative foundation for determining the required sample size both of individual biobanks and of large disease-based consortia. Despite universal acknowledgment of the importance of large sample sizes, our results suggest that contemporary initiatives are still, at best, at the lower end of the range of desirable sample size. Insufficient power remains particularly problematic for studies exploring gene-gene or gene-environment interactions. Discussion Sample size calculation must be both accurate and realistic, and we must continue to strengthen national and international cooperation in the design, conduct, harmonization and integration of studies in human genome epidemiology. C1 [Burton, Paul R.] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England. [Burton, Paul R.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Burton, Paul R.; Fortier, Isabel; Khoury, Muin J.; Little, Julian] Univ Montreal, P3G, Montreal, PQ H3C 3J7, Canada. [Hansell, Anna L.; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Fortier, Isabel] Univ Montreal, Dept Med Sociale & Prevent, Montreal, PQ, Canada. [Manolio, Teri A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Natl Off Publ Hlth Genom, Atlanta, GA USA. [Little, Julian] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. RP Burton, PR (reprint author), Univ Leicester, Dept Hlth Sci, Adrian Bldg,Room 217,Univ Rd, Leicester LE1 7RH, Leics, England. EM pb51@le.ac.uk RI Burton, Paul/H-7527-2016 FU UK Biobank; Wellcome Trust; Medical Research Council; Department of Health; Scottish Executive and Northwest Regional Development Agency; European Union under the Framework 6 program; Wellcome Trust Intermediate Clinical Fellow [075883] FX We gratefully acknowledge the support of the steering committee of UK Biobank in encouraging and discussing the implications of this research. Initial power calculations were funded by UK Biobank from its joint funders: Wellcome Trust, Medical Research Council, Department of Health, Scottish Executive and Northwest Regional Development Agency. This work was also supported as a central element of the research programmes of P 3 G ( the Public Population Project in Genomics) funded by Genome Canada and Genome Quebec, and PHOEBE ( Promoting Harmonization of Epidemiological Biobanks in Europe) funded by the European Union under the Framework 6 program. A. L. H. is a Wellcome Trust Intermediate Clinical Fellow ( grant number 075883). J.L. is a Canada Research Chair in Human Genome Epidemiology. The programme of methods research in genetic epidemiology in Leicester is funded in part by MRC Cooperative Grant G9806740. We wish to thank those who kindly provided us with advice and data: Gabriele Nagel, Sabine Rohrman, Bertrand Hemon, Paolo Vineis [ European Prospective Investigation of Cancer and Nutrition ( EPIC)]; Peter Rothwell ( Stroke Prevention Research Unit, Radcliffe Infirmary, Oxford); Joan Soriano, GlaxoSmithKline ( for estimates of UK COPD incidence) and the UK Small Area Health Statistics Unit, Imperial College London. NR 79 TC 117 Z9 120 U1 4 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2009 VL 38 IS 1 BP 263 EP 273 DI 10.1093/ije/dyn147 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 404PB UT WOS:000263164400035 PM 18676414 ER PT J AU Tuan, RS AF Tuan, Rocky S. TI Chondroregulatory signals in osteoarthritis SO INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY LA English DT Meeting Abstract CT Annual General Meeting of the British-Society-for-Matrix-Biology CY APR 07-08, 2008 CL York Univ, York, ENGLAND SP British Soc Matrix Biol HO York Univ C1 [Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Tuan, Rocky S.] NIH, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov NR 0 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 0959-9673 J9 INT J EXP PATHOL JI Int. J. Exp. Pathol. PD FEB PY 2009 VL 90 IS 1 BP A51 EP A51 PG 1 WC Pathology SC Pathology GA 395HW UT WOS:000262516200023 ER PT J AU Teufel, A Maass, T Galle, PR Malik, N AF Teufel, Andreas Maass, Thorsten Galle, Peter R. Malik, Nasir TI The longevity assurance homologue of yeast lag1 (Lass) gene family SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Review DE longevity; homeodomain; ceramide; cancer; apoptosis; stress response ID CERAMIDE SYNTHESIS; CANCER-THERAPY; CELL-DEATH; SYNTHASE; PROTEINS; COA; DOMAINS; MEMBERS; HOX; METABOLISM AB The Lass gene family contains a group of highly conserved genes that are found in eukaryotic species. The founding member. lag1. was discovered in a screen for yeast longevity genes. Subsequently, lag1 homologs were discovered in other organisms including six mammalian paralogs. All Lass genes encode a highly conserved Lag1 domain and many also have an additional Hox domain. Lass proteins are ceramide synthases and therefore are critical for ceramide biosynthesis. Ceramide synthase is also a critical enzyme in the sphingolipid biosynthetic pathway. As ceramide and sphingolipids are key intermediates in diverse cellular processes such as cell growth, apoptosis, and stress response and may also play a role in cancer development, the function of Lass proteins is of great interest. In this review, we summarize the state of knowledge regarding Lass protein structure, biological function, and their emerging role in cancer development. C1 [Teufel, Andreas; Maass, Thorsten; Galle, Peter R.] Johannes Gutenberg Univ Mainz, Dept Med, D-55101 Mainz, Germany. [Malik, Nasir] NIDA, Cellular Neurobiol Branch, NIH, Baltimore, MD USA. RP Teufel, A (reprint author), Johannes Gutenberg Univ Mainz, Dept Internal Med 1, Bldg 605,Langenbeckstr 1, D-55101 Mainz, Germany. EM teufel@uni-mainz.de NR 36 TC 28 Z9 28 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD FEB PY 2009 VL 23 IS 2 BP 135 EP 140 DI 10.3892/ijmm_00000110 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 396DD UT WOS:000262571500001 PM 19148536 ER PT J AU Schlett, CL Massaro, JM Lehman, SJ Bamberg, F O'Donnell, CJ Fox, CS Hoffmann, U AF Schlett, C. L. Massaro, J. M. Lehman, S. J. Bamberg, F. O'Donnell, C. J. Fox, C. S. Hoffmann, U. TI Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE adipose tissue; intra-abdominal fat; tomography; spiral computed; Framingham Heart Study; metabolic risk factors ID CORONARY-ARTERY-DISEASE; COMPUTED-TOMOGRAPHY; RISK-FACTORS; CARDIOVASCULAR-DISEASE; PERIADVENTITIAL FAT; PERICARDIAL FAT; EPICARDIAL FAT; HEART-FAILURE; MEN; ATHEROSCLEROSIS AB Background: Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue. Methods: Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n = 100) who underwent multidetector CT of the thorax (ECG triggering, 2.5mm slice thickness) and the abdomen (helical CT acquisition, 2.5mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between -195 and -45 HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined. Results: The intra-and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97 and 0.97; 0.99 and 0.98, respectively). Similarly, the relative intra-and inter-observer difference was small for both AAT (-1.85 +/- 1.28% and 7.85 +/- 6.08%; respectively) and TAT (3.56 +/- 0.83% and -4.56 +/- 0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r = 0.65 and 0.77, P<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r = 0.39 and 0.42, P<0.0001 and P = 0.009), waist circumference (r = 0.49 and 0.57, P<0.0001 for both) and body mass index (r = 0.47 and 0.58, P<0.0001 for both). Conclusion: Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors and clinical outcomes. C1 [Schlett, C. L.; Lehman, S. J.; Bamberg, F.; Hoffmann, U.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Massaro, J. M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [O'Donnell, C. J.; Fox, C. S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [O'Donnell, C. J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiol Div, Boston, MA 02114 USA. [Fox, C. S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Metab,Dept Med, Boston, MA 02114 USA. RP Hoffmann, U (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung and Blood Institute [N01-HC-25195]; German Federal Ministry of Education and Research; Foundation of German Business, Berlin FX The Framingham Heart Study is supported by the National Heart, Lung and Blood Institute (N01-HC-25195). CL Schlett is supported in part by grants from the German Federal Ministry of Education and Research and the Foundation of German Business, Berlin. NR 31 TC 44 Z9 46 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2009 VL 33 IS 2 BP 226 EP 232 DI 10.1038/ijo.2008.267 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 407JU UT WOS:000263360200006 PM 19139753 ER PT J AU Eiriksdottir, G Smith, AV Aspelund, T Hafsteinsdottir, SH Olafsdottir, E Launer, LJ Harris, TB Gudnason, V AF Eiriksdottir, G. Smith, A. V. Aspelund, T. Hafsteinsdottir, S. H. Olafsdottir, E. Launer, L. J. Harris, T. B. Gudnason, V. TI The interaction of adiposity with the CRP gene affects CRP levels: Age, Gene/Environment Susceptibilty-Reykjavik Study SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE CRP gene; CRP levels; adiposity; gene/environment interaction; AGES-Reykjavik Study ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; TYPE-2 DIABETES-MELLITUS; BODY-FAT DISTRIBUTION; METABOLIC-SYNDROME; MYOCARDIAL-INFARCTION; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE; RISK; POLYMORPHISMS AB Objective: Common diseases often have an inflammatory component reflected by associated markers such as serum C-reactive protein (CRP) levels. Circulating CRP levels have also been associated with adipose tissue as well as with specific CRP genotypes. We examined the interaction between measures of body mass index (BMI), waist circumference and fat percent (total fat measured by bioimpedance) with genotypes of the CRP gene in the determination of CRP levels. Methods: The first 2296 participants (mean age 76 +/- 6 years, 42% men) in the Age, Gene/Environment Susceptibility-Reykjavik Study, a multidisciplinary epidemiological study to determine risk factors in aging, were genotyped for 10 single nucleotide polymorphisms (SNPs) in the CRP gene. General linear models with age and terms for interaction of CRP genotypes with BMI, waist circumference and percent fat were used to evaluate the association of genotypes to CRP levels (high-sensitivity method, range 0-10mgl(-1)) in men and women separately. Results: We focused on the SNP rs1205 that represents the allele that captures the strongest effects of the gene on CRP levels. Carriers of the rs1205 G allele had significantly higher CRP levels than noncarriers in a dose-dependent manner. Compared to the AA genotype, the slope of the increase in CRP with increasing BMI (P = 0.045) and waist circumference (P = 0.014) was different for the G allele carriers and of similar magnitude in both men and women. The rs1205 interactions were not significant for fat mass percent, suggesting a possible association with fat localization. Conclusions: This study further illuminates the known association between measures of adiposity and CRP levels and is shown to be dependent on variation in the rs1205 SNP of the CRP gene. The correlated increase in CRP levels with adiposity is accentuated by presence of the G allele. C1 [Eiriksdottir, G.; Smith, A. V.; Aspelund, T.; Hafsteinsdottir, S. H.; Olafsdottir, E.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, T.] Univ Iceland, Dept Math, Reykjavik, Iceland. [Gudnason, V.] Landspitali Univ Hosp, Dept Med, Reykjavik, Iceland. [Launer, L. J.; Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Eiriksdottir, G (reprint author), Hjartavernd Iceland Heart Assoc, Holtasmari 1, IS-201 Kopavogur, Iceland. EM gudny@hjarta.is RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845 FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program, Hjartavernd; Althingi FX This study was funded by National Institutes of Health contract N01-AG-12100, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). NR 36 TC 19 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2009 VL 33 IS 2 BP 267 EP 272 DI 10.1038/ijo.2008.274 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 407JU UT WOS:000263360200011 PM 19139754 ER PT J AU Moreira, EF Larrayoz, IM Lee, JW Rodriguez, IR AF Moreira, Ernesto F. Larrayoz, Ignacio M. Lee, Jung Wha Rodriguez, Ignacio R. TI 7-Ketocholesterol Is Present in Lipid Deposits in the Primate Retina: Potential Implication in the Induction of VEGF and CNV Formation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; LOW-DENSITY-LIPOPROTEIN; LIVER-X-RECEPTORS; NF-KAPPA-B; FACTOR GENE; IN-VITRO; ATHEROSCLEROTIC PLAQUES; BIOLOGICAL-SYSTEMS; EPITHELIAL-CELLS; BRUCHS MEMBRANE AB PURPOSE. 7-Ketocholesterol is a highly toxic oxysterol found in abundance in atherosclerotic plaques and is believed to play a critical role in atherosclerosis. The purpose of this study was to identify and localize 7-ketocholesterol (7kCh) in the primate retina and to examine the potential consequences of its presence in oxidized lipid deposits in the retina. METHODS. Unsterified 7kCh was identified and quantified by high-performance liquid chromatography-mass spectrometry. Localization of 7kCh was performed by immunohistochemistry. VEGF induction was determined by qRT-PCR. Cell viability was determined by measuring cellular dehydrogenase activity. Analyses were performed using ARPE19 and human vascular endothelial cells (HMVECs). RESULTS. 7-Ketocholesterol is localized mainly to deposits in the choriocapillaris and Bruch's membrane and on the surfaces of vascular endothelial cells of the neural retina. RPE/choriocapillaris regions contained approximately four times more 7kCh than the neural retina. In ARPE19 cells and HMVECs, oxidized LDL and 7kCh induced VEGF 8- to 10-fold above controls. Hypoxia inducible factor (HIF)-1 alpha levels did not increase as a result of 7kCh treatment, suggesting an HIF-independent induction pathway. Cholesterol sulfate, a liver X receptor (LXR) antagonist, had marked attenuation of the 7kCh-mediated VEGF induction. LXR-specific siRNAs also reduced VEGF induction. Inhibition of NF-kappa B with BAY 11-7082 reduced IL-8 but not VEGF induction. CONCLUSIONS. The location of 7-kCh in the retina and its induction of VEGF in cultured RPE cells and HMVECs suggest it may play a critical role in choroidal neovascularization. The pathway for VEGF induction seems to be independent of HIF-1 alpha and NF-kappa B but seems to be partially regulated by LXRs. (Invest Ophthalmol Vis Sci. 2009;50:523-532) DOI:10.1167/iovs.08-2373 C1 [Rodriguez, Ignacio R.] NEI, NIH, Sect Mech Retinal Dis, LRCMB, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, NIH, Sect Mech Retinal Dis, LRCMB, 7 Mem Dr,MSC0706,Bldg 7,Room 302, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov RI Larrayoz, Ignacio/I-5613-2012 OI Larrayoz, Ignacio/0000-0003-1629-152X FU National Eye Institute FX Supported by the National Eye Institute Intramural Research Program. NR 45 TC 46 Z9 46 U1 0 U2 6 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2009 VL 50 IS 2 BP 523 EP 532 DI 10.1167/iovs.08-2373 PG 10 WC Ophthalmology SC Ophthalmology GA 397MD UT WOS:000262665900005 PM 18936140 ER PT J AU Koonin, EV Novozhilov, AS AF Koonin, Eugene V. Novozhilov, Artem S. TI Origin and Evolution of the Genetic Code: The Universal Enigma SO IUBMB LIFE LA English DT Review DE genetic code; translation; evolution ID TRANSFER-RNA IDENTITY; PROTEIN AMINO-ACIDS; ERROR MINIMIZATION; COEVOLUTION THEORY; TRIPLET-CODE; COMPARATIVE GENOMICS; TRANSLATION SYSTEM; FROZEN ACCIDENT; SELECTION; ALPHABET AB The genetic code is nearly universal, and the arrangement or the codons in the standard codon table is highly nonrandom. The three main concepts on the origin and evolution of the code are the stereochemical theory, according to which codon assignments are dictated by physicochemical affinity between amino acids and the cognate codons (anticodons); the coevolution theory, which posits that the code structure coevolved with amino acid biosynthesis pathways; and the error minimization theory under which selection to minimize the adverse effect or point mutations anti translation errors was the principal factor of the code's evolution. These theories are not. mutually exclusive and are also compatible with the frozen accident hypothesis, that is, the notion that the standard code might have no special properties but was fixed simply because all extant life forms share a common ancestor, with subsequent changes to the code, mostly, precluded by the deleterious effect of codon reassignment. Mathematical analysis of the structure and possible evolutionary trajectories of the code shows that it is highly robust to translational misreading but there are numerous more robust codes, so the standard code potentially could evolve from a random code via a short sequence of codon seriesreassignments. Thus, much of the evolution that led to the standard code could be a combination of frozen accident with selection for error minimization although contributions from coevolution of the code with metabolic pathways and weak affinities between amino acids and nucleotide triplets cannot be ruled out. However, such scenarios for the code evolution are based on formal schemes whose relevance to the actual primordial evolution is uncertain. A real understanding of the code origin and evolution is likely to be attainable only in conjunction with a credible scenario for the evolution of the coding principle itself and the translation system. (c) 2008 IUBMB C1 [Koonin, Eugene V.; Novozhilov, Artem S.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), 8600 Rockville Pike, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Novozhilov, Artem/D-7544-2012; Novozhilov, Artem/C-9248-2013 OI Novozhilov, Artem/0000-0001-5469-2557 FU Aspen Center for Physics (Aspen, CO) [8/10/2008-8/31/2008]; Department of Health and Human Services intramural program (NIH, National Library of Medicine) FX Although the study of the evolution of the genetic code is a relatively well-focused field, the literature accumulated over the 50 years of research is extensive, and we could not possibly cover all of it in a brief review article. Our sincere apologies to all colleagues whose relevant work is not cited because of space restrictions. EVK is grateful to Nigel Goldenfeld, Paul Higgs, and Claus Wilke for insightful discussions during the workshop on "Evolution: from Atoms to Organisms" at the Aspen Center for Physics (Aspen, CO), 8/10/2008-8/31/2008. The authors' research is supported by the Department of Health and Human Services intramural program (NIH, National Library of Medicine). NR 140 TC 80 Z9 89 U1 3 U2 51 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1521-6543 J9 IUBMB LIFE JI IUBMB Life PD FEB PY 2009 VL 61 IS 2 BP 99 EP 111 DI 10.1002/iub.146 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403HX UT WOS:000263074800003 PM 19117371 ER PT J AU Hartley, T Stewart, C Stewart, R Munroe, DJ AF Hartley, Todd Stewart, Claudia Stewart, Robin Munroe, David J. TI Cost-Effective Addition of High-Throughput Colony Picking Capability to a Standard Liquid-Handling Platform SO JALA LA English DT Article DE colony picking; liquid; ALH 3000 AB We have developed a general strategy for the addition of high-throughput colony picking capability to most standard liquid-handling robotic platform This strategy is easily implemented and requires minimal capital outlay (less than $2500 00) To illustrate this strategy, we describe the modification of a Caliper Life Sciences Sciclone ALH (Automated Liquid Handler) 3000 together with a general calibration methodology that can be applied to most liquid-handling robot capable of X, Y, Z positioning (JALA 2009,14 22-26) C1 [Hartley, Todd; Stewart, Claudia; Stewart, Robin; Munroe, David J.] SAIC Frederick Inc, NCI Frederick, Frederick, MD USA. RP Hartley, T (reprint author), Lab Mol Technol, 915 Tollhouse Ave,Suite 209, Frederick, MD 21701 USA. FU National Cancer Institute National Institutes of Health [N01 CO-12400] FX This project has been funded in whole or in port 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 2 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1535-5535 J9 JALA-J ASSOC LAB AUT JI JALA PD FEB PY 2009 VL 14 IS 1 BP 22 EP 26 DI 10.1016/j.jala.2008.03.004 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 691HO UT WOS:000285071100005 ER PT J AU Jennings, JM Ellen, JM Deeds, BG Harris, DR Muenz, LR Barnes, W Lee, S Auerswald, CL AF Jennings, Jacky M. Ellen, Jonathan M. Deeds, Bethany Griffin Harris, D. Robert Muenz, Larry R. Barnes, William Lee, Sonia Auerswald, Colette L. CA Adolescent Trials Network HIV AIDS TI RECENT PARTNER-SPECIFIC HIV TRANSMISSION RISK FOR YOUTH LIVING WITH HIV SO JOURNAL OF ADOLESCENT HEALTH LA English DT Meeting Abstract C1 [Jennings, Jacky M.; Ellen, Jonathan M.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Jennings, Jacky M.; Ellen, Jonathan M.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21218 USA. [Deeds, Bethany Griffin] Natl Inst Drug Abuse, Div Epidemiol, Serv & Prevent Res, Bethesda, MD USA. [Harris, D. Robert; Muenz, Larry R.] Westat Corp, Rockville, MD USA. [Barnes, William] George Washington Univ, Childrens Natl Med Ctr, Washington, DC USA. [Lee, Sonia] NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. [Auerswald, Colette L.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Auerswald, Colette L.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD FEB PY 2009 VL 44 IS 2 MA 29 BP S25 EP S26 PG 2 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 406BN UT WOS:000263270100059 ER PT J AU Alexis, NE Zhou, H Lay, JC Devlin, R Kleeberger, S Peden, DB AF Alexis, N. E. Zhou, H. Lay, J. C. Devlin, R. Kleeberger, S. Peden, D. B. TI GSTM1(null) Has No Effect on the FEV1 Response to Acute Ozone Exposure but Significantly Affects the Proportion of Inflammatory Cells in the Airways of Allergic and Non Allergic Individuals SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Alexis, N. E.; Zhou, H.; Lay, J. C.; Peden, D. B.] Ctr Environm Med Asthma Lung Biol, Chapel Hill, NC USA. [Alexis, N. E.] Univ N Carolina, Chapel Hill, NC USA. [Devlin, R.] US EPA, Clin Res Branch, Chapel Hill, NC USA. [Kleeberger, S.] NIEHS, Res Triangle Pk, NC USA. RI Lay, John/A-6380-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 530 BP S139 EP S139 DI 10.1016/j.jaci.2008.12.517 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301003 ER PT J AU Calatroni, A Arbes, SJ Gergen, PJ Mitchell, HE Zeldin, DC AF Calatroni, A. Arbes, S. J. Gergen, P. J. Mitchell, H. E. Zeldin, D. C. TI Classification of 19 Allergen-Specific IgE Antibodies Tested in NHANES 2005-2006 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Calatroni, A.; Arbes, S. J.; Mitchell, H. E.] Rho Inc, Chapel Hill, NC USA. [Gergen, P. J.] NIAID, NIH, Bethesda, MD 20892 USA. [Zeldin, D. C.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 740 BP S193 EP S193 DI 10.1016/j.jaci.2008.12.732 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301213 ER PT J AU Carter, MC Uzzaman, A Maric, I Noel, P Metcalfe, D AF Carter, M. C. Uzzaman, A. Maric, I. Noel, P. Metcalfe, D. TI Long Term Clinical and Histologic Follow-up of Pediatric Onset Mastocytosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Carter, M. C.; Uzzaman, A.; Metcalfe, D.] NIAID, NIH, LAD, Bethesda, MD 20892 USA. [Maric, I.; Noel, P.] NIH, CC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 763 BP S199 EP S199 DI 10.1016/j.jaci.2008.12.756 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301236 ER PT J AU Cheadle, C Gao, PS Grigoryev, D Rafaels, NM Wright, JM Plunkett, BA Chen, YC Stockton, M Togias, A Beaty, TH Mathias, RA Schroeder, JT Barnes, KC AF Cheadle, C. Gao, P. S. Grigoryev, D. Rafaels, N. M. Wright, J. M. Plunkett, B. A. Chen, Y. C. Stockton, M. Togias, A. Beaty, T. H. Mathias, R. A. Schroeder, J. T. Barnes, K. C. TI Identification of a Transcriptional Signature Associated with Specific Immune Response to Cockroach Allergen SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Cheadle, C.; Gao, P. S.; Grigoryev, D.; Rafaels, N. M.; Wright, J. M.; Plunkett, B. A.; Chen, Y. C.; Stockton, M.; Togias, A.; Schroeder, J. T.; Barnes, K. C.] Johns Hopkins Sch Med, Baltimore, MD USA. [Beaty, T. H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mathias, R. A.] NHGRI, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 855 BP S222 EP S222 DI 10.1016/j.jaci.2008.12.850 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301327 ER PT J AU Chen, L Huang, J Kuo, M Wang, J Huang, H Huang, S AF Chen, L. Huang, J. Kuo, M. Wang, J. Huang, H. Huang, S. TI Interaction of Clara Cell 10 kd Protein (CC10) and Formyl Peptide Receptor-Like 1 (FPRL1) Suppresses Lung Fibroblast Cytokine Release and Neutrophil Superoxide Generation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Chen, L.; Huang, J.; Huang, H.] Chang Gung Mem Hosp, Tao Yuan, Taiwan. [Chen, L.; Huang, J.] Chang Gung Univ, Tao Yuan, Taiwan. [Kuo, M.] Chang Gung Univ, Inst Basic Med Sci, Dept Microbiol & Immunol, Tao Yuan, Taiwan. [Wang, J.] Natl Canc Inst, Mol Immunoregulat Lab, Frederick, MD USA. [Huang, S.] Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 174 BP S49 EP S49 DI 10.1016/j.jaci.2008.12.154 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300187 ER PT J AU DiVietro, JA Bansal, G Kuehn, HS Gilfillan, AM Druey, KM AF DiVietro, J. A. Bansal, G. Kuehn, H. S. Gilfillan, A. M. Druey, K. M. TI RGS13 Controls G-Protein-Coupled Receptor-Evoked Responses of Human Mast Cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [DiVietro, J. A.; Bansal, G.; Kuehn, H. S.; Gilfillan, A. M.; Druey, K. M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 753 BP S196 EP S196 DI 10.1016/j.jaci.2008.12.746 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301226 ER PT J AU Donohue, KM Perera, F Chanock, S Tang, D Hoepner, L Wang, S Liu, R Chen, R Miller, RL AF Donohue, K. M. Perera, F. Chanock, S. Tang, D. Hoepner, L. Wang, S. Liu, R. Chen, R. Miller, R. L. TI GST Polymorphisms and Atopic Dermatitis in an Inner City Cohort SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy Asthma & Immunol (AAAAI) C1 [Donohue, K. M.] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Chanock, S.; Chen, R.] NCI, Bethesda, MD 20892 USA. [Tang, D.] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY USA. [Hoepner, L.] Columbia Univ, Columbia Ctr Childrens Environm Hlth, Mailman Sch Publ Hlth, New York, NY USA. [Hoepner, L.] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY USA. [Miller, R. L.] Columbia Univ, New York Presbyterian Hosp, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 SU S MA 259 BP S71 EP S71 DI 10.1016/j.jaci.2008.12.241 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300272 ER PT J AU Gao, L Coe, E Campbell, M Yang, M Hand, T Rafaels, NM Poloczek, A Watson, H Dunston, G Hansel, N Diette, G Adkinson, N Mathias, RA Beaty, TH Johns, RA Barnes, KC AF Gao, L. Coe, E. Campbell, M. Yang, M. Hand, T. Rafaels, N. M. Poloczek, A. Watson, H. Dunston, G. Hansel, N. Diette, G. Adkinson, N., Jr. Mathias, R. A. Beaty, T. H. Johns, R. A. Barnes, K. C. TI Polymorphisms in Resistin (RETN) and Resistin-like Beta (RETNLB) and Risk of Asthma in Independent Populations of African Descent SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Gao, L.; Coe, E.; Campbell, M.; Yang, M.; Hand, T.; Rafaels, N. M.; Poloczek, A.; Hansel, N.; Diette, G.; Adkinson, N., Jr.; Beaty, T. H.; Johns, R. A.; Barnes, K. C.] Johns Hopkins Univ, Baltimore, MD USA. [Watson, H.] Univ W Indies, W Indies, Barbados. [Dunston, G.] Howard Univ, Washington, DC 20059 USA. [Mathias, R. A.] NHGRI, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 633 BP S166 EP S166 DI 10.1016/j.jaci.2008.12.623 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301106 ER PT J AU Gruenberg, DA Gern, JE Holland, SM Seroogy, CM AF Gruenberg, D. A. Gern, J. E. Holland, S. M. Seroogy, C. M. TI Overwhelming MAI and Pneumococcal Infection in a 19 Month Female with Normal IFN gamma RI Expression SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Gruenberg, D. A.; Gern, J. E.; Seroogy, C. M.] Univ Wisconsin Hosp & Clin, Madison, WI 53792 USA. [Holland, S. M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 35 BP S13 EP S13 DI 10.1016/j.jaci.2008.12.062 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300046 ER PT J AU Haberg, SE AF Haberg, S. E. TI Folic Acid Supplements in Pregnancy and Respiratory Health in Early Childhood SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Haberg, S. E.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 55 BP S18 EP S18 DI 10.1016/j.jaci.2008.12.083 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300066 ER PT J AU Jaramillo, R Massing, M Sichere, SH Wood, RA Bock, SA Burks, AW Zeldin, DC Liu, AH AF Jaramillo, R. Massing, M. Sichere, S. H. Wood, R. A. Bock, S. A. Burks, A. W. Zeldin, D. C. Liu, A. H. TI High-Level Sensitization to Foods is Associated with Asthma ER Visits and Current Asthma in the US: Results from NHANES 2005-2006 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Jaramillo, R.; Massing, M.] SRA Int Inc, Durham, NC USA. [Sichere, S. H.] Mt Sinai Sch Med, Jaffe Food Allergy Inst, New York, NY USA. [Wood, R. A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bock, S. A.; Liu, A. H.] Natl Jewish Hlth, Denver, CO USA. [Bock, S. A.; Liu, A. H.] Univ Colorado, Sch Med, Aurora, CO USA. [Burks, A. W.] Duke Univ, Med Ctr, Durham, NC USA. [Zeldin, D. C.] NIH Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 419 BP S111 EP S111 DI 10.1016/j.jaci.2008.12.404 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300432 ER PT J AU Josephs, AR Prussin, C AF Josephs, A. R. Prussin, C. TI Assessment of Spleen Tyrosine Kinase Expression in Basophils using Flow Cytometry SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Josephs, A. R.; Prussin, C.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 756 BP S197 EP S197 DI 10.1016/j.jaci.2008.12.749 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301229 ER PT J AU Kirshenbaum, AS Wu, Y Brown, JM Gilfillan, AM Lantz, LM Reese, G Vieths, S Metcalfe, DD AF Kirshenbaum, A. S. Wu, Y. Brown, J. M. Gilfillan, A. M. Lantz, L. M. Reese, G. Vieths, S. Metcalfe, D. D. TI Identification of Shrimp Tropomyosin (Pen a 1) as an IgE-Independent Mast Cell Secretagogue SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Kirshenbaum, A. S.; Wu, Y.; Brown, J. M.; Gilfillan, A. M.; Lantz, L. M.; Metcalfe, D. D.] NIAID, NIH, Bethesda, MD 20892 USA. [Reese, G.; Vieths, S.] Paul Ehrlich Inst, D-6070 Langen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 664 BP S174 EP S174 DI 10.1016/j.jaci.2008.12.655 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301137 ER PT J AU Klion, AD Wilson, TM Brown, M Maric, I Metcalfe, DD Nutman, TB AF Klion, A. D. Wilson, T. M. Brown, M. Maric, I. Metcalfe, D. D. Nutman, T. B. TI Surface and Soluble IL-5 Receptor Alpha Expression in Patients with Eosinophilia and Mastocytosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Klion, A. D.; Wilson, T. M.; Brown, M.; Maric, I.; Metcalfe, D. D.; Nutman, T. B.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 973 BP S251 EP S251 DI 10.1016/j.jaci.2008.12.970 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301445 ER PT J AU Liu, AH Sicherer, SH Wood, RA Bock, SA Burks, AW Jaramillo, R Spruell, B Massing, M Zeldin, DC AF Liu, A. H. Sicherer, S. H. Wood, R. A. Bock, S. A. Burks, A. W. Jaramillo, R. Spruell, B. Massing, M. Zeldin, D. C. TI In the United States, Black Male Children have an Increased Risk of Food Allergy: Results from NHANES 2005-2006 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Liu, A. H.; Bock, S. A.] Natl Jewish Hlth, Denver, CO USA. [Liu, A. H.; Bock, S. A.] Univ Colorado, Sch Med, Aurora, CO USA. [Sicherer, S. H.] Mt Sinai Sch Med, Jaffe Food Allergy Inst, New York, NY USA. [Wood, R. A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Burks, A. W.] Duke Univ, Med Ctr, Durham, NC USA. [Jaramillo, R.; Spruell, B.; Massing, M.] SRA Int Inc, Durham, NC USA. [Zeldin, D. C.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. NR 0 TC 4 Z9 4 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 1037 BP S267 EP S267 DI 10.1016/j.jaci.2008.12.1036 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301509 ER PT J AU Pomes, A Li, M Glesner, J Wunschmann, S King, EM Chapman, MD Wlodawer, A Gustchina, A AF Pomes, A. Li, M. Glesner, J. Wuenschmann, S. King, E. M. Chapman, M. D. Wlodawer, A. Gustchina, A. TI The X-Ray Crystal Structure of Two Complexes of the Cockroach Allergen Bla g 2 with Fragments of Monoclonal Antibodies Defines Two Non-overlapping Epitopes SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Pomes, A.; Glesner, J.; Wuenschmann, S.; King, E. M.; Chapman, M. D.] INDOOR Biotechnol Inc, Charlottesville, VA USA. [Li, M.] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Li, M.; Wlodawer, A.; Gustchina, A.] Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 885 BP S229 EP S229 DI 10.1016/j.jaci.2008.12.881 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301357 ER PT J AU Radinger, MK Kim, M Metcalfe, DD Gilfillan, AM AF Radinger, M. K. Kim, M. Metcalfe, D. D. Gilfillan, A. M. TI Lentivirus-mediated Short Hairpin RNA Knockdown Of Glycogen Synthase Kinase-3 beta Markedly Decreases Fc epsilon RI-mediated Human Mast Cell Cytokine Production SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Radinger, M. K.; Kim, M.; Metcalfe, D. D.; Gilfillan, A. M.] NIAID, Lab Allerg Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 758 BP S197 EP S197 DI 10.1016/j.jaci.2008.12.751 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301231 ER PT J AU Sever, ML Arbes, SJ Watson, EC Spencer, HL Vaughn, B Vann, WF Zeldin, DC AF Sever, M. L. Arbes, S. J., Jr. Watson, E. C. Spencer, H. L., Jr. Vaughn, B. Vann, W. F., Jr. Zeldin, D. C. TI Oral Bacteria and History of Allergic Disease in Children: A Pilot Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Sever, M. L.; Watson, E. C.; Spencer, H. L., Jr.; Zeldin, D. C.] NIEHS, Environm Cardiopulm Dis Grp, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Sever, M. L.] Univ N Carolina, UNC Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Arbes, S. J., Jr.; Vaughn, B.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Spencer, H. L., Jr.] Meharry Med Coll, Sch Dent, Nashville, TN 37208 USA. [Vann, W. F., Jr.] Univ N Carolina, Dept Pediat Dent, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 59 BP S19 EP S19 DI 10.1016/j.jaci.2008.12.087 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300070 ER PT J AU Slager, RE Levan, TD Poole, JA Sandler, DP Hoppin, JA AF Slager, R. E. LeVan, T. D. Poole, J. A. Sandler, D. P. Hoppin, J. A. TI Occupational Risk Factors for Rhinitis Among Farmers in the Agricultural Health Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Slager, R. E.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [LeVan, T. D.; Poole, J. A.] Univ Nebraska Med Ctr, Omaha, NE USA. [Sandler, D. P.; Hoppin, J. A.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 1031 BP S266 EP S266 DI 10.1016/j.jaci.2008.12.1029 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301503 ER PT J AU Tran, D AF Tran, D. TI Dysfunctional FOXP3+Regulatory T cells in leukocyte Adhesion Deficiency Type 1 (LAD-1) Patients with Reversion Mutations and Inflammatory Bowel Disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Tran, D.] NIAID, NIH, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 43 BP S15 EP S15 DI 10.1016/j.jaci.2008.12.070 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300054 ER PT J AU Tsai, YJ Mathias, R Grant, A Rafaels, N Hand, T Togias, A Hansel, N Diette, G Adkinson, NF Liu, MC Faruque, M Watson, H Scott, A Ruczinski, I Dunston, G Beaty, T Barnes, KC AF Tsai, Y. J. Mathias, R. Grant, A. Rafaels, N. Hand, T. Togias, A. Hansel, N. Diette, G. Adkinson, N. F., Jr. Liu, M. C. Faruque, M. Watson, H. Scott, A. Ruczinski, I. Dunston, G. Beaty, T. Barnes, K. C. TI A Genome Wide Approach to Identify Genetic Determinants of Asthma Traits Related to Airway Function in Two Populations of African Descent SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Mathias, R.] NHGRI, Baltimore, MD USA. [Togias, A.] NIAID, Bethesda, MD 20892 USA. [Faruque, M.; Dunston, G.] Howard Univ, Washington, DC 20059 USA. NR 0 TC 0 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 567 BP S148 EP S148 DI 10.1016/j.jaci.2008.12.555 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596301040 ER PT J AU Visness, CM Daniels, JL Kaufman, JS Yeatts, KB London, SJ Siega-Riz, AM Calatroni, A Zeldin, DC AF Visness, C. M. Daniels, J. L. Kaufman, J. S. Yeatts, K. B. London, S. J. Siega-Riz, A. M. Calatroni, A. Zeldin, D. C. TI Childhood Obesity is Associated with Both Atopy and Current Asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Visness, C. M.; Calatroni, A.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Daniels, J. L.; Kaufman, J. S.; Yeatts, K. B.; Siega-Riz, A. M.] Univ N Carolina, Chapel Hill, NC USA. [London, S. J.; Zeldin, D. C.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 264 BP S72 EP S72 DI 10.1016/j.jaci.2008.12.246 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300277 ER PT J AU Wu, H Romieu, I Sienra-Monge, J Li, H del Rio-Navarro, B London, SJ AF Wu, H. Romieu, I. Sienra-Monge, J. Li, H. del Rio-Navarro, B. London, S. J. TI Genetic Variation In ORM1-like 3 (ORMDL3) And Gasdermin-like (GSDML) And Childhood Asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Wu, H.; Li, H.; London, S. J.] NIEHS, NIH, Lab Resp Biol, Div Intramural Res,DHHS, Res Triangle Pk, NC 27709 USA. [Romieu, I.] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Sienra-Monge, J.; del Rio-Navarro, B.] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 185 BP S52 EP S52 DI 10.1016/j.jaci.2008.12.165 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300198 ER PT J AU Yang, Z Mukhopadhyay, I Druey, KM AF Yang, Z. Mukhopadhyay, I. Druey, K. M. TI Regulation of Airway Smooth Muscle Functions by RGS5 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY MAR 13-17, 2009 CL Washington, DC SP Amer Acad Allergy, Asthma & Immunol C1 [Yang, Z.; Mukhopadhyay, I.; Druey, K. M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2009 VL 123 IS 2 MA 449 BP S118 EP S118 DI 10.1016/j.jaci.2008.12.435 PG 1 WC Allergy; Immunology SC Allergy; Immunology GA 410RR UT WOS:000263596300462 ER PT J AU Stergiopoulou, T Meletiadis, J Sein, T Papaioannidou, P Tsiouris, I Roilides, E Walsh, TJ AF Stergiopoulou, Theodouli Meletiadis, Joseph Sein, Tin Papaioannidou, Paraskevi Tsiouris, Ioannis Roilides, Emmanuel Walsh, Thomas J. TI Comparative pharmacodynamic interaction analysis between ciprofloxacin, moxifloxacin and levofloxacin and antifungal agents against Candida albicans and Aspergillus fumigatus SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article ID HEALTHY-VOLUNTEERS; J774 MACROPHAGES; PATHOGENIC FUNGI; AMPHOTERICIN-B; 4 QUINOLONES; IN-VITRO; FLUCONAZOLE; COMBINATION; EFFLUX; PLASMA AB Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Ciprofloxacin, a carboxyfluoroquinolone, was previously observed to demonstrate the pharmacodynamic interactions with antifungal agents by altering their growth inhibitory activity against Candida albicans and Aspergillus fumigatus. However, little is known about the interaction between other extended-spectrum fluoroquinolones, such as levofloxacin and moxifloxacin, and antifungal agents against C. albicans and A. fumigatus. Using a microdilution chequerboard technique, we employed isobolographic analysis adapted to incorporate a non-active agent in order to analyse the potential in vitro interaction between ciprofloxacin, levofloxacin or moxifloxacin and the following representative antifungal agents: amphotericin B, fluconazole or voriconazole and caspofungin. Synergistic interactions [interaction indices (Iis) 0.69-0.83, P < 0.05] were observed between amphotericin B (0.07-0.31 mg/L) and either ciprofloxacin (0.19-7.65 mg/L) or levofloxacin (0.41-32.88 mg/L) against C. albicans and A. fumigatus. Synergy (Iis 0.56-0.87, P < 0.05) also was found between voriconazole (0.09-0.14 mg/L) and ciprofloxacin (0.22-11.41 mg/L) as well as between caspofungin (8.94-22.07 mg/L) and levofloxacin (0.14-5.17 mg/L) against A. fumigatus. Some antagonistic (Iis 1.16-1.29, P < 0.05) interactions were observed between fluoroquinolones and fluconazole against C. albicans. In general, ciprofloxacin enhanced the activity of antifungal agents more than moxifloxacin and levofloxacin against both C. albicans and A. fumigatus. The knowledge of the pharmacodynamic interactions between fluoroquinolones and antifungal agents may guide selection and potentially improve the outcome of immunosuppressed patients with concurrent bacterial and fungal infections. C1 [Stergiopoulou, Theodouli; Meletiadis, Joseph; Sein, Tin; Roilides, Emmanuel; Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Paediat Oncol Branch, Bethesda, MD 20892 USA. [Stergiopoulou, Theodouli; Tsiouris, Ioannis; Roilides, Emmanuel] Aristotle Univ Thessaloniki, Hippokrat Hosp, Pediat Dept 3, GR-54006 Thessaloniki, Greece. [Meletiadis, Joseph] Univ Athens, Attiko Univ Hosp, Lab Clin Microbiol, Athens, Greece. [Sein, Tin] SAIC Frederick Inc, Frederick, MD 21702 USA. [Papaioannidou, Paraskevi] Aristotle Univ Thessaloniki, Fac Med, Dept Pharmacol, GR-54006 Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Paediat Oncol Branch, 10 Ctr Dr,Bldg 10-Rm 1-5750, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov RI Papaioannidou, Paraskevi/D-9864-2011; OI Papaioannidou, Paraskevi/0000-0001-8880-0288 FU National Cancer Institute, Bethesda, MD, USA; Hippokration Hospital, Aristotle University of Thessaloniki, Greece FX This study was supported by the intramural research programme of the National Cancer Institute, Bethesda, MD, USA, and by the Hippokration Hospital, Aristotle University of Thessaloniki, Greece. NR 19 TC 21 Z9 23 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD FEB PY 2009 VL 63 IS 2 BP 343 EP 348 DI 10.1093/jac/dkn473 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 395LD UT WOS:000262524700021 PM 19109335 ER PT J AU Hortobagyi, T Richardson, SP Lomarev, M Shamim, E Meunier, S Russman, H Dang, N Hallett, M AF Hortobagyi, Tibor Richardson, Sarah Pirio Lomarev, Mikhael Shamim, Ejaz Meunier, Sabine Russman, Heike Dang, Nguyet Hallett, Mark TI Chronic low-frequency rTMS of primary motor cortex diminishes exercise training-induced gains in maximal voluntary force in humans SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE muscle; transcranial magnetic stimulation; cortical excitability ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN CORTICOSPINAL EXCITABILITY; EVOKED V-WAVE; H-REFLEX; ELECTRICAL-STIMULATION; NEURAL ADAPTATIONS; NEUROMUSCULAR FATIGUE; CORTICAL PLASTICITY; MUSCLE ACTIVATION; SKELETAL-MUSCLE AB Hortobagyi T, Richardson SP, Lomarev M, Shamim E, Meunier S, Russman H, Dang N, Hallett M. Chronic low-frequency rTMS of primary motor cortex diminishes exercise training-induced gains in maximal voluntary force in humans. J Appl Physiol 106: 403-411, 2009. First published November 13, 2008; doi: 10.1152/japplphysiol. 90701.2008.-Although there is consensus that the central nervous system mediates the increases in maximal voluntary force (maximal voluntary contraction, MVC) produced by resistance exercise, the involvement of the primary motor cortex (M1) in these processes remains controversial. We hypothesized that 1-Hz repetitive transcranial magnetic stimulation ( rTMS) of M1 during resistance training would diminish strength gains. Forty subjects were divided equally into five groups. Subjects voluntarily (Vol) abducted the first dorsal interosseus (FDI) ( 5 bouts x 10 repetitions, 10 sessions, 4 wk) at 70-80% MVC. Another group also exercised but in the 1-min-long interbout rest intervals they received rTMS [Vol+rTMS, 1 Hz, FDI motor area, 300 pulses/session, 120% of the resting motor threshold (rMT)]. The third group also exercised and received sham rTMS ( Vol+Sham). The fourth group received only rTMS (rTMS_only). The 37.5% and 33.3% gains in MVC in Vol and Vol+Sham groups, respectively, were greater (P = 0.001) than the 18.9% gain in Vol+rTMS, 1.9% in rTMS_only, and 2.6% in unexercised control subjects who received no stimulation. Acutely, within sessions 5 and 10, single-pulse TMS revealed that motor-evoked potential size and recruitment curve slopes were reduced in Vol+rTMS and rTMS_only groups and accumulated to chronic reductions by session 10. There were no changes in rMT, maximum compound action potential amplitude (M(max)), and peripherally evoked twitch forces in the trained FDI and the untrained abductor digiti minimi. Although contributions from spinal sources cannot be excluded, the data suggest that M1 may play a role in mediating neural adaptations to strength training. C1 [Hortobagyi, Tibor] E Carolina Univ, Dept Exercise & Sport Sci, Greenville, NC 27858 USA. [Richardson, Sarah Pirio] Univ New Mexico, Albuquerque, NM 87131 USA. [Lomarev, Mikhael] Bekhierev Neuropsychol Inst, St Petersburg, Russia. [Shamim, Ejaz; Meunier, Sabine; Dang, Nguyet; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. [Russman, Heike] CHU Vaudois, CH-1011 Lausanne, Switzerland. RP Hortobagyi, T (reprint author), E Carolina Univ, Dept Exercise & Sport Sci, 332A Ward Sports Med Bldg, Greenville, NC 27858 USA. EM hortobagyit@ecu.edu RI meunier, sabine/G-7622-2014 OI meunier, sabine/0000-0002-6167-4602 FU National Institute of Neurological Disorders and Stroke [NS-049783]; East Carolina University's Division of Research and Graduate Studies FX This work was supported in part by National Institute of Neurological Disorders and Stroke Grant NS-049783 and by a Research Development Grant from East Carolina University's Division of Research and Graduate Studies. NR 59 TC 17 Z9 18 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB PY 2009 VL 106 IS 2 BP 403 EP 411 DI 10.1152/japplphysiol.90701.2008 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 403ZL UT WOS:000263120400010 PM 19008488 ER PT J AU Scaglione, BJ Salerno, E Gala, K Pan, M Langer, JA Mostowski, HS Bauer, S Marti, G Li, Y Tsiagbe, VK Raveche, ES AF Scaglione, Brian J. Salerno, Erica Gala, Kinisha Pan, Manjing Langer, Jerome A. Mostowski, Howard S. Bauer, Steven Marti, Gerald Li, Yu Tsiagbe, Vincent K. Raveche, Elizabeth S. TI Regulatory T cells as central regulators of both autoimmunity and B cell malignancy in New Zealand Black mice SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Autoimmunity; Regulatory T cells; Tumor immunity ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SYSTEMIC-LUPUS-ERYTHEMATOSUS; IMMUNOLOGICAL SELF-TOLERANCE; AUTO-IMMUNE DISEASE; NZB MICE; INTERFERON-ALPHA; MURINE LUPUS; LYMPHOPROLIFERATIVE DISEASE; AUTOANTIBODY PRODUCTION; LEUKOCYTE INTERFERONS AB Regulatory T cells (Tregs) play an important role in protection against autoimmune disease and are also known to be potent inhibitors of anti-tumor immune responses. The New Zealand Black (NZB) mouse is a murine model for both autoimmune diseases, since high levels of autoantibodies are present, and human CLL, due to the expansion of malignant B-1 cells. In this study, we examined the functional role of CD4(+)CD25(+) Foxp3(+) Tregs in these different manifestations. Flow cytometric analysis showed increased levels of Tregs in NZB mice compared to healthy C57Bl/6 controls. Aged NZB mice that have developed a B-1 cell malignancy identified as IgM(+)CD5(+), have the most pronounced increase in Tregs. Ex vivo treatment of splenocytes from NZB mice with IFN-alpha resulted in a decrease in the frequency of Tregs and malignant B-1 cells. In vivo treatment of both NZB and C57Bl/6 mice with poly (I:C), a potent inducer of IFN-alpha, also led to a decrease in the levels of Tregs and malignant B-1 cells (NZB only) while amplifying autoimmune manifestations. These results indicate that while high levels of Tregs found in NZB mice might suppress a more severe autoimmune disease, they may also contribute to the development of the B cell malignancy. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Salerno, Erica; Gala, Kinisha; Tsiagbe, Vincent K.; Raveche, Elizabeth S.] Univ Med & Dent, New Jersey Med Sch, Newark, NJ 07103 USA. [Pan, Manjing; Langer, Jerome A.] Univ Med & Dent, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Mostowski, Howard S.; Bauer, Steven; Marti, Gerald] US FDA, Ctr Biol Evaluat, NIH, Bethesda, MD 20892 USA. [Tsiagbe, Vincent K.] Univ Med & Dent, New Jersey Dent Sch, Newark, NJ 07103 USA. RP Raveche, ES (reprint author), Univ Med & Dent, New Jersey Med Sch, MSB C512,185 S Orange Ave, Newark, NJ 07103 USA. EM raveches@umdnj.edu OI Bauer, Steven/0000-0003-2831-846X; Langer, Jerome/0000-0002-4617-3260 NR 68 TC 8 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD FEB PY 2009 VL 32 IS 1 BP 14 EP 23 DI 10.1016/j.jaut.2008.10.001 PG 10 WC Immunology SC Immunology GA 413BT UT WOS:000263768600003 PM 19022624 ER PT J AU Wang, J Zhou, XB Li, FH Bradley, PL Chang, SF Perrimon, N Wong, STC AF Wang, Jun Zhou, Xiaobo Li, Fuhai Bradley, Pamela L. Chang, Shih-Fu Perrimon, Norbert Wong, Stephen T. C. TI An image score inference system for RNAi genome-wide screening based on fuzzy mixture regression modeling SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE High-content screening; Image score inference ID SEGMENTATION; TEXTURE; RHO; CLASSIFICATION; RECOGNITION; FEATURES; CELLS AB With recent advances in fluorescence microscopy imaging techniques and methods of gene knock down by RNA interference (RNAi), genome-scale high-content screening (HCS) has emerged as a powerful approach to systematically identify all parts of complex biological processes. However, a critical barrier preventing fulfillment of the success is the lack of efficient and robust methods for automating RNAi image analysis and quantitative evaluation of the gene knock down effects on huge volume of HCS data. Facing such opportunities and challenges, we have started investigation of automatic methods towards the development of a fully automatic RNAi-HCS system. Particularly important are reliable approaches to cellular phenotype classification and image-based gene function estimation. We have developed a HCS analysis platform that consists of two main components: fluorescence image analysis and image scoring. For image analysis, we used a two-step enhanced watershed method to extract cellular boundaries from HCS images. Segmented cells were classified into several predefined phenotypes based on morphological and appearance features. Using statistical characteristics of the identified phenotypes as a quantitative description of the image, a score is generated that reflects gene function. Our scoring model integrates fuzzy gene class estimation and single regression models. The final functional score of an image was derived using the weighted combination of the inference from several support vector-based regression models. We validated our phenotype classification method and scoring system on our cellular phenotype and gene database with expert ground truth labeling. We built a database of high-content, 3-channel, fluorescence microscopy images of Drosophila Kc(167) cultured cells that were treated with RNAi to perturb gene function. The proposed informatics system for microscopy image analysis is tested on this database. Both of the two main components, automated phenotype classification and image scoring system, were evaluated. The robustness and efficiency of our system were validated in quantitatively predicting the biological relevance of genes. (C) 2008 Elsevier Inc. All rights reserved. C1 [Wang, Jun; Chang, Shih-Fu] Columbia Univ, Dept Elect Engn, New York, NY 10027 USA. [Zhou, Xiaobo; Li, Fuhai; Wong, Stephen T. C.] Harvard Univ, Sch Med, Ctr Bioinformat, Harvard Ctr Neurodegenerat & Repair, Boston, MA 02215 USA. [Bradley, Pamela L.] NIH, Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. [Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Wang, J (reprint author), Columbia Univ, Dept Elect Engn, 1300 SW Mudd,500 W 120th St, New York, NY 10027 USA. EM jwang@columbia.edu; zhou@crystal.harvard.edu FU HCNR; Harvard Medical School (Wong) FX The authors thank Baillie Yip for labeling training data sets. They also thank research members of the Life Science Imaging Group of the Center for Bioinformatics, Harvard Center for Neurodegeneration and Repair (HCNR) and Brigham and Women's Hospital, Harvard Medical School, for their technical comments. The research is funded by the HCNR, Harvard Medical School (Wong). NR 35 TC 9 Z9 9 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 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2009 VL 42 IS 1 BP 32 EP 40 DI 10.1016/j.jbi.2008.04.007 PG 9 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 414RK UT WOS:000263882700004 PM 18547870 ER PT J AU Vaidyanathan, J Vaidlyanathan, TK Ravichandran, S AF Vaidyanathan, J. Vaidlyanathan, T. K. Ravichandran, S. TI Computer Simulated Screening of Dentin Bonding Primer Monomers Through Analysis of Their Chemical Functions and Their Spatial 3D Alignment SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE adhesion; collagen; computer modeling/simulation; dental/craniofacial material; tissue adhesion ID COLLAGEN; BINDING AB Binding interactions between dentin bonding primer monomers and dentinal collagen were studied by an analysis of their chemical functions and their spatial 3D alignment. A trial set of 12 monomers used as primers in dentin adhesives was characterized to assess them for binding to a complementary target. HipHop utility in the Catalyst software from Accelrys was used for the study. Ten hypotheses were generated by HipHop procedures involving (a) conformational generation using a poling technique to promote conformational variation, (b) extraction of functions to remodel ligands as function-based structures, and (c) identification of common patterns of functional alignment displayed by low energy conformations. The hypotheses, designated as pharmacaphores, were also scored and ranked. Analysis of pharmacaphore models through mapping of ligands revealed important differences between ligands. Top-ranked poses from direct docking simulations using type 1 collagen target were mapped in a rigid manner to the highest ranked pharmacophore model. The visual match observed in mapping and associated fit values suggest a strong correspondence between direct and indirect docking simulations. The results elegantly demonstrate that an indirect approach used to identify pharmacaphore models from adhesive ligands without a target may be a simple and viable approach to assess their intermolecular interactions with an intended target. Inexpensive indirect/direct virtual screening of hydrophilic monomer candidates may be a practical way to assess their initial promise for dentin primer use well before additional experimental evaluation of their priming/bonding efficacy. This is also of value in the search/design of new compounds for priming dentin. (c) 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 88B: 447-457, 2009 C1 [Vaidyanathan, J.; Vaidlyanathan, T. K.] Univ Med & Dent New Jersey, New Jersey Dent Sch, Dept Restorat Dent, Newark, NJ 07103 USA. [Ravichandran, S.] NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Vaidyanathan, J (reprint author), Univ Med & Dent New Jersey, New Jersey Dent Sch, Dept Restorat Dent, Newark, NJ 07103 USA. EM jvaidyan@umdnj.edu FU NIDCR NIH HHS [R01 DE 14370] NR 20 TC 3 Z9 3 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4973 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD FEB PY 2009 VL 88B IS 2 BP 447 EP 457 DI 10.1002/jbm.b.31134 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 397TB UT WOS:000262683900018 PM 18546179 ER PT J AU Shen, Y Vernon, R Baker, D Bax, A AF Shen, Yang Vernon, Robert Baker, David Bax, Ad TI De novo protein structure generation from incomplete chemical shift assignments SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE NMR chemical shift; Protein structure prediction; Solid-state NMR structure determination; Paramagnetic protein; CS-Rosetta ID STATE NMR-SPECTROSCOPY; MOLECULAR FRAGMENT REPLACEMENT; SOLID-STATE; SEQUENCE HOMOLOGY; MICROCRYSTALLINE UBIQUITIN; SECONDARY STRUCTURE; NUCLEIC-ACIDS; C-13 NMR; CONFORMATION; RESOLUTION AB NMR chemical shifts provide important local structural information for proteins. Consistent structure generation from NMR chemical shift data has recently become feasible for proteins with sizes of up to 130 residues, and such structures are of a quality comparable to those obtained with the standard NMR protocol. This study investigates the influence of the completeness of chemical shift assignments on structures generated from chemical shifts. The Chemical-Shift-Rosetta (CS-Rosetta) protocol was used for de novo protein structure generation with various degrees of completeness of the chemical shift assignment, simulated by omission of entries in the experimental chemical shift data previously used for the initial demonstration of the CS-Rosetta approach. In addition, a new CS-Rosetta protocol is described that improves robustness of the method for proteins with missing or erroneous NMR chemical shift input data. This strategy, which uses traditional Rosetta for pre-filtering of the fragment selection process, is demonstrated for two paramagnetic proteins and also for two proteins with solid-state NMR chemical shift assignments. C1 [Shen, Yang; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Vernon, Robert; Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Vernon, Robert; Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Shen, Yang/C-3064-2008; Baker, David/K-8941-2012 OI Shen, Yang/0000-0003-1408-8034; Baker, David/0000-0001-7896-6217 FU NIDDK; NIH FX This work was funded by the Intramural Research Program of the NIDDK, NIH, and by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH; the NIGMS, NIH, and the Howard Hughes Medical Institutes ( to D. B.). We also thank Rosetta@home participants and the BOINC project for contributing computing power. NR 56 TC 135 Z9 137 U1 3 U2 34 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD FEB PY 2009 VL 43 IS 2 BP 63 EP 78 DI 10.1007/s10858-008-9288-5 PG 16 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 391NT UT WOS:000262240700001 PM 19034676 ER PT J AU Katz, SI AF Katz, Stephen I. TI Musculoskeletal Research at the National Institute of Arthritis and Musculoskeletal and Skin Diseases: A Snapshot SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Editorial Material C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Katz, SI (reprint author), NIAMSD, NIH, Bldg 31,Room 4C32,31 Ctr Dr, Bethesda, MD 20892 USA. EM katzs@od.niams.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 2 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD FEB PY 2009 VL 91A IS 2 BP 474 EP 475 DI 10.2106/JBJS.H.01607 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 403LA UT WOS:000263082900027 PM 19181994 ER PT J AU Voss, TC Schiltz, RL Sung, MH Johnson, TA John, S Hager, GL AF Voss, Ty C. Schiltz, R. Louis Sung, Myong-Hee Johnson, Thomas A. John, Sam Hager, Gordon L. TI Combinatorial probabilistic chromatin interactions produce transcriptional heterogeneity SO JOURNAL OF CELL SCIENCE LA English DT Article DE Chromatin; Steroid receptor; Stochastics; Transcription ID STOCHASTIC GENE-EXPRESSION; MAMMARY-TUMOR VIRUS; HORMONE-BINDING DOMAINS; GLUCOCORTICOID-RECEPTOR; LIVING CELLS; SINGLE-CELL; NUCLEAR RECEPTORS; MMTV PROMOTER; DYNAMICS; COACTIVATOR AB Gene regulation often appears deterministic in the average cell population, but transcription is a probabilistic process at the single-cell level. Although many mechanisms are invoked to account for this behavior, it is difficult to determine how cell-to-cell variation in the interactions of transcription factors with target chromatin impact transcriptional output. Here, we use cells that contain a 200-copy tandem array of promoter or reporter gene units to simultaneously visualize transient interaction, equilibrium or steady-state binding of fluorescent-protein-labeled glucocorticoid receptor with its DNA response elements, the recruitment of diverse coregulators, and transcriptional output at the single-cell level. These regulatory proteins associate with target chromatin via a probabilistic mechanism that produces cell-to-cell variability in binding. The multiple steps of this process are partially independent and differ between individual regulators. The association level of each regulator influences the transcriptional output in individual cells, but this does not account for all transcriptional heterogeneity. Additionally, specific combinatorial interactions of the glucocorticoid receptor and coregulators with response elements regulate transcription at the single-cell level. Like many endogenous genes, the average array transcriptional activity evolves over time. This apparently deterministic average temporal promoter progression involves changes in the probability that specific combinatorial glucocorticoid receptor and coregulator interactions will occur on the response elements in single cells. These data support the emerging 'return-to-template' transcription model, which mechanistically unifies the observed extremely transient interactions between the transcription factor and response elements, cell-to-cell variability in steady-state association of factors with chromatin, and the resulting heterogeneous gene expression between individual cells. C1 [Voss, Ty C.; Schiltz, R. Louis; Sung, Myong-Hee; Johnson, Thomas A.; John, Sam; Hager, Gordon L.] NCI, Ctr Canc Res, NIH, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Ctr Canc Res, NIH, Lab Receptor Biol & Gene Express, Bldg 41,B602, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX The authors thank Richard N. Day, Catherine L. Smith, and Tom Misteli for helpful discussion during preparation of the manuscript. The mCherry FP cDNA was a generous gift from Roger Tsien. Anindya Hendarwanto provided expert technical support. Tatiana Karpova assisted with experiments performed in the NCI Core Fluorescence Imaging Facility. This research was supported ( in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Deposited in PMC for release after 12 months. NR 46 TC 18 Z9 18 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB 1 PY 2009 VL 122 IS 3 BP 345 EP 356 DI 10.1242/jcs.035865 PG 12 WC Cell Biology SC Cell Biology GA 396HE UT WOS:000262582000006 PM 19126674 ER PT J AU Carlson, GA Findling, RL Post, RM Birmaher, B Blumberg, HP Correll, C DelBello, MP Fristad, M Frazier, J Hammen, C Hinshaw, SP Kowatch, R Leibenluft, E Meyer, SE Pavuluri, MN Wagner, KD Tohen, M AF Carlson, Gabrielle A. Findling, Robert L. Post, Robert M. Birmaher, Boris Blumberg, Hilary P. Correll, Christoph DelBello, Melissa P. Fristad, Mary Frazier, Jean Hammen, Constance Hinshaw, Stephen P. Kowatch, Robert Leibenluft, Ellen Meyer, Stephanie E. Pavuluri, Mani N. Wagner, Karen Dineen Tohen, Mauricio TI AACAP 2006 Research Forum-Advancing Research in Early-Onset Bipolar Disorder: Barriers and Suggestions SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID SEVERE MOOD DYSREGULATION; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MAGNETIC-RESONANCE SPECTROSCOPY; FOLLOW-UP; MAJOR DEPRESSION; RISK-FACTORS; CHILDREN; CHILDHOOD; MANIA; ADOLESCENTS AB Objective: The 2006 Research Forum addressed the goal of formulating a research agenda for early-onset bipolar disorder (EOBP) and improving outcome by understanding the risk and protective factors that contribute to its severity and chronicity. Method: Five work groups outlined barriers and research gaps in EOBP genetics, neuroimaging, prodromes, psychosocial factors, and pharmacotherapy. Results: There was agreement that the lack of consensus on the definition and diagnosis of EOBP is the primary barrier to advancing research in BP in children and adolescents. Related issues included: the difficulties in managing co-morbidity both statistically and clinically; acquiring adequate sample sizes to study the genetics, biology, and treatment; understanding the EOBP's developmental aspects; and identifying environmental mediators and moderators of risk and protection. Similarly, both psychosocial and medication treatment strategies for children with BP are hamstrung by diagnostic issues. To advance the research in EOBP, both training and funding mechanisms need to be developed with these issues in mind. Conclusions: EOBP constitutes a significant public health concern. Barriers are significant but identifiable and thus are not insurmountable. To advance the understanding of EOBP, the field must be committed to resolving diagnostic and assessment issues. Once achieved, with adequate personnel and funding resources, research into the field of EOBP will doubtless be advanced at a rapid pace. C1 [Findling, Robert L.] Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Dept Psychiat, Cleveland, OH 44106 USA. [Carlson, Gabrielle A.] SUNY Stony Brook, Sch Med, Dept Child & Adolescent Psychiat, Stony Brook, NY 11794 USA. [Post, Robert M.] George Washington Univ, Dept Psychiat, Bethesda, MD USA. [Birmaher, Boris] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. [Blumberg, Hilary P.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Blumberg, Hilary P.] Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Correll, Christoph] Zucker Hillside Hosp, Glen Oaks, NY USA. [DelBello, Melissa P.] Univ Cincinnati, Coll Med, Div Bipolar Disorders Res, Cincinnati, OH USA. [Fristad, Mary] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Frazier, Jean] UMASS Med Sch, Dept Psychiat, Worcester, MA USA. [Hammen, Constance] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Hinshaw, Stephen P.] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. [Kowatch, Robert] Univ Cincinnati, Med Ctr, Dept Psychiat, Cincinnati, OH 45267 USA. [Leibenluft, Ellen] NIMH, Unit Affect Disorders, Pediat & Dev Neuropsychiat Branch, Mood & Anxiety Program, Bethesda, MD 20892 USA. [Meyer, Stephanie E.] Cedars Sinai Med Ctr, Div Child & Adolescent Psychiat, Los Angeles, CA USA. [Pavuluri, Mani N.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Wagner, Karen Dineen] Univ Texas Galveston, Med Branch, Dept Child & Adolescent Psychiat, Galveston, TX 77550 USA. [Tohen, Mauricio] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Findling, RL (reprint author), Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Dept Psychiat, 10524 Euclid Ave, Cleveland, OH 44106 USA. EM robert.findling@UHhospitals.org NR 87 TC 13 Z9 13 U1 2 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB PY 2009 VL 19 IS 1 BP 3 EP 12 DI 10.1089/cap.2008.100 PG 10 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 415DC UT WOS:000263913500002 PM 19232018 ER PT J AU Mueller, SC Mandell, D Leschek, EW Pine, DS Merke, DP Ernst, M AF Mueller, Sven C. Mandell, Darcy Leschek, Ellen W. Pine, Daniel S. Merke, Deborah P. Ernst, Monique TI Early Hyperandrogenism Affects the Development of Hippocampal Function: Preliminary Evidence from a Functional Magnetic Resonance Imaging Study of Boys with Familial Male Precocious Puberty SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID CONGENITAL ADRENAL-HYPERPLASIA; FACIAL EXPRESSIONS; STEROID-HORMONES; AMYGDALA VOLUME; RAT-BRAIN; RECEPTOR; DISORDER; ANDROGEN; EMOTION; MEMORY AB The way in which sex hormones influence cognitive and affective brain development is poorly understood. Despite increasing knowledge in the area of pediatric mood disorders, little is known about the influence of sex hormones on the regulation of emotion. Animal studies and preliminary human studies suggest a strong impact of testosterone on limbic structures such as the hippocampus and amygdala. We used functional magnetic resonance imaging (fMRI) to examine emotional processing in familial male- precocious puberty (FMPP), an extremely rare gonadotropin-independent form of precocious puberty characterized by early excess testosterone secretion. We compared this group (n = 7, mean age = 13 +/- 3.3 years) to healthy age and sex-matched controls (n = 14, mean age = 13 +/- 2.3 years). Participants were presented with emotional and neutral face stimuli and were required either to judge the hostility of the presented face, their subjective level of anxiety, or the width of the nose of the presented faces (nonemotional condition). In a fourth, passive viewing condition, no responses were required. Boys with FMPP responded faster to fearful faces during perception of threat compared to unaffected controls. Concurrently, fMRI data revealed significant differences in hippocampus activation in response to fearful faces relative to baseline whereas controls showed no differences. In contrast, no significant activation of the amygdala was found. These data are consistent with previous studies of the effects of sex hormones on brain function and support the role of testosterone on emotional development. C1 [Mueller, Sven C.; Mandell, Darcy; Pine, Daniel S.; Ernst, Monique] NIMH, Emot Dev & Affect Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Leschek, Ellen W.] NIDDK, NIH, Bethesda, MD USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Clin, NIH, Bethesda, MD USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, NIH, Bethesda, MD USA. RP Ernst, M (reprint author), 15K North Dr, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU Intramural Program of the National Institute of Mental Health; Eunice Rennedy Shriver National Institute of Child Health and Human Development FX The research was supported by the Intramural Program of the National Institute of Mental Health and Eunice Rennedy Shriver National Institute of Child Health and Human Development. NR 56 TC 15 Z9 15 U1 2 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB PY 2009 VL 19 IS 1 BP 41 EP 50 DI 10.1089/cap.2008.031 PG 10 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 415DC UT WOS:000263913500006 PM 19232022 ER PT J AU Eastell, R Arnold, A Brandi, ML Brown, EM D'Amour, P Hanley, DA Rao, DS Rubin, MR Goltzman, D Silverberg, SJ Marx, SJ Peacock, M Mosekilde, L Bouillon, R Lewiecki, EM AF Eastell, R. Arnold, A. Brandi, M. L. Brown, E. M. D'Amour, P. Hanley, D. A. Rao, D. Sudhaker Rubin, M. R. Goltzman, D. Silverberg, S. J. Marx, S. J. Peacock, M. Mosekilde, L. Bouillon, R. Lewiecki, E. M. TI Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article; Proceedings Paper CT 3rd International Workshop on Asymptomatic Primary Hyperparathyroidism CY MAY 13, 2008 CL Orlando, FL SP Endocrine Soc, Amer Assoc Clin Endocrinologists, Amer Soc Bone & Mineral Res, Canadian Soc Endorcrinol & Metabolism, Canadian Endocrine Update ID VITAMIN-D INSUFFICIENCY; SERUM PARATHYROID-HORMONE; MULTIPLE-ENDOCRINE-NEOPLASIA; FAMILIAL ISOLATED HYPERPARATHYROIDISM; CARBOXYL-TERMINAL FRAGMENTS; BONE-MINERAL DENSITY; GERM-LINE MUTATIONS; JAW TUMOR SYNDROME; D DEFICIENCY; SECONDARY HYPERPARATHYROIDISM AB Objective: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostic tests for this condition in clinical practice. Participants: Interested professional societies selected a representative for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed. The conclusions were then circulated to the participating professional societies. Evidence: Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting. Consensus Process: Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies. Conclusions: We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second-and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) DNA sequence testing can be useful in familial hyperparathyroidism or hypercalcemia; 4) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 5) serum 25-hydroxyvitamin D levels should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; and 6) the estimated glomerular filtration rate should be used to determine the level of kidney function in PHPT: an estimated glomerular filtration rate of less than 60 ml/min . 1.73 m(2) should be a benchmark for decisions about surgery in established asymptomatic PHPT. (J Clin Endocrinol Metab 94: 340-350, 2009) C1 [Eastell, R.] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England. [Arnold, A.] Univ Connecticut, Sch Med, Ctr Mol Med, Farmington, CT 06030 USA. [Arnold, A.] Univ Connecticut, Sch Med, Div Endocrinol & Metab, Farmington, CT 06030 USA. [Brandi, M. L.] Univ Florence, Dept Internal Med, I-50133 Florence, Italy. [Brown, E. M.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [D'Amour, P.] Hop St Luc, Ctr Hosp Univ Montreal, Res Ctr, Montreal, PQ H3C 3J7, Canada. [Hanley, D. A.] Univ Calgary, Div Endocrinol & Metab, Dept Med, Calgary, AB T2N 1N4, Canada. [Hanley, D. A.] Univ Calgary, Div Endocrinol & Metab, Dept Community Hlth Sci, Calgary, AB T2N 1N4, Canada. [Hanley, D. A.] Univ Calgary, Div Endocrinol & Metab, Dept Oncol, Calgary, AB T2N 1N4, Canada. [Rao, D. Sudhaker] Henry Ford Hosp, Bone & Mineral Res Lab, Detroit, MI 48202 USA. [Rubin, M. R.; Silverberg, S. J.] Columbia Univ Coll Phys & Surg, Div Endocrinol, New York, NY 10032 USA. [Goltzman, D.] McGill Univ, Dept Med, Montreal, PQ H3G 1A4, Canada. McGill Univ, Ctr Hlth, Montreal, PQ H3G 1A4, Canada. [Marx, S. J.] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Peacock, M.] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. [Mosekilde, L.] Aarhus Univ Hosp, Dept Endocrinol, DK-8000 Aarhus, Denmark. [Bouillon, R.] Katholieke Univ Leuven, Lab Expt Med & Endocrinol, B-3001 Louvain, Belgium. [Lewiecki, E. M.] Univ New Mexico, Sch Med, New Mexico Clin Res & Osteoporosis Ctr, Albuquerque, NM 87106 USA. RP Eastell, R (reprint author), No Gen Hosp, Acad Unit Bone Metab, Metab Bone Ctr, Sorby Wing, Herries Rd, Sheffield S5 7AU, S Yorkshire, England. EM r.eastell@sheffield.ac.uk RI Eastell, Richard/G-5851-2011 OI Eastell, Richard/0000-0002-0323-3366 NR 84 TC 166 Z9 172 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2009 VL 94 IS 2 BP 340 EP 350 DI 10.1210/jc.2008-1758 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 403HC UT WOS:000263072700003 PM 19193909 ER PT J AU Moore, AF Jablonski, KA Mason, CC McAteer, JB Arakaki, RF Goldstein, BJ Kahn, SE Kitabchi, AE Hanson, RL Knowler, WC Florez, JC AF Moore, Allan F. Jablonski, Kathleen A. Mason, Clinton C. McAteer, Jarred B. Arakaki, Richard F. Goldstein, Barry J. Kahn, Steven E. Kitabchi, Abbas E. Hanson, Robert L. Knowler, William C. Florez, Jose C. CA Diabet Prevention Program Res Grp TI The Association of ENPP1 K121Q with Diabetes Incidence Is Abolished by Lifestyle Modification in the Diabetes Prevention Program SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MEMBRANE GLYCOPROTEIN PC-1; INSULIN-RESISTANCE; GENETIC SUSCEPTIBILITY; NO EVIDENCE; POLYMORPHISM; GLUCOSE; OBESITY; VARIANTS; RECEPTOR; RISK AB Context: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q(rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. Objective and Intervention: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). Design, Setting, Participants, and Outcome: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. Results: Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10(95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance. Conclusions: ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk. (J Clin Endocrinol Metab 94: 449-455, 2009) C1 [Moore, Allan F.; McAteer, Jarred B.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Moore, Allan F.; McAteer, Jarred B.; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Moore, Allan F.; McAteer, Jarred B.; Florez, Jose C.] Harvard & Massachusetts Inst Technol, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Moore, Allan F.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. [Mason, Clinton C.; Hanson, Robert L.; Knowler, William C.] NIDDKD, Phoenix, AZ 85014 USA. [Arakaki, Richard F.] Univ Hawaii, Dept Med Diabet & Endocrinol, Honolulu, HI 96813 USA. [Goldstein, Barry J.] Thomas Jefferson Univ, Jefferson Med Coll, Div Endocrinol Diabet & Metab Dis, Philadelphia, PA 19107 USA. [Kahn, Steven E.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Kitabchi, Abbas E.] Univ Tennessee, Hlth Sci Ctr, Div Endocrinol Diabet & Metab, Memphis, TN 38163 USA. RP Florez, JC (reprint author), George Washington Univ, Diabet Prevent Program, Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health [R01 DK072041, K23 DK65978-05]; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging, the Centers for Disease Control and Prevention; Office of Research on Women's Health; American Diabetes Association FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study and for collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan Inc., Health-O-Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of centers, investigators, and staff can be found in the Appendix(published as supplemental data on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org). NR 36 TC 29 Z9 30 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2009 VL 94 IS 2 BP 449 EP 455 DI 10.1210/jc.2008-1583 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 403HC UT WOS:000263072700019 PM 19017751 ER PT J AU Maggio, M Ceda, GP Lauretani, F Bandinelli, S Metter, EJ Artoni, A Gatti, E Ruggiero, C Guralnik, JM Valenti, G Ling, SM Basaria, S Ferrucci, L AF Maggio, Marcello Ceda, Gian Paolo Lauretani, Fulvio Bandinelli, Stefania Metter, E. Jeffrey Artoni, Andrea Gatti, Elisa Ruggiero, Carmelinda Guralnik, Jack M. Valenti, Giorgio Ling, Shari M. Basaria, Shehzad Ferrucci, Luigi TI Estradiol and Inflammatory Markers in Older Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ELDERLY-MEN; SERUM TESTOSTERONE; SEX-HORMONES; ASSOCIATION; ESTROGEN; DISEASE; MUSCLE; HYPERESTROGENEMIA; INTERLEUKIN-6; INCHIANTI AB Background: Aging is characterized by a mild proinflammatory state. In older men, low testosterone levels have been associated with increasing levels of proinflammatory cytokines. It is still unclear whether estradiol (E2), which generally has biological activities complementary to testosterone, affects inflammation. Methods: We analyzed data obtained from 399 men aged 65-95 yr enrolled in the Invecchiare in Chianti study with complete data on body mass index (BMI), serum E2, testosterone, IL-6, soluble IL-6 receptor, TNF-alpha, IL-1 receptor antagonist, and C-reactive protein. The relationship between E2 and inflammatory markers was examined using multivariate linear models adjusted for age, BMI, smoking, physical activity, chronic disease, and total testosterone. Results: In age-adjusted analysis, log (E2) was positively associated with log (IL-6) (r=0.19; P=0.047), and the relationship was statistically significant (P=0.032) after adjustments for age, BMI, smoking, physical activity, chronic disease, and serum testosterone levels. Log ( E2) was not significantly associated with log (C-reactive protein), log (soluble IL-6 receptor), or log (TNF-alpha) in both age-adjusted and fully adjusted analyses. Conclusions: In older men, E2 is weakly positively associated with IL-6, independent of testosterone and other confounders including BMI. (J Clin Endocrinol Metab 94: 518-522, 2009) C1 [Maggio, Marcello; Ceda, Gian Paolo; Artoni, Andrea; Gatti, Elisa; Valenti, Giorgio] Univ Hosp Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Unit, Geriatr Rehabil Dept, I-43100 Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil, I-50122 Florence, Italy. [Metter, E. Jeffrey; Ruggiero, Carmelinda; Ling, Shari M.; Basaria, Shehzad; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Aging Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Basaria, Shehzad] Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol,Bayview Med Ctr, Baltimore, MD 21224 USA. RP Ferrucci, L (reprint author), NIA, NIH, NIA ASTRA Unit, Harbor Hosp, 3001 S Hanover St, Baltimore, MD 21225 USA. EM marcellomaggio2001@yahoo.it; ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Ceda, Gian Paolo/0000-0002-9648-8295; Lauretani, Fulvio/0000-0002-5287-9972 FU Italian Ministry of Health; U. S. National Institute on Aging [N01-AG-916413, N01-AG-821336]; Intramural Research Program of the U. S. National Institute on Aging [263 MD 9164 13, 263 MD 821336]; [ICS 110.1/RS97.71] FX The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health and in part by the U. S. National Institute on Aging (contracts N01-AG-916413 and N01-AG-821336) and by the Intramural Research Program of the U. S. National Institute on Aging (contracts 263 MD 9164 13 and 263 MD 821336). None of the sponsoring institutions interfered with the collection, presentation, or interpretation of the data reported here. NR 29 TC 15 Z9 15 U1 2 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2009 VL 94 IS 2 BP 518 EP 522 DI 10.1210/jc.2008-0940 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 403HC UT WOS:000263072700029 PM 19050054 ER PT J AU Semple, RK Sleigh, A Murgatroyd, PR Adams, CA Bluck, L Jackson, S Vottero, A Kanabar, D Charlton-Menys, V Durrington, P Soos, MA Carpenter, TA Lomas, DJ Cochran, EK Gorden, P O'Rahilly, S Savage, DB AF Semple, Robert K. Sleigh, Alison Murgatroyd, Peter R. Adams, Claire A. Bluck, Les Jackson, Sarah Vottero, Alessandra Kanabar, Dipak Charlton-Menys, Valentine Durrington, Paul Soos, Maria A. Carpenter, T. Adrian Lomas, David J. Cochran, Elaine K. Gorden, Phillip O'Rahilly, Stephen Savage, David B. TI Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TYROSINE KINASE DOMAIN; RECEPTOR GENE; PHOSPHOINOSITIDE 3-KINASE; PLASMA ADIPONECTIN; CLINICAL-COURSE; ADIPOSE-TISSUE; FATTY LIVER; MUTATIONS; SUFFICIENT; TRIGLYCERIDE AB Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis. C1 [Semple, Robert K.; Adams, Claire A.; Soos, Maria A.; O'Rahilly, Stephen; Savage, David B.] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England. [Sleigh, Alison; Carpenter, T. Adrian] Univ Cambridge, Addenbrookes Hosp, Wolfson Brain Imaging Ctr, Cambridge CB2 0QQ, England. [Murgatroyd, Peter R.] Addenbrookes Hosp, Wellcome Trust Clin Res Facil, Cambridge, England. [Bluck, Les; Jackson, Sarah] MRC Human Nutr Res, Cambridge, England. [Vottero, Alessandra] Univ Parma, Dept Pediat, I-43100 Parma, Italy. [Kanabar, Dipak] Evalina Childrens Hosp, London, England. [Charlton-Menys, Valentine; Durrington, Paul] Univ Manchester, Cardiovasc Res Grp, Core Technol Facil, Manchester, Lancs, England. [Lomas, David J.] Univ Cambridge, Addenbrookes Hosp, Dept Radiol, Cambridge CB2 0QQ, England. [Cochran, Elaine K.; Gorden, Phillip] NIDDK, Clin Endocrinol Branch, Bethesda, MD USA. RP Semple, RK (reprint author), Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Hills Rd, Cambridge CB2 0QQ, England. EM rksl6@cam.ac.uk; dbs23@medschl.cam.ac.uk OI Semple, Robert/0000-0001-6539-3069; Sleigh, Alison/0000-0002-3859-8701; LOMAS, David/0000-0003-2904-8617 FU Wellcome Trust [080952/Z/06/Z, 078986/Z/06/Z]; GlaxoSmithKline; United Kingdom NIHR Cambridge Biomedical Research Centre; United Kingdom Medical Research Council Centre for Obesity and Related Metabolic Diseases FX This work was supported by grants from the Wellcome Trust (to R.K. Semple: intermediate Clinical Fellowship 080952/Z/06/Z; to S. O'Rahilly: Programme Grant 078986/Z/06/Z), GlaxoSmithKline (to D.B. Savage: GSK Clinical Fellowship), the United Kingdom NIHR Cambridge Biomedical Research Centre, and the United Kingdom Medical Research Council Centre for Obesity and Related Metabolic Diseases. NR 40 TC 143 Z9 147 U1 0 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2009 VL 119 IS 2 BP 315 EP 322 DI 10.1172/JCI37432 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 403LP UT WOS:000263084400012 PM 19164855 ER PT J AU Widemann, BC Goodspeed, W Goodwin, A Fojo, T Balis, FM Fox, E AF Widemann, Brigitte C. Goodspeed, Wendy Goodwin, Anne Fojo, Tito Balis, Frank M. Fox, Elizabeth TI Phase I Trial and Pharmacokinetic Study of Ixabepilone Administered Daily for 5 Days in Children and Adolescents With Refractory Solid Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-17, 2005 CL Orlando, FL SP Amer Soc Clin Oncol ID EPOTHILONE-B-ANALOG; METASTATIC BREAST-CANCER; CLINICAL-TRIAL; PEDIATRIC-PATIENTS; PROSTATE-CANCER; DAILY SCHEDULE; BMS-247550; CHEMOTHERAPY; ONCOLOGY; TAXANE AB Purpose The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents. Patients and Methods Patients >= 2 and <= 18 years with relapsed or refractory solid tumors were enrolled onto sequential cohorts to the following five dose levels: 3.0 (n = 3), 4.5 (n = 4), 6.0 (n = 3), 8.0 (n = 6), and 10 (n = 3) mg/m(2)/d. Eligibility criteria, dose levels, definitions of DLT and MTD, and pharmacokinetic sampling times were designed to be as similar as possible to the adult phase I trial of ixabepilone on the same schedule. Results Nineteen children (median age, 10 years; range, 2 to 18 years) were enrolled, and 18 (12 with sarcomas) were assessable for toxicity. DLTs (grade 4 neutropenia for > 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m(2)/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m(2)/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 +/- 247 mL/min/m(2), volume of distribution at steady-state was 12.2 +/- 5.4 L/kg, and half-life was 14 hours. Conclusion The recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m(2)/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults. C1 [Widemann, Brigitte C.; Goodspeed, Wendy; Goodwin, Anne; Fojo, Tito; Balis, Frank M.; Fox, Elizabeth] NCI, Pediat & Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, 10 Ctr Dr,Bldg 10-Rm 1-5742, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov FU Intramural NIH HHS NR 26 TC 7 Z9 7 U1 0 U2 0 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 FEB 1 PY 2009 VL 27 IS 4 BP 550 EP 556 DI 10.1200/JCO.2008.17.6644 PG 7 WC Oncology SC Oncology GA 400UK UT WOS:000262894400013 PM 19075272 ER PT J AU Freidlin, B Korn, EL AF Freidlin, Boris Korn, Edward L. TI Monitoring for Lack of Benefit: A Critical Component of a Randomized Clinical Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; ADVANCED PANCREATIC-CANCER; COOPERATIVE-ONCOLOGY-GROUP; SURGICAL ADJUVANT BREAST; NECK-CANCER; PLUS GEMCITABINE; BOWEL PROJECT; DOUBLE-BLIND; RADIOTHERAPY; COMBINATION AB To balance patient interests against the need for acquiring evidence, ongoing randomized clinical trials are formally monitored for early convincing indication of benefit or lack of benefit. In lethal diseases like cancer, where new therapies are often toxic and may have limited preliminary efficacy data, monitoring for lack of benefit is particularly important. We review the complex nature of stopping a randomized trial for lack of benefit and argue that many cancer trials could be improved by a more aggressive approach to monitoring. On the other hand, we caution that some commonly used monitoring guidelines may result in stopping for lack of benefit even when a nontrivial beneficial effect is observed. C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diagnosis, EPN 8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 45 TC 18 Z9 18 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 FEB 1 PY 2009 VL 27 IS 4 BP 629 EP 633 DI 10.1200/JCO.2008.17.8905 PG 5 WC Oncology SC Oncology GA 400UK UT WOS:000262894400024 PM 19064977 ER PT J AU de Gonzalez, AB Jee, SH Engels, EA AF de Gonzalez, Amy Berrington Jee, Sun-Ha Engels, Eric A. TI No Association Between Hepatitis B and Pancreatic Cancer in a Prospective Study in Korea SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID VIRUS C1 [de Gonzalez, Amy Berrington; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Jee, Sun-Ha] Yonsei Univ, Dept Epidemiol & Hlth Promot, Seoul 120749, South Korea. RP de Gonzalez, AB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 7 TC 5 Z9 5 U1 0 U2 0 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 FEB 1 PY 2009 VL 27 IS 4 BP 648 EP 648 DI 10.1200/JCO.2008.20.7514 PG 1 WC Oncology SC Oncology GA 400UK UT WOS:000262894400035 PM 19103724 ER PT J AU van Noord, C Straus, SMJM Sturkenboom, MCJM Hofman, A Aarnoudse, AJLHJ Bagnardi, V Kors, JA Newton-Cheh, C Witteman, JCM Stricker, BHC AF van Noord, Charlotte Straus, Sabine M. J. M. Sturkenboom, Miriam C. J. M. Hofman, Albert Aarnoudse, Albert-Jan L. H. J. Bagnardi, Vincenzo Kors, Jan A. Newton-Cheh, Christopher Witteman, Jacqueline C. M. Stricker, Bruno H. C. TI Psychotropic Drugs Associated With Corrected QT Interval Prolongation SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE QTc interval; psychotropic drugs; electrocardiography; arrhythmia ID TORSADE-DE-POINTES; LEFT-VENTRICULAR HYPERTROPHY; NON-ANTIARRHYTHMIC DRUGS; MYOCARDIAL-INFARCTION; HEART-FAILURE; ROTTERDAM; RISK; POPULATION; ELECTROCARDIOGRAMS; REPOLARIZATION AB Aims: To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drue effect. we conducted a prospective population-based cohort study. Methods: This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (>= 55 years) who had triennial electrocardiograms (ECGs). The primary end point,; of the study were the length of the QTc interval at each ECG. the difference in QTc interval between consecutive ECGs within one person, and the risk of ail abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age. sex, diabetes mellitus. hypertension, myocardial infarction, heart failure. and use of class I QTc-prolonging drugs. Results: Of the 8222 participants. 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison With Consecutive ECGs of participants not using tricyclic antidepressants. in particular starting amitriptyline (8.5 milliseconds: 95% CI. 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds: 9 % CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds: 95% CI. 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% Cl 4.8-32.4 milliseconds). Conclusions: In this population-based prospective cohort Stud),, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a significant intraindividual increase in the QTc interval in comparison to the change in nonusers. The tricyclic antidepressants seem to prolong the QTc interval as a class effect. C1 [van Noord, Charlotte; Straus, Sabine M. J. M.; Sturkenboom, Miriam C. J. M.; Hofman, Albert; Aarnoudse, Albert-Jan L. H. J.; Witteman, Jacqueline C. M.; Stricker, Bruno H. C.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [van Noord, Charlotte; Straus, Sabine M. J. M.] Dutch Med Evaluat Board, The Hague, Netherlands. [Aarnoudse, Albert-Jan L. H. J.; Stricker, Bruno H. C.] Inspectorate Hlth Care, The Hague, Netherlands. [Bagnardi, Vincenzo] Univ Milano Bicocca, Dept Stat, Milan, Italy. [Bagnardi, Vincenzo] European Inst Oncol, Div Epidemiol & Biostat, Milan, Italy. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, England. [Newton-Cheh, Christopher] MIT, Cambridge, MA 02139 USA. [Newton-Cheh, Christopher] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Stricker, Bruno H. C.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. RP Stricker, BHC (reprint author), Erasmus MC, Dept Epidemiol, Dr Molewaterpl 50,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM b.stricker@erasmusmc.nl NR 39 TC 49 Z9 49 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2009 VL 29 IS 1 BP 9 EP 15 DI 10.1097/JCP.0b013e318191c6a8 PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 395YA UT WOS:000262558200003 PM 19142100 ER PT J AU Becker, RE Greig, NH AF Becker, Robert E. Greig, Nigel H. TI Neuropsychiatric Clinical Trials Should They Accommodate Real-World Practices or Set Standards for Clinical Practices? SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Review DE clinical trials; errors; biases; real world conditions; protocol standards ID SAMPLE-SIZE REQUIREMENTS; EVIDENCE-BASED MEDICINE; ALZHEIMERS-DISEASE; MEASUREMENT ERROR; COGNITIVE IMPAIRMENT; ROFECOXIB LITIGATION; PLACEBO-RESPONSE; DRUG DEVELOPMENT; DOUBLE-BLIND; DEPRESSION AB Evidence-based psychiatry seeks the best research evidence for use in patient care. Recent research Suggests that problems with accuracy, precision, bias, and other sources, of unreliability potentially interfere with the validity of psychiatry's evidence base. Because many negative clinical research studies go Unpublished, awareness and fuller understanding of these problems are blocked by lack of access to relevant data. Based on the importance of scientific soundness of neuropsychiatric research and patient care, we argue for increased attentiveness by investigators and practitioners to how clinical trials (CTs) interdependently estimate the efficacy of treatments and the effectiveness of methods as fair tests of efficacy. Deference by CT investigators to real-world practice conditions at research sites because of the unreliability introduced into data by these practices does not ensure unbiased evaluations of treatment efficacy. We argue for more systematic attention to sources of unreliability in CT investigations and increased commitments to assure the validity of the neuropsychiatric evidence base. These recommendations aim to determine neuropsychiatric drug efficacy with greater certainty to better quantify the clinical importance of drug-associated effects and to provide CT-evidenced guidance for practitioners to most effectively use drug efficacy in patient care. C1 [Becker, Robert E.; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, 5th Floor BRC Bldg,251 Bayview Blvd, Baltimore, MD 21224 USA. EM rebecker2008@comcast.net FU National Institute on Aging, National Institutes of Health FX The authors are supported in part by the Intramural Research program of the National Institute on Aging, National Institutes of Health. The authors have received no other funding for this work and have no financial conflicts of interest. The views expressed within this article are those of the authors and may not represent those of the National Institute on Aging, National Institutes of Health. NR 73 TC 8 Z9 8 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2009 VL 29 IS 1 BP 56 EP 64 DI 10.1097/JCP.0b013e318192e2fa PG 9 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 395YA UT WOS:000262558200013 PM 19142109 ER PT J AU Paukner, A Huntsberry, ME Suomi, SJ AF Paukner, Annika Huntsberry, Mary E. Suomi, Stephen J. TI Tufted Capuchin Monkeys (Cebus apella) Spontaneously Use Visual but Not Acoustic Information to Find Hidden Food Items SO JOURNAL OF COMPARATIVE PSYCHOLOGY LA English DT Article DE foraging choices; visual information; acoustic information; capuchin monkey; inferential reasoning ID TOOL USE; INFERENCES; LOCATION AB Foraging choices in tufted capuchins monkeys are guided by perceptual, cognitive, and motivational factors, but little is known about how these factors might interact. The present study investigates how different types of sensory information affect capuchins' ability to locate hidden food. In two experiments, capuchins were presented with two cups, one baited and one empty. Monkeys were given visual, acoustic, or acoustic-visual information related to the baited cup, the empty cup, or both baited and empty cup. Results show that capuchins spontaneously used visual information to locate food, and that information indicating presence and absence of food led to higher success rates than information indicating only absence of food. In contrast, acoustic information did not lead to success rates above chance levels and failed to enhance performance in combination with visual information. Capuchins spontaneously avoided a visually empty cup, but they did not appear to associate sounds with either the presence or absence of food. Being able to locate food items with the aid of acoustic cues might be a learned process that requires interactive experiences with the task's contingencies. RP Paukner, A (reprint author), NIH, Comparat Ethol Lab, Anim Ctr, POB 529, Poolesville, MD 20837 USA. EM pauknera@mail.nih.gov FU Division of Intramural Research, National Institute of Child Health and Human Development FX This research was supported by funds from the Division of Intramural Research, National Institute of Child Health and Human Development. We thank Pier Ferrari for critical comments on earlier drafts of this article. NR 21 TC 24 Z9 24 U1 0 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7036 J9 J COMP PSYCHOL JI J. Comp. Psychol. PD FEB PY 2009 VL 123 IS 1 BP 26 EP 33 DI 10.1037/a0013128 PG 8 WC Behavioral Sciences; Psychology; Psychology, Multidisciplinary; Zoology SC Behavioral Sciences; Psychology; Zoology GA 410WX UT WOS:000263610100004 PM 19236142 ER PT J AU Li, LP AF Li, Leping TI GADEM: A Genetic Algorithm Guided Formation of Spaced Dyads Coupled with an EM Algorithm for Motif Discovery SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article DE ChIP; de novo motif discovery; expectation-maximization; genetic algorithm; k-mer; spaced dyad ID EMBRYONIC STEM-CELLS; FACTOR-BINDING-SITES; GENOME-WIDE ANALYSIS; REGULATORY ELEMENTS; CHROMATIN-IMMUNOPRECIPITATION; NONCODING SEQUENCES; MULTIPLE SEQUENCES; DNA; PATTERNS; IDENTIFICATION AB Genome-wide analyses of protein binding sites generate large amounts of data; a ChIP dataset might contain 10,000 sites. Unbiased motif discovery in such datasets is not generally feasible using current methods that employ probabilistic models. We propose an efficient method, GADEM, which combines spaced dyads and an expectation-maximization ( EM) algorithm. Candidate words (four to six nucleotides) for constructing spaced dyads are prioritized by their degree of overrepresentation in the input sequence data. Spaced dyads are converted into starting position weight matrices (PWMs). GADEM then employs a genetic algorithm (GA), with an embedded EM algorithm to improve starting PWMs, to guide the evolution of a population of spaced dyads toward one whose entropy scores are more statistically significant. Spaced dyads whose entropy scores reach a pre-specified significance threshold are declared motifs. GADEM performed comparably with MEME on 500 sets of simulated "ChIP" sequences with embedded known P53 binding sites. The major advantage of GADEM is its computational efficiency on large ChIP datasets compared to competitors. We applied GADEM to six genome-wide ChIP datasets. Approximately, 15 to 30 motifs of various lengths were identified in each dataset. Remarkably, without any prior motif information, the expected known motif ( e. g., P53 in P53 data) was identified every time. GADEM discovered motifs of various lengths (6-40 bp) and characteristics in these datasets containing from 0.5 to > 13 million nucleotides with run times of 5 to 96 h. GADEM can be viewed as an extension of the well-known MEME algorithm and is an efficient tool for de novo motif discovery in large-scale genome-wide data. The GADEM software is available at www.niehs.nih.gov/research/resources/software/GADEM/. C1 Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Li, LP (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. EM li3@niehs.nih.gov FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [ES101765- 05] FX We thank David Umbach and Grace Kissling for discussions and careful reading of the manuscript. We thank Clare Weinberg and Shyamal Peddada for discussions. We thank the reviewers for their thought provoking comments. We thank Robert Bass for creating the GADEM web site and the Computational Biology Facility at NIEHS for computing time. This research was supported by Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to L. L. ( ES101765- 05). NR 51 TC 48 Z9 50 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 J9 J COMPUT BIOL JI J. Comput. Biol. PD FEB PY 2009 VL 16 IS 2 BP 317 EP 329 DI 10.1089/cmb.2008.16TT PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 403BS UT WOS:000263057400016 PM 19193149 ER PT J AU Joiner, WM Shelhamer, M AF Joiner, Wilsaan M. Shelhamer, Mark TI A model of time estimation and error feedback in predictive timing behavior SO JOURNAL OF COMPUTATIONAL NEUROSCIENCE LA English DT Article DE Prediction; Saccade; Timing; Error feedback ID SACCADIC EYE-MOVEMENTS; INTERNAL CLOCK; PARKINSONS-DISEASE; PHASE-TRANSITIONS; SYNCHRONIZATION STRATEGIES; TEMPORAL DISCRIMINATION; STIMULUS SEQUENCE; THEORETICAL-MODEL; BASAL GANGLIA; HUMAN BRAIN AB Two key features of sensorimotor prediction are preprogramming and adjusting of performance based on previous experience. Oculomotor tracking of alternating visual targets provides a simple paradigm to study this behavior in the motor system; subjects make predictive eye movements (saccades) at fast target pacing rates (> 0.5 Hz). In addition, the initiation errors (latencies) during predictive tracking are correlated over a small temporal window (correlation window) suggesting that tracking performance within this time range is used in the feedback process of the timing behavior. In this paper, we propose a closed-loop model of this predictive timing. In this model, the timing between movements is based on an internal estimation of stimulus timing (an internal clock), which is represented by a (noisy) signal integrated to a threshold. The threshold of the integrate-to-fire mechanism is determined by the timing between movements made within the correlation window of previous performance and adjusted by feedback of recent and projected initiation error. The correlation window size increases with repeated tracking and was estimated by two independent experiments. We apply the model to several experimental paradigms and show that it produces data specific to predictive tracking: a gradual shift from reaction to prediction on initial tracking, phase transition and hysteresis as pacing frequency changes, scalar property, continuation of predictive tracking despite perturbations, and intertrial correlations of a specific form. These results suggest that the process underlying repetitive predictive motor timing is adjusted by the performance and the corresponding errors accrued over a limited time range and that this range increases with continued confidence in previous performance. C1 [Joiner, Wilsaan M.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Shelhamer, Mark] Johns Hopkins Univ Hosp, Sch Med, Dept Biomed Engn, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. RP Joiner, WM (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM joinerw@nei.nih.gov FU NIH [T32MH20069, EY015193]; NSF [BCS-0615106] FX The study was supported by NIH T32MH20069 and EY015193 and NSF BCS-0615106. NR 82 TC 9 Z9 9 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5313 J9 J COMPUT NEUROSCI JI J. Comput. Neurosci. PD FEB PY 2009 VL 26 IS 1 BP 119 EP 138 DI 10.1007/s10827-008-0102-x PG 20 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 407QI UT WOS:000263379000008 PM 18563546 ER PT J AU Kong, H Kim, Y Lee, Y Ch, B Jung, S Jung, Y Kim, YM AF Kong, Hyesik Kim, Youngsoo Lee, Yonghyun Choi, Boim Jung, Sunhwa Jung, Yunjin Kim, Young Mi TI Sulfate-conjugated methylprednisolone: Evaluation as a colon-specific methylprednisolone prodrug and comparison with sulfate-conjugated prednisolone and dexamethasone SO JOURNAL OF DRUG TARGETING LA English DT Article DE Colon-specific prodrug; methylprednisolone; sulfation; sulfate conjugates; drug delivery; glucocorticoid ID INFLAMMATORY-BOWEL-DISEASE; STEADY-STATE PHARMACOKINETICS; IN-VITRO PROPERTIES; 21-SULFATE SODIUM; POTENTIAL PRODRUGS; DRUG-DELIVERY; RATS; COLITIS AB Methylprednisolone 21-sulfate sodium (MPS) was prepared and evaluated as a colon-specific methylprednisolone prodrug and its colon-specific property was compared with prednisolone 21-sulfate sodium (PDS) and dexamethasone 21-sulfate sodium (DS), reported previously as colon-specific prodrugs of the glucocorticoids. The synthetic process and yield of MPS was simple and high. The apparent partition coefficient of methylprednisolone (MP) was greatly reduced by sulfate conjugation. The sulfate conjugates MPS, PDS, and DS were (bio)chemically stable in the homogenates of the upper intestine. In marked contrast, the sulfate conjugates were deconjugated to liberate the corresponding glucocorticoids in the cecal contents. Although the rates of deconjugation were not significantly different, the corresponding glucocorticoids were accumulated with distinct profiles depending on the metabolic susceptibility of the unconjugated glucocorticoids to microbial reductase(s). Upon oral administration of the sulfate conjugates to rats, the plasma concentrations of the conjugates were extremely low and the urinary recoveries were less than 5% of the doses. These results suggest that, like PDS and DS, MPS administered orally is delivered efficiently to the large intestine followed by deconjugation to liberate MP and the metabolic susceptibility of the unconjugated glucocorticoids may affect therapeutic availability of the sulfate conjugates. C1 [Kim, Youngsoo; Lee, Yonghyun; Jung, Sunhwa; Jung, Yunjin] Pusan Natl Univ, Coll Pharm, Lab Biomed Chem, Pusan 609735, South Korea. [Kong, Hyesik] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Choi, Boim; Kim, Young Mi] Pusan Natl Univ, Coll Pharm, Med Chem Lab, Pusan 609735, South Korea. RP Jung, Y (reprint author), Pusan Natl Univ, Coll Pharm, Lab Biomed Chem, Pusan 609735, South Korea. EM jungy@pusan.ac.kr; ymikim@pusan.ac.kr FU Pusan National University research grant FX This work was supported for two years by the Pusan National University research grant. NR 17 TC 8 Z9 10 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1061-186X J9 J DRUG TARGET JI J. Drug Target. PD FEB PY 2009 VL 17 IS 2 BP 159 EP 167 DI 10.1080/10611860802546637 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 453EO UT WOS:000266593200008 PM 18988065 ER PT J AU Singh, SR Hou, SX AF Singh, Shree Ram Hou, Steven X. TI Multipotent stem cells in the Malpighian tubules of adult Drosophila melanogaster SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Review DE kidney; Malpighian tubules; kidney development; multipotent stem cells; renal and nephric stem cells; renal cancer; Drosophila melanogaster ID RENAL PROGENITOR CELLS; SIDE POPULATION CELLS; KIDNEY DEVELOPMENT; EPITHELIAL-CELLS; SELF-RENEWAL; POSTISCHEMIC KIDNEY; SIGNALING PATHWAYS; JAK/STAT PATHWAY; MODEL ORGANISMS; GROWTH-FACTOR AB Excretion is an essential process of an organism's removal of the waste products of metabolism to maintain a constant chemical composition of the body fluids despite changes in the external environment. Excretion is performed by the kidneys in vertebrates and by Malpighian tubules (MTs) in Drosophila. The kidney serves as an excellent model organ to investigate the cellular and molecular mechanisms underlying organogenesis. Mammals and Drosophila share common principles of renal development. Tissue homeostasis, which is accomplished through self-renewal or differentiation of stem cells, is critical for the maintenance of adult tissues throughout the lifetime of an animal. Growing evidence suggests that stem cell self-renewal and differentiation is controlled by both intrinsic and extrinsic factors. Deregulation of stem cell behavior results in cancer formation, tissue degeneration, and premature aging. The mammalian kidney has a low rate of cellular turnover but has a great capacity for tissue regeneration following an ischemic injury. However, there is an ongoing controversy about the source of regenerating cells in the adult kidney that repopulate injured renal tissues. Recently, we identified multipotent stem cells in the MTs of adult Drosophila and found that these stem cells are able to proliferate and differentiate in several types of cells in MTs. Furthermore, we demonstrated that an autocrine JAK-STAT (Janus kinase-signal transducers and activators of transcription) signaling regulates stem cell self-renewal or differentiation of renal stem cells. The Drosophila MTs provide an excellent in vivo system for studying the renal stem cells at cellular and molecular levels. Understanding the molecular mechanisms governing stem cell self-renewal or differentiation in vivo is not only crucial to using stem cells for future regenerative medicine and gene therapy, but it also will increase our understanding of the mechanisms underlying cancer formation, aging and degenerative diseases. Identifying and understanding the cellular processes underlying the development and repair of the mammalian kidney may enable more effective, targeted therapies for acute and chronic kidney diseases in humans. C1 [Singh, Shree Ram; Hou, Steven X.] NCI, Mouse Canc Genet Program, NIH, Ft Detrick, MD 21702 USA. RP Hou, SX (reprint author), NCI, Mouse Canc Genet Program, NIH, Ft Detrick, MD 21702 USA. EM hous@mail.nih.gov RI Singh, Shree Ram/B-7614-2008 OI Singh, Shree Ram/0000-0001-6545-583X FU National Institutes of Health; National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Deposited in PMC for release after 12 months. NR 103 TC 18 Z9 20 U1 1 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD FEB 1 PY 2009 VL 212 IS 3 BP 413 EP 423 DI 10.1242/jeb.024216 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 396HD UT WOS:000262581900017 PM 19151216 ER PT J AU Cao, Y Calafat, AM Doerge, DR Umbach, DM Bernbaum, JC Twaddle, NC Ye, XY Rogan, WJ AF Cao, Yang Calafat, Antonia M. Doerge, Daniel R. Umbach, David M. Bernbaum, Judy C. Twaddle, Nathan C. Ye, Xiaoyun Rogan, Walter J. TI Isoflavones in urine, saliva, and blood of infants: data from a pilot study on the estrogenic activity of soy formula SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE phytoestrogen; isoflavone; genistein; daidzein; infant feeding; soy formula ID HUMAN-MILK; PHYTOESTROGENS; GENISTEIN; DAIDZEIN; PHARMACOKINETICS; CONSUMPTION; EXCRETION; EXPOSURE; PROTEIN; PLASMA AB In the United States, about 25% of infant formula sold is based on soy protein, which is an important source of estrogenic isoflavones in the human food supply. Nevertheless, few studies report isoflavone levels in infants. We did a partly cross-sectional and partly longitudinal pilot study to examine children's exposure to isoflavones from different feeding methods. A total of 166 full-term infants between birth and 1 year of age were recruited into soy formula, cow milk formula, or breast milk regimens according to their feeding histories. A total of 381 urine, 361 saliva, and 88 blood samples were collected at 382 visits. We used automated online solid-phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for measuring three isoflavones ( daidzein, genistein, and equol) in urine, and used similar LC/MS/MS techniques for saliva and blood spots. Concentrations of daidzein and genistein were undetectable in most blood or saliva samples from children fed breast milk or cow milk formula. The proportion of non-detectable values was somewhat lower in urine than in the other matrices. Concentrations of equol were detectable only in a few urine samples. For both daidzein and genistein, urine contained the highest median concentrations, followed by blood and then saliva. Urinary concentrations of genistein and daidzein were about 500 times higher in the soy formula-fed infants than in the cow milk formula-fed infants. The correlations between matrices for either analyte were strikingly lower than the correlation between the two analytes in any single matrix. We did not find significant correlations between isoflavone concentrations and the levels of certain hormones in children fed soy formula. Our results, based on much larger numbers of infants, strongly confirm previous reports, but whether phytoestrogens in soy formula are biologically active in infants is still an open question. We plan further longitudinal studies focusing on physical and developmental findings reflecting the effects of estrogen exposure. C1 [Cao, Yang; Rogan, Walter J.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Calafat, Antonia M.; Ye, Xiaoyun] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Doerge, Daniel R.; Twaddle, Nathan C.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Umbach, David M.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Bernbaum, Judy C.] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, POB 12233,Mail Drop A3-05,FedEx UPS 111 TW Alexa, Res Triangle Pk, NC 27709 USA. EM rogan@niehs.nih.gov RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 FU Intramural NIH HHS [Z99 ES999999] NR 31 TC 65 Z9 70 U1 8 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD FEB PY 2009 VL 19 IS 2 BP 223 EP 234 DI 10.1038/jes.2008.44 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 395CT UT WOS:000262500600007 PM 18665197 ER PT J AU Maras, JE Newby, PK Bakun, PJ Ferrucci, L Tucker, KL AF Maras, Janice E. Newby, P. K. Bakun, Peter J. Ferrucci, Luigi Tucker, Katherine L. TI Whole grain intake: The Baltimore Longitudinal Study of Aging SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE Whole grains; Wheat; Bran; Germ; Fiber; Database; Food composition ID CARDIOVASCULAR-DISEASE; DIETARY FIBER; RISK-FACTORS; HEALTH; CONSUMPTION; CANCER; MEN AB Our objective was to identify major dietary Sources of whole grains and to describe the construction of a database of whole grain content of foods. Dietary information was collected with 7-d food records from men and women in the Baltimore Longitudinal Study of Aging, mean age 62.1 +/- 16.0 years, who participated in the dietary assessment portion of the study (n = 1516), and estimates of whole grain intake were obtained from a newly developed database. The Pyramid Servings database and 1994-1996 Continuing Survey of Food Intakes by Individuals (CSFII) recipe ingredients database were then used to calculate both servings and gram weights of whole grain intakes. Mean intakes of whole grains, refined grains, and total grains, as well as frequency of intake for major whole grain food groups and whole grain content for each group, were calculated. Top contributors of whole grains were ready-to-eat breakfast cereals (made with whole grain as well as bran), hot breakfast cereals (made with whole grain), multi-grain bread, and whole wheat bread. While more research is needed to better understand the benefits of whole grains, the development of research tools, including databases to accurately assess whole grain intake, is a critical step in completing such research. (C) 2008 Elsevier Inc. All rights reserved. C1 [Maras, Janice E.; Bakun, Peter J.; Tucker, Katherine L.] Tufts Univ, Dietary Assessment & Epidemiol Res Program, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Newby, P. K.] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Newby, P. K.] Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA USA. [Ferrucci, Luigi] NIA, Baltimore Longitudinal Study Aging, Baltimore, MD 21224 USA. RP Tucker, KL (reprint author), Tufts Univ, Dietary Assessment & Epidemiol Res Program, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM Katherine.tucker@tufts.edu RI Tucker, Katherine/A-4545-2010; OI Tucker, Katherine/0000-0001-7640-662X FU NIA NIH HHS [Z01 AG000015-50] NR 26 TC 12 Z9 14 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD FEB PY 2009 VL 22 IS 1 BP 53 EP 58 DI 10.1016/j.jfca.2008.10.005 PG 6 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 430KW UT WOS:000264989000008 PM 20126297 ER PT J AU Arora, NK Gustafson, DH AF Arora, Neeraj K. Gustafson, David H. TI Perceived Helpfulness of Physicians' Communication Behavior and Breast Cancer Patients' Level of Trust Over Time SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE breast cancer; trust; patient-physician communication; longitudinal analysis ID FUNCTIONAL ASSESSMENT; CARE; QUALITY; RELIABILITY; VALIDATION; SUPPORT; SCALE; WOMEN AB We evaluated the association between physicians' communication behavior and breast cancer patients' trust in their physicians. Longitudinal survey conducted at baseline, 2-month, and 5-month follow-up during first year of diagnosis. Newly diagnosed breast cancer patients (N = 246). We collected data on patient perceptions of the helpfulness of informational, emotional, and decision-making support provided by physicians and patients' trust. Linear regression models evaluated the association of concurrent and prior levels of physician support with patients' trust. At baseline, patients who received helpful informational, emotional, and decision-making support from physicians reported greater trust (p < 0.05, p < 0.001, and p < 0.01, respectively). At the 2-month assessment, baseline informational support and informational and emotional support at 2-months were associated with greater trust (p < 0.05, p < 0.01, and p < 0.05, respectively). At the 5-month assessment, only helpful emotional support from physicians at 5 months was associated with greater trust (p < 0.01). Interestingly, while perceived helpfulness of all three types of physician support decreased significantly over time, patient trust remained high and unchanged. Findings suggest that while informational and decision-making support may be more important to patient trust early in the course of treatment, emotional support from physicians may be important to maintain trust throughout the initial year of diagnosis. C1 [Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Gustafson, David H.] Univ Wisconsin, Ctr Hlth Enhancement Syst Studies, Madison, WI USA. RP Arora, NK (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Executive Blvd,MSC 7344,Execut Plaza N 4005, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov FU National Institute of Child Health and Human Development; National Cancer Institute [5R01HD32922] FX This research was supported by the National Institute of Child Health and Human Development and the National Cancer Institute under grant no. 5R01HD32922: PI: David H. Gustafson. NR 19 TC 13 Z9 16 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2009 VL 24 IS 2 BP 252 EP 255 DI 10.1007/s11606-008-0880-x PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 397GO UT WOS:000262651100016 PM 19089501 ER PT J AU Grady, KI Ulisney, KI Kirklin, JK Naftel, DC Gelijns, AC Young, JB Martin, T Chisholm, K Moskowitz, A AF Grady, K. I. Ulisney, K. I. Kirklin, J. K. Naftel, D. C. Gelijns, A. C. Young, J. B. Martin, T. Chisholm, K. Moskowitz, A. TI Important Improvements in Quality of Life after MCSD Implant: First Results from INTERMACS SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation CY APR 22-25, 2009 CL Paris, FRANCE SP Int Soc Heart & Lung Transplantat C1 [Grady, K. I.; Moskowitz, A.] Northwestern Univ, Med Ctr, Bluhm Cardiovasc Inst, Chicago, IL 60611 USA. [Ulisney, K. I.] Natl Heart Lung & Blood Inst, Bethesda, MD USA. [Kirklin, J. K.; Naftel, D. C.] Univ Alabama, Birmingham, AL USA. [Gelijns, A. C.] Columbia Univ, Med Ctr, New York, NY USA. [Young, J. B.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Martin, T.] Newark Beth Israel Hosp, Newark, NJ USA. [Chisholm, K.] Univ Arizona, Med Ctr, Tucson, AZ USA. 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 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2009 VL 28 IS 2 MA 408 BP S207 EP S207 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 409XT UT WOS:000263539800405 ER PT J AU Holman, WI Kirklin, JK Naftel, DC Kormos, RL Desvign-Nickens, P Camucho, M Ascheim, D AF Holman, W. I. Kirklin, J. K. Naftel, D. C. Kormos, R. L. Desvign-Nickens, P. Camucho, M. Ascheim, D. TI Early Infections after MCSD Implant In 455 Patients: Incidence, Location and Outcome SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation CY APR 22-25, 2009 CL Paris, FRANCE SP Int Soc Heart & Lung Transplantat C1 [Holman, W. I.; Kirklin, J. K.; Naftel, D. C.; Kormos, R. L.] Univ Alabama, Birmingham, AL USA. [Kormos, R. L.] Univ Pittsburgh, Pittsburgh, PA USA. [Desvign-Nickens, P.] NHLBI, Bethesda, MD 20892 USA. [Camucho, M.] Newark Beth Israel Med Ctr, Newark, NJ USA. [Ascheim, D.] Columbia Univ, New York, NY USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2009 VL 28 IS 2 MA 254 BP S155 EP S155 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 409XT UT WOS:000263539800254 ER PT J AU Kormos, RL Teuteberg, JJ Kirklin, JK Naftel, DC Stevenson, LW Milano, CA Miller, MA Pagani, FD Rogers, JG Aaronson, KD AF Kormos, R. L. Teuteberg, J. J. Kirklin, J. K. Naftel, D. C. Stevenson, L. W. Milano, C. A. Miller, M. A. Pagani, F. D. Rogers, J. G. Aaronson, K. D. TI Adverse Event (AE) Rates In Patients Receiving Pulsatile VAD's: Incidence and Composition Change Dramatically 3 Months after Implant SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation CY APR 22-25, 2009 CL Paris, FRANCE SP Int Soc Heart & Lung Transplantat C1 [Kormos, R. L.; Teuteberg, J. J.] Univ Pittsburgh, Pittsburgh, PA USA. [Kirklin, J. K.; Naftel, D. C.] Univ Alabama, Birmingham, AL USA. [Stevenson, L. W.] Brigham & Womens Med Ctr, Boston, MA USA. [Milano, C. A.; Rogers, J. G.] Duke Univ, Med Ctr, Durham, NC USA. [Miller, M. A.] NHLBI, Bethesda, MD 20892 USA. [Rogers, J. G.; Aaronson, K. D.] Univ Michigan, Med Ctr, Ann Arbor, MI 48109 USA. 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 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2009 VL 28 IS 2 MA 416 BP S210 EP S210 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 409XT UT WOS:000263539800412 ER PT J AU Kormos, RL Kirklin, JK Naftel, DG Young, JB Acker, M Jessup, M Jeevanandam, V Baldwin, TL Camacho, M Ascheim, DD AF Kormos, R. L. Kirklin, J. K. Naftel, D. G. Young, J. B. Acker, M. Jessup, M. Jeevanandam, V. Baldwin, T. L. Camacho, M. Ascheim, D. D. TI Early Neurological Adverse Events (NAE) after Pulsatile VAD implantation in 455 Patients: Incidence, Severity and Outcome SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation CY APR 22-25, 2009 CL Paris, FRANCE SP Int Soc Heart & Lung Transplantat C1 [Kormos, R. L.] Univ Pittsburgh, Pittsburgh, PA USA. [Kirklin, J. K.; Naftel, D. G.] Univ Alabama, Birmingham, AL USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Young, J. B.; Acker, M.; Jessup, M.] Univ Penn, Philadelphia, PA USA. [Jeevanandam, V.] Univ Chicago, Chicago, IL 60637 USA. [Baldwin, T. L.] NHLBI, Bethesda, MD 20892 USA. [Camacho, M.] Newark Beth Israel Med Ctr, Newark, NJ USA. [Ascheim, D. D.] Columbia Univ, New York, NY USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2009 VL 28 IS 2 MA 181 BP S129 EP S129 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 409XT UT WOS:000263539800181 ER PT J AU Pipeling, MR Whitlock, AB Migueles, SA Connors, M McDyer, JF AF Pipeling, M. R. Whitlock, A. B. Migueles, S. A. Connors, M. McDyer, J. F. TI Striking Expansion and Persistence of T-bet(+)CD8(+) CMV-Specific T Cells with Primary Infection in Lung Transplant Recipients SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation CY APR 22-25, 2009 CL Paris, FRANCE SP Int Soc Heart & Lung Transplantat C1 [Pipeling, M. R.; Whitlock, A. B.; McDyer, J. F.] Johns Hopkins Univ, Baltimore, MD USA. [Migueles, S. A.; Connors, M.] NIH, Bethesda, MD 20892 USA. 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 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2009 VL 28 IS 2 SU S MA 539 BP S253 EP S253 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 409XT UT WOS:000263539800535 ER PT J AU Ulisney, KL Grady, KL Kirklin, JK Naftet, DC Gelijns, AC Moskowitz, AJ Young, JB Myers, SL Wissman, SA AF Ulisney, K. L. Grady, K. L. Kirklin, J. K. Naftet, D. C. Gelijns, A. C. Moskowitz, A. J. Young, J. B. Myers, S. L. Wissman, S. A. TI Evaluating Quality of Life Prior to MCSD Implant Is a Challenge: Results from INTERMACS SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation CY APR 22-25, 2009 CL Paris, FRANCE SP Int Soc Heart & Lung Transplantat C1 [Ulisney, K. L.] NHLBI, Bethesda, MD 20892 USA. [Grady, K. L.] Northwestern Univ, Med Ctr, Bluhm Cardiovasc Inst, Chicago, IL 60611 USA. [Kirklin, J. K.; Naftet, D. C.; Myers, S. L.] Univ Alabama, Birmingham, AL USA. [Gelijns, A. C.; Moskowitz, A. J.] Columbia Univ, Med Ctr, New York, NY USA. [Young, J. B.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Wissman, S. A.] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2009 VL 28 IS 2 MA 587 BP S269 EP S270 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 409XT UT WOS:000263539800583 ER PT J AU Otoo, GE Lartey, AA Perez-Escamilla, R AF Otoo, Gloria E. Lartey, Anna A. Perez-Escamilla, Rafael TI Perceived Incentives and Barriers to Exclusive Breastfeeding Among Periurban GhanaianWomen SO JOURNAL OF HUMAN LACTATION LA English DT Article DE Africa; exclusive breastfeeding; Ghana; incentives; barriers; focus groups ID INSUFFICIENT MILK; MOTHERS; AFRICA; COMMUNITY AB Focus group discussions were conducted to elicit the perceived incentives and barriers to exclusive breastfeeding in Ghana Thirty-five breastfeeding women were recruited from the Manya and Yilo Krobo districts of the eastern region. Participants had a mean age of 2.75 years and had at least one child < a months old. Almost all of the participants believed that exclusive breastfeeding is the superior infant feeding method and should be practiced for the first c months postpartum. However there was widespread belief that infants can be given water if it is clean. Mothers reported that exclusive breastfeeding was easier when breast milk began to flow soon after delivery. The main obstacles to exclusive breastfeeding identified were maternal employment, breast and nipple problems, perceived milk insufficiency, and pressure from family. Addressing the concerns put forward by these participants can be used to enhance exclusive breastfeeding promotion in this region. J Hum Lact. 25(1):34-41. C1 [Otoo, Gloria E.] Univ Connecticut, Dept Nutr Sci, Storrs, CT 06269 USA. [Lartey, Anna A.] Univ Ghana, Dept Nutr & Food Sci, Legon, Ghana. [Perez-Escamilla, Rafael] NIH, EXPORT CEHDL, Bethesda, MD USA. RP Otoo, GE (reprint author), Univ Connecticut, Dept Nutr Sci, 3624 Horsebarn Hill Rd Ext, Storrs, CT 06269 USA. FU NIH/NICHD [HD43620] FX This project was funded by the RIING Project through NIH/NICHD grant HD43620. The authors acknowledge the participation of all mothers in this study. They are grateful to Deda Ogum Mary Ohipeni Richlove Ocansey, and Emelia Asamoah for the assistance with the focus group discussions. NR 22 TC 17 Z9 17 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-3344 J9 J HUM LACT JI J. Hum. Lact. PD FEB PY 2009 VL 25 IS 1 BP 34 EP 41 DI 10.1177/0890334408325072 PG 8 WC Nursing; Obstetrics & Gynecology; Pediatrics SC Nursing; Obstetrics & Gynecology; Pediatrics GA 403ZP UT WOS:000263120800010 PM 18971507 ER PT J AU Pacheco-Rodriguez, G Kumaki, F Steagall, WK Zhang, Y Ikeda, Y Lin, JP Billings, EM Moss, J AF Pacheco-Rodriguez, Gustavo Kumaki, Fumiyuki Steagall, Wendy K. Zhang, Yi Ikeda, Yoshihiko Lin, Jing-Ping Billings, Eric M. Moss, Joel TI Chemokine-Enhanced Chemotaxis of Lymphangioleiomyomatosis Cells with Mutations in the Tumor Suppressor TSC2 Gene SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SMOOTH-MUSCLE-CELLS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; TUBEROUS SCLEROSIS COMPLEX; CHEMOKINE/CHEMOKINE RECEPTOR NOMENCLATURE; BREAST-CANCER METASTASIS; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; STROMAL FIBROBLASTS; POLYMORPHISM; EXPRESSION; LYMPHANGIOMYOMATOSIS AB Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction caused by LAM cells (smooth-muscle-like cells) that have mutations in the tumor suppressor genes tuberous sclerosis complex (TSC) 1 or 2 and have the capacity to metastasize. Since chemokines and their receptors function in chemotaxis of metastatic cells, we hypothesized that LAM cells may be recruited by chemokine(s) in the lung. Quantification of 25 chemokines in bronchoalveolar lavage fluid from LAM patients and healthy volunteers revealed that concentrations of CCL2, CXCL1, and CXCL5 were significantly higher in samples from LAM patients than those from healthy volunteers. In vitro, CCL2 or MCP-1 induced selective migration of cells, showing loss of heterozygosity of TSC2 from a heterogeneous population of cells grown from explanted LAM lungs. Additionally, the frequencies of single-nucleotide polymorphisms in the CCL2 gene promoter region differed significantly in LAM patients and healthy volunteers (p = 0.018), and one polymorphism was associated significantly more frequently with the decline of lung function. The presence (i.e., potential functionality) of chemokine receptors was evaluated using immunohistochemistry in lung sections from 30 LAM patients. Expression of chemokines and these receptors varied among LAM patients and differed from that seen in some cancers (e.g., breast cancer and melanoma cells). These observations are consistent with the notion that chemokines such as CCL2 may serve to determine mobility and specify the site of metastasis of the LAM cell. The Journal of Immunology, 2009, 182: 1270-1277. C1 [Pacheco-Rodriguez, Gustavo; Kumaki, Fumiyuki; Steagall, Wendy K.; Zhang, Yi; Ikeda, Yoshihiko; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Lin, Jing-Ping] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. [Billings, Eric M.] NHLBI, Integrat Computat Biol Lab, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,Room 6D05,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU National Institutes of Health; National Heart, Lung, and Blood Institute; Oak Ridge Institute for Science and Education FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. Y.I. was contracted through a Senior Fellowship from the Oak Ridge Institute for Science and Education. NR 62 TC 26 Z9 27 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 FEB 1 PY 2009 VL 182 IS 3 BP 1270 EP 1277 PG 8 WC Immunology SC Immunology GA 400BD UT WOS:000262842100009 PM 19155472 ER PT J AU Eberly, MD Kader, M Hassan, W Rogers, KA Zhou, JZ Mueller, YM Mattapallil, MJ Piatak, M Lifson, JD Katsikis, PD Roederer, M Villinger, F Mattapallil, JJ AF Eberly, Matthew D. Kader, Muhamuda Hassan, Wail Rogers, Kenneth A. Zhou, Jianzhong Mueller, Yvonne M. Mattapallil, Mary J. Piatak, Michael, Jr. Lifson, Jeffrey D. Katsikis, Peter D. Roederer, Mario Villinger, Francois Mattapallil, Joseph J. TI Increased IL-15 Production Is Associated with Higher Susceptibility of Memory CD4 T Cells to Simian Immunodeficiency Virus during Acute Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NONHUMAN-PRIMATES; RHESUS MACAQUES; SIV INFECTION; HOMEOSTATIC PROLIFERATION; LYMPHOCYTE-PROLIFERATION; ACTIVATION; EXPRESSION; INDUCTION; CYTOKINE; TYPE-1 AB Acute SIV infection is characterized by explosive infection of memory CD4 T cells in peripheral and mucosal tissues. Interestingly, relatively few memory CD4 T cells are infected until as late as days 7-8 after challenge. However, by day 10 postinfection, most of the memory CD4 T cells are infected and carry viral DNA. The rapidity with which infection expands within 2-3 days to encompass virtually the entire memory CD4 T cell compartment suggests significant alterations in the susceptibility of memory CD4 T cells to infection during this period. The mechanism(s) underlying this increased permissiveness to infection is not known. In this study, we show that IL-15 secretion significantly correlates with the up-regulated expression of CD4 on memory CD4 T cells that is associated with increased permissiveness to SIV infection. Activation and proliferation of memory CD8, but not memory CD4 T cells, preceded the amplification of viral infection. Although memory CD4 T cells did not express normal activation markers, they displayed a significant up-regulation in the density of CD4 but not CCR5 expression between days 7 and 10 postinfection that correlated with increased plasma IL-15 levels and infection in these cells. Culture of purified CD4 T cells with IL-15 and/or SIV was associated with a significant increase in the expression of CD4 and infection of these sorted cells. Our results demonstrate that IL-15 contributes to the increased susceptibility of memory CD4 T cells to SIV during the early phase of acute SIV infection. The Journal of Immunology, 2009, 182: 1439-1448. C1 [Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Rogers, Kenneth A.; Zhou, Jianzhong; Villinger, Francois] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Mueller, Yvonne M.; Katsikis, Peter D.] Drexel Univ, Coll Med, Philadelphia, PA 19129 USA. [Mattapallil, Mary J.] NEI, NIH, Bethesda, MD 20892 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Roederer, Mario] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Mattapallil, JJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Room B4068, Bethesda, MD 20814 USA. EM jmattapallil@usuhs.mil FU National Institutes of Allergy and Infectious Diseases [K22 AI07812]; National Institute of Dental and Craniofacial Research [R21 DE018339]; National Institute of Allergy and Infectious Diseases [R01 AI062437]; National Cancer Institute, National Institutes of Health [NO1-CO-124000] FX The described project was supported by Grant K22 AI07812 from the National Institutes of Allergy and Infectious Diseases and Grant R21 DE018339 from the National Institute of Dental and Craniofacial Research awarded to J.J.M. and in part from R01 AI062437 from the National Institute of Allergy and Infectious Diseases awarded to P.D.K Studies were supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-124000. NR 41 TC 35 Z9 35 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 FEB 1 PY 2009 VL 182 IS 3 BP 1439 EP 1448 PG 10 WC Immunology SC Immunology GA 400BD UT WOS:000262842100028 PM 19155491 ER PT J AU Claudio, E Sonder, SU Saret, S Carvalho, G Ramalingam, TR Wynn, TA Chariot, A Garcia-Perganeda, A Leonardi, A Paun, A Chen, A Ren, NY Wang, HS Siebenlist, U AF Claudio, Estefania Sonder, Soren Ulrik Saret, Sun Carvalho, Gabrielle Ramalingam, Thirumalai R. Wynn, Thomas A. Chariot, Alain Garcia-Perganeda, Antonio Leonardi, Antonio Paun, Andrea Chen, Amy Ren, Nina Y. Wang, Hongshan Siebenlist, Ulrich TI The Adaptor Protein CIKS/Act1 Is Essential for IL-25-Mediated Allergic Airway Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; IN-VIVO; NEGATIVE REGULATOR; GENE-EXPRESSION; IL-25; IL-17; RECEPTOR; INTERLEUKIN-17; IDENTIFICATION; CYTOKINES AB IL-17 is the signature cytokine of recently discovered Th type 17 (Th17) cells, which are prominent in defense against extracellular bacteria and fungi as well as in autoimmune diseases, such as rheumatoid arthritis and experimental autoimmune encephalomyelitis in animal models. IL-25 is a member of the IL-17 family of cytokines, but has been associated with Th2 responses instead and may negatively cross-regulate Th17/IL-17 responses. IL-25 can initiate an allergic asthma-like inflammation in the airways, which includes recruitment of eosinophils, mucus hypersecretion, Th2 cytokine production, and airways hyperreactivity. We demonstrate that these effects of IL-25 are entirely dependent on the adaptor protein CIKS (also known as Act1). Surprisingly, this adaptor is necessary to transmit IL-17 signals as well, despite the very distinct biologic responses that these two cytokines elicit. We identify CD11c(+) macrophage-like lung cells as physiologic relevant targets of IL-25 in vivo. The Journal of Immunology, 2009, 182: 1617-1630. C1 [Claudio, Estefania; Sonder, Soren Ulrik; Saret, Sun; Carvalho, Gabrielle; Chariot, Alain; Garcia-Perganeda, Antonio; Leonardi, Antonio; Paun, Andrea; Ren, Nina Y.; Wang, Hongshan; Siebenlist, Ulrich] NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. [Ramalingam, Thirumalai R.; Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Chen, Amy] NHGRI, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIH, Immunoregulat Lab, Bldg 10,Room 11B15, Bethesda, MD 20892 USA. EM USiebenlist@niaid.nih.gov RI Wynn, Thomas/C-2797-2011; OI LEONARDI, Antonio/0000-0001-8636-9623 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 39 TC 83 Z9 88 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 FEB 1 PY 2009 VL 182 IS 3 BP 1617 EP 1630 PG 14 WC Immunology SC Immunology GA 400BD UT WOS:000262842100048 PM 19155511 ER PT J AU Garcia-Pineres, AJ Hildesheim, A Dodd, L Kemp, TJ Yang, J Fullmer, B Harro, C Lowy, DR Lempicki, RA Pinto, LA AF Garcia-Pineres, Alfonso J. Hildesheim, Allan Dodd, Lori Kemp, Troy J. Yang, Jun Fullmer, Brandie Harro, Clayton Lowy, Douglas R. Lempicki, Richard A. Pinto, Ligia A. TI Gene Expression Patterns Induced by HPV-16 L1 Virus-Like Particles in Leukocytes from Vaccine Recipients SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; RANDOMIZED CONTROLLED-TRIAL; CELLULAR IMMUNE-RESPONSES; BLOOD MONONUCLEAR-CELLS; NASOPHARYNGEAL CARCINOMA; QUADRIVALENT VACCINE; SUSTAINED EFFICACY; ADULT VOLUNTEERS; DENDRITIC CELLS; WHOLE-BLOOD AB Human papillomavirus (HPV) virus-like particle (VLP) vaccines were recently licensed. Although neutralizing Ab titers are thought to be the main effectors of protection against infection, early predictors of long-term efficacy are not yet defined and a comprehensive understanding of innate and adaptive immune responses to vaccination is still lacking. Here, microarrays were used to compare the gene expression signature in HPV-16 L1 VLP-stimulated PBMCs from 17 vaccine and 4 placebo recipients before vaccination and 1 mo after receiving the second immunization. Vaccination with a monovalent HPV-16 L1 VLP vaccine was associated with modulation of genes involved in the inflammatory/defense response, cytokine, IFN, and cell cycle pathways in VLP-stimulated PBMCs. Additionally, there was up-regulation of probesets associated with cytotoxic (GZMB, TNFSF10) and regulatory (INDO, CTLA4) activities. The strongest correlations with neutralizing Ab titers were found for cyclin D2 (CCND2) and galectin (LGALS2). Twenty-two differentially expressed probesets were selected for confirmation by RT-PCR in an independent sample set. Agreement with microarray data was seen for more than two-thirds of these probesets. Up-regulation of immune/defense response genes by HPV-16 L1 VLP, in particular, IFN-induced genes, was observed in PBMCs collected before vaccination, with many of these genes being further induced following vaccination. In conclusion, we identified important innate and adaptive response-related genes induced by vaccination with HPV-16 L1 VLP. Further studies are needed to identify gene expression signatures of immunogenicity and long-term protection with potential utility in prediction of long-term HPV vaccination outcomes in clinical trials. The Journal of Immunology, 2009, 182: 1706-1729. C1 [Garcia-Pineres, Alfonso J.; Kemp, Troy J.; Pinto, Ligia A.] NCI, Sci Applicat Int Corp Frederick, HPV Immunol Lab, Frederick, MD 21702 USA. [Hildesheim, Allan] NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Dodd, Lori] NIH, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Yang, Jun; Fullmer, Brandie; Lempicki, Richard A.] NCI, SAIC Frederick, Lab Bioinformat & Immunopathogenesis, Frederick, MD 21702 USA. [Harro, Clayton] Johns Hopkins Univ, Ctr Immunizat Res, Baltimore, MD 21205 USA. [Lowy, Douglas R.] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pinto, LA (reprint author), NCI, Sci Applicat Int Corp Frederick, HPV Immunol Lab, Bldg 469,Room 120, Frederick, MD 21702 USA. EM lpinto@ncifcrf.gov RI Lempicki, Richard/E-1844-2012; Hildesheim, Allan/B-9760-2015 OI Lempicki, Richard/0000-0002-7059-409X; Hildesheim, Allan/0000-0003-0257-2363 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 (N01-CO-12400). NR 53 TC 14 Z9 15 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 FEB 1 PY 2009 VL 182 IS 3 BP 1706 EP 1729 PG 24 WC Immunology SC Immunology GA 400BD UT WOS:000262842100058 PM 19155521 ER PT J AU Inozume, T Hanada, KI Wang, QJ Yang, JC AF Inozume, Takashi Hanada, Ken-ichi Wang, Qiong J. Yang, James C. TI IL-17 Secreted by Tumor Reactive T Cells Induces IL-8 Release by Human Renal Cancer Cells SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE renal cell carcinoma; IL-17; IL-8; microenvironment ID COLLAGEN-INDUCED ARTHRITIS; AUTOIMMUNE INFLAMMATION; INTERLEUKIN-17; EXPRESSION; DISTINCT; ACTIVATION; PHENOTYPE; CYTOKINE; MELANOMA; ANTIGENS AB T(H)17 is a newly identified pathogenic memory CD4(+) T-cell lineage with potent agonist effects in some murine experimental autoimmunity models, however. its role in tumor immunology is still unclear. Clinical experience with interleukin (IL)-2 and ipilumumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody], particularly in treating immunogenic malignancies Such as melanoma and renal cell carcinoma (RCC), has suggested an association between a variety Of autoimmune phenomena and tumor regression. To investigate this issue in patients with RCC, we isolated T-cell clones from peripheral blood that released IL-17 on stimulation with their autologous RCC tumor line. Clones were generated from I patient before any treatment by in vitro stimulation with dendritic cells, autologous tumor, and IL-2 in the presence of anti-CTLA4 antibody. That patient subsequently received treatment with ipilimumab and showed both objective tumor regression and immune-mediated colitis. Limiting dilution cloning of his tumor-dendritic cell-stimulated T cells produced the 3G8D CD4(+) clone, which secreted both IL-17 and interferon-gamma when cocultured with the autologous RCC line (transduced with class II transactivation Molecule to induce major histocompatibility complex-class 11 expression), Broader analysis of its cytokine secretion profile showed large amounts of IL-8 when cocultured with RCC. but not when triggered with phorbol 12-myristate 13-acetate and ionomycin. This led to the discovery that IL-8 was being produced by the RCC cells in response to T-cell-derived IL-17. This effect of exogeneous IL-17 on IL-8 release front tumor was seen in 5 of 8 RCCs, but not in other tumors tested. preliminary data on the frequency of IL-17-secreting T cells in the lymphocytes infiltrating RCCS Suggest that there may be a positive correlation between this frequeney and IL-8 production by nonlymphoid cells as determined by quantitative reverse transcription-polymerase chain reaction. This report extends the known bidirectional interactions between immune cells and malignant cells in the tumor microenvironment that can shape and modulate the host immune response to cancer. C1 [Inozume, Takashi; Hanada, Ken-ichi; Wang, Qiong J.; Yang, James C.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, NIH, 9000 Rockville Pike,Bldg 10 CRC,Room 3W-3840, Bethesda, MD 20892 USA. EM JamesYang@mail.nih.gov RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 NR 28 TC 26 Z9 28 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD FEB-MAR PY 2009 VL 32 IS 2 BP 109 EP 117 PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 411NC UT WOS:000263655300002 PM 19238009 ER PT J AU Singh, V Ji, QY Feigenbaum, L Leighty, RM Hurwitz, AA AF Singh, Vinod Ji, Qingyong Feigenbaum, Lionel Leighty, Robert M. Hurwitz, Arthur A. TI Melanoma Progression Despite Infiltration by In Vivo-primed TRP-2-specific T Cells SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE melanoma; T cells; adoptive immunotherapy; T-cell receptor transgene ID TYROSINASE-RELATED PROTEIN-2; TUMOR-ANTIGEN; CANCER-IMMUNOTHERAPY; CLONAL DELETION; TRANSGENIC MICE; SELF-ANTIGENS; B16 MELANOMA; LOW AVIDITY; TOLERANCE; LYMPHOCYTES AB Many antigens recognized by tumor-reactive cytotoxic CD8(+) T cells are self-antigens. Tyrosinase-related protein 2 (TRP-2) is a melanogenic enzyme expressed by both melanocytes and melanoma,.; that is reported to be a candidate melanoma rejection antigen. To study the role of self-reactive CD8(+) T cells in tumor immunity and autoimmunity, we generated mice that bear I T-cell receptor transgene (TCR Tg) specific for the TRP-2((180-188)) epitope. TRP-2 TCR Tg mice did not spontaneously develop depigmentation despite systemic expression of TRP-2 in the skin. Peripheral T cells from these TCR Tg mice exhibited a naive phenotype and proliferated in response to TRP-2 in vitro. In addition, transfer of in vitro-activated Tg T cells reduced 1316 Pulmonary tumor burden, but not subcutaneous tumors. We next sought to determine the in vivo responses or the Tg T cells to endogenous and tumor-derived TRP-2. Adoptive transfer of naive TCR Tg T cells into wild-type C57BL/6 mice, in combination with a TRP-2-pulsed dendritic cell vaccines induced proliferation of the Tg T cells and resulted in migration of the Tg T cells into a subcutaneous B16 melanoma tumor. Although these tumor-infiltrating Tg T cells remained reactive against TRP-2, they did not reduce growth of the primary subcutaneous tumor; similarly, these in vivo-primed effector cells had no significant effect on the growth of pulmonary nodules. These data demonstrate that despite in vivo priming, tumor-infiltrating T cells may fail to reduce tumor burden. Determining the basis for the inability of the tumor microenvironment to sustain effective antitumor responses will be critical for designing newer, more potent antitumor immunotherapies. C1 [Singh, Vinod; Hurwitz, Arthur A.] NCI, Canc & Inflammat Program, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. [Leighty, Robert M.] NCI, Data Management Serv, Frederick, MD 21701 USA. [Ji, Qingyong] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. RP Hurwitz, AA (reprint author), NCI, Canc & Inflammat Program, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. EM hurwitza@nciferf.gov FU NCI, NIH FX Supported by the Intramural Research Program, NCI, NIH. NR 40 TC 21 Z9 21 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD FEB-MAR PY 2009 VL 32 IS 2 BP 129 EP 139 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 411NC UT WOS:000263655300004 PM 19238011 ER PT J AU Vietri, NJ Purcell, BK Tobery, SA Rasmussen, SL Leffel, EK Twenhafel, NA Ivins, BE Kellogg, MD Webster, WM Wright, ME Friedlander, AM AF Vietri, Nicholas J. Purcell, Bret K. Tobery, Steven A. Rasmussen, Suzanne L. Leffel, Elizabeth K. Twenhafel, Nancy A. Ivins, Bruce E. Kellogg, Mark D. Webster, Wendy M. Wright, Mary E. Friedlander, Arthur M. TI A Short Course of Antibiotic Treatment Is Effective in Preventing Death from Experimental Inhalational Anthrax after Discontinuing Antibiotics SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PROTECTIVE ANTIGEN; BACILLUS-ANTHRACIS; IMMUNOGLOBULIN-G; PROPHYLAXIS; PATHOGENESIS; ANTIBODIES; PATHOLOGY; OUTBREAK; VACCINE; SPORES AB Background. Postexposure prophylaxis of inhalational anthrax requires prolonged antibiotic therapy or antibiotics and vaccination. The duration of treatment for established anthrax is controversial, because retained spores may germinate and cause disease after antibiotics are discontinued. Using rhesus macaques, we determined whether a short course of antibiotic treatment, as opposed to prophylaxis, could effectively treat inhalational anthrax and prevent disease caused by the germination of spores after discontinuation of antibiotics. Methods. Two groups of 10 rhesus macaques were exposed to an aerosol dose of Bacillus anthracis spores. Animals in group 1 received ciprofloxacin prophylaxis beginning 1-2 h after exposure. Those in group 2 began receiving ciprofloxacin after becoming bacteremic, and treatment was continued for 10 days. When each group 2 animal completed 10 days of therapy, the prophylactic antibiotic was discontinued in the paired group 1 animal. Results. In group 1 (prophylaxis), no deaths occurred during antibiotic treatment, but only 2 (20%) of 10 animals survived after antibiotics were discontinued. In contrast, in group 2 (treatment), 3 deaths occurred during antibiotic treatment, but all 7 animals (100%) alive after 10 days of therapy survived when antibiotics were discontinued. Conclusions. In the treatment of inhalational anthrax, the prolonged course of antibiotics required to achieve prophylaxis may not be necessary to prevent anthrax that results from the germination of retained spores after the discontinuation of antibiotics. C1 [Vietri, Nicholas J.; Purcell, Bret K.; Tobery, Steven A.; Rasmussen, Suzanne L.; Ivins, Bruce E.; Webster, Wendy M.] USA, Med Res Inst Infect Dis, Div Bacteriol, Frederick, MD 21702 USA. [Twenhafel, Nancy A.] USA, Med Res Inst Infect Dis, Div Pathol, Frederick, MD 21702 USA. [Kellogg, Mark D.] USA, Med Res Inst Infect Dis, Div Diagnost Syst, Frederick, MD 21702 USA. [Leffel, Elizabeth K.] USA, Med Res Inst Infect Dis, Ctr Aerobiol Sci, Frederick, MD 21702 USA. [Wright, Mary E.] NIAID, Bethesda, MD 20892 USA. RP Vietri, NJ (reprint author), USA, Med Res Inst Infect Dis, Div Bacteriol, 1425 Porter St, Frederick, MD 21702 USA. EM nicholas.vietri@amedd.army.mil; arthur.friedlander@amedd.army.mil OI Kellogg, Mark/0000-0003-1868-2153 NR 30 TC 16 Z9 16 U1 0 U2 1 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 FEB 1 PY 2009 VL 199 IS 3 BP 336 EP 341 DI 10.1086/596063 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 392UB UT WOS:000262326600007 PM 19099484 ER PT J AU Safaeian, M Falk, RT Rodriguez, AC Hildesheim, A Kemp, T Williams, M Morera, L Barrantes, M Herrero, R Porras, C Pinto, L AF Safaeian, Mahboobeh Falk, Roni T. Rodriguez, Ana Cecilia Hildesheim, Allan Kemp, Troy Williams, Marcus Morera, Lidiana Barrantes, Manuel Herrero, Rolando Porras, Carolina Pinto, Ligia TI Factors Associated with Fluctuations in IgA and IgG Levels at the Cervix during the Menstrual Cycle SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 24th International Papillomavirus Conference and Clinical Workshop CY NOV 03-09, 2007 CL Beijing, PEOPLES R CHINA ID PARTICLE VACCINE; YOUNG-WOMEN; SECRETIONS; MUCUS; IMMUNOGLOBULINS; INFECTION; CYTOKINES; EFFICACY; TYPE-18; SERUM AB Objective. The objective of this analysis was to describe patterns and determinants of cervical immunoglobulin A (IgA) and G (IgG) levels during the menstrual cycle. Methods. A total of 154 women who attended 3 visits coinciding with the follicular, periovulatory, and luteal phases of their menstrual cycle were studied. Cervical secretions were collected at each visit for determination of total IgA and IgG levels. Questionnaires administered at each visit inquired about demographic characteristics and behavioral practices. Results. Total IgA and IgG levels were higher among oral contraceptive (OC) users than among naturally cycling women ( hereafter, "non-OC users"). IgA and IgG levels decreased at midcycle, particularly among non-OC users. After adjustment for phase of the current cycle, specimen weight, and detection of blood in the sample, report of a recent illness was associated with lower IgA and IgG levels and increased age with higher IgA and IgG levels among OC users and non-OC users. Increased lifetime number of pregnancies was associated with a higher IgA level among non-OC users and a higher IgG level among OC users. Change in immunoglobulin levels between visits was associated with sample weight and the presence of blood for both OC users and non-OC users. Conclusions. Phase of the current menstrual cycle and OC use were significant determinants of cervical IgA and IgG levels. The impacts of endogenous and exogenous hormones on cervical immunoglobulin levels should be further investigated. C1 [Safaeian, Mahboobeh] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, Rockville, MD 20852 USA. [Kemp, Troy; Williams, Marcus; Pinto, Ligia] NCI, HPV Immunol Lab, SAIC Frederick, Frederick, MD USA. [Rodriguez, Ana Cecilia; Morera, Lidiana; Barrantes, Manuel; Herrero, Rolando; Porras, Carolina] Fdn INCIENSA, San Jose, Costa Rica. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, 6120 Execut Blvd,Ste 550, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov RI 段, 沛沛/C-9902-2010; Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU Intramural NIH HHS [Z99 CA999999, ZIA CP010216-4]; NCI NIH HHS [N01CO12400] NR 22 TC 12 Z9 12 U1 0 U2 0 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 FEB 1 PY 2009 VL 199 IS 3 BP 455 EP 463 DI 10.1086/596060 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 392UB UT WOS:000262326600024 PM 19133811 ER PT J AU Leppert, IR Almli, CR McKinstry, RC Mulkern, RV Pierpaoli, C Rivkin, MJ Pike, GB AF Leppert, Ilana R. Almli, C. Robert McKinstry, Robert C. Mulkern, Robert V. Pierpaoli, Carlo Rivkin, Michael J. Pike, G. Bruce CA Brain Dev Cooperative Grp TI T-2 Relaxometry of Normal Pediatric Brain Development SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE T-2 relaxometry; pediatric; brain development; myelination; multicenter ID MAGNETIC-RESONANCE; WHITE-MATTER; RELAXATION-TIMES; MR ASSESSMENT; NIH MRI; 1.5 T; MATURATION; MYELINATION; AGE; INFANTS AB Purpose: To establish normal age-related changes in the magnetic resonance (MR) T-2 relaxation time constants of brain using data collected as part of the National Institutes of Health (NIH) MRI Study of Normal Brain Development. Materials and Methods: This multicenter study of normal brain and behavior development provides both longitudinal and cross-sectional data, and has enabled us to investigate T2 evolution in several brain regions in healthy children within the age range of birth through 4 years 5 months. Due to the multicenter nature of the study and the extended period of data collection, periodically scanned inanimate and human phantoms were used to assess intra- and intersite variability. Results: The main finding of this work. based on over 340 scans, is the identification and parameterization of the monoexponential evolution of T2 from birth through 4 years 5 months of age in various brain structures. Conclusion: The exponentially decaying T2 behavior is believed to reflect the rapid changes in water content as well as myelination during brain development. The data will become publicly available as part of a normative pediatric MRI and clinical/behavioral database, thereby providing a basis for comparison in studies assessing normal brain development, and studies of deviations due to various neurological, neuropsychiatric, and developmental disorders. C1 [Leppert, Ilana R.; Pike, G. Bruce] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. [Almli, C. Robert] Washington Univ, Sch Med, Dept Neurol, Program Neurosci,Dev Neuropsychobiol Lab, St Louis, MO 63110 USA. [McKinstry, Robert C.] Washington Univ, Med Ctr, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [McKinstry, Robert C.] Washington Univ, Med Ctr, St Louis Childrens Hosp, St Louis, MO 63110 USA. [Mulkern, Robert V.] Harvard Univ, Childrens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Pierpaoli, Carlo] NICHHD, NIH, Bethesda, MD 20892 USA. [Rivkin, Michael J.] Harvard Univ, Childrens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Rivkin, Michael J.] Harvard Univ, Childrens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Rivkin, Michael J.] Harvard Univ, Childrens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Leppert, IR (reprint author), McGill Univ, Montreal Neurol Inst, 3801 Univ St,WB325, Montreal, PQ H3A 2B4, Canada. EM ilana@bic.mni.mcgill.ca RI Pierpaoli, Carlo/E-1672-2011; Basser, Peter/H-5477-2011; Pike, Bruce/K-5562-2014; OI Pike, Bruce/0000-0001-8924-683X; Freund, Lisa/0000-0003-2095-4023; Gwinn, Katrina/0000-0002-8277-651X FU NIH FX We thank the NIH contracting officers for their support. We also acknowledge the important contribution and remarkable spirit of John Haselgrove, PhD (deceased). The views expressed in this article do not necessarily represent the official views of the National Institute of Mental Health, the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke, the National Institutes of Health, the U.S. Department of Health and Human Services, or the United States government. NR 39 TC 32 Z9 32 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD FEB PY 2009 VL 29 IS 2 BP 258 EP 267 DI 10.1002/jmri.21646 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 399SJ UT WOS:000262819300002 PM 19161173 ER PT J AU Farasat, S Wei, MH Herman, M Liewehr, DJ Steinberg, SM Bale, SJ Fleckman, P Toro, JR AF Farasat, S. Wei, M-H Herman, M. Liewehr, D. J. Steinberg, S. M. Bale, S. J. Fleckman, P. Toro, J. R. TI Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID BATHING SUIT ICHTHYOSIS; HUMAN GENETIC-DISEASE; LAMELLAR ICHTHYOSIS; KERATINOCYTE TRANSGLUTAMINASE; HARLEQUIN ICHTHYOSIS; NONSENSE MUTATIONS; TRANSPORTER ABCA12; PRENATAL EXCLUSION; MISSENSE MUTATION; JAPANESE PATIENT AB Background: Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary disorder of cornification. Mutations in the transglutaminase-1 (TGM1) gene, which encodes for the epidermal enzyme transglutaminase-1 (TGase-1), are one of the causes of ARCI. Methods: The TGM1 mutation spectrum was characterised and genotype-phenotype correlations investigated in 104 patients with ARCI ascertained through the National Registry for Ichthyosis and Related Disorders in the USA. Methods: Germline mutations in TGM1 were identified in 55% (57/104) of patients with ARCI. Arginine residues in TGase-1 were mutated in 39% (22/57) of patients overall and 54% (20/37) of those with missense mutations. In total, 55% (12/22) of missense mutations were within CpG dinucleotides and 92% (11/12) of these mutations were C-->T or G-->A transitions. The genotype-phenotype investigation found that ARCI with TGM1 mutations was significantly associated with presence of collodion membrane at birth (p = 0.006), ectropion (p = 0.001), plate-like scales (p = 0.005) and alopecia (p = 0.001). Patients who had at least one mutation predicted to truncate TGase-1 were more likely to have more severe hypohidrosis (p = 0.001) and overheating (p = 0.0007) at onset of symptoms than were those with exclusively TGM1 missense mutations. A logistic model was developed, which predicted that individuals with collodion membrane, alopecia and/or eye problems are about four times more likely to have TGM1 mutations than patients without these findings. Conclusion: This is the largest investigation of patients with ARCI to date. It expands the TGM1 mutation spectrum and confirms that despite genetic and phenotypic heterogeneity in ARCI, TGM1 is the main causative gene for this disorder. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of CpG dinucleotides. C1 [Farasat, S.; Herman, M.; Toro, J. R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wei, M-H] SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. [Liewehr, D. J.; Steinberg, S. M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bale, S. J.] GeneDx Inc, Gaithersburg, MD USA. [Fleckman, P.] Univ Washington, Div Dermatol, Seattle, WA 98195 USA. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Execut Plaza S,Room 7012, Bethesda, MD 20892 USA. EM toroj@mail.nih.gov FU National Institutes of Health (NIH); Pfizer, Inc; National Center for Research Resources (NCRR) [025014-01] FX We thank the ARCI families for their participation in the National Registry of Ichthyosis and Related Disorders. We also thank the members of the American Academy of Dermatology for their help in the recruitment of ARCI families and the members of the Foundation of Ichthyosis and Related Skin Types ( FIRST). SF is a fellow of the National Institutes of Health (NIH) Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer, Inc ( via a grant to the Foundation for NIH from Pfizer, Inc). SJB is president of GeneDx (Gaithersburg, MD), and SF, M-HW, MH, SMS, DJL and JRT work for the US government. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organisations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the NIH and FIRST. The project described was also supported by a grant ( no 025014-01) from the National Center for Research Resources (NCRR), a component of the NIH, and the NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. NR 69 TC 27 Z9 30 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2009 VL 46 IS 2 BP 103 EP 111 DI 10.1136/jmg.2008.060905 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 402RQ UT WOS:000263031200005 PM 18948357 ER PT J AU Zabow, G Koretsky, AP Moreland, J AF Zabow, G. Koretsky, A. P. Moreland, J. TI Design and fabrication of a micromachined multispectral magnetic resonance imaging agent SO JOURNAL OF MICROMECHANICS AND MICROENGINEERING LA English DT Article ID IRON-OXIDE; NANOPARTICLES; NANOCRYSTALS; DEVICES; SENSITIVITY; MRI AB This paper describes the fabrication details of magnetic nano- and microstructures that enable a new class of multispectral magnetic resonance imaging agents. Magnetic field and associated geometrical fabrication constraints particular to these new multispectral contrast agents are described, and fabrication schemes based on both electrochemical deposition and thermal evaporation are presented. Relative advantages and disadvantages of top-down microfabrication approaches versus traditional bottom-up chemical synthesis routes are discussed with a focus on trade-offs between resulting microparticle functionality and fabrication process economy. It is shown that large numbers of contrast agent nano- or microstructures can be simultaneously fabricated, suggesting that top-down microfabricated contrast agents may represent an economical, attractive alternative to those based on chemically synthesized molecules or nanoparticles. C1 [Zabow, G.; Moreland, J.] Natl Inst Stand & Technol, Electromagnet Div, Boulder, CO USA. [Zabow, G.; Koretsky, A. P.] NINCDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Zabow, G (reprint author), Natl Inst Stand & Technol, Electromagnet Div, Boulder, CO USA. EM zabow@boulder.nist.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NIH NINDS Intramural Research Program; National Research Council FX We thank Dr Stephen Dodd for helpful discussions, technical advice and assistance. This work was supported in part by the NIH NINDS Intramural Research Program. GZ also acknowledges support from a National Research Council fellowship award. NR 18 TC 8 Z9 8 U1 0 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0960-1317 J9 J MICROMECH MICROENG JI J. Micromech. Microeng. PD FEB PY 2009 VL 19 IS 2 AR 025020 DI 10.1088/0960-1317/19/2/025020 PG 10 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Instruments & Instrumentation; Physics, Applied SC Engineering; Science & Technology - Other Topics; Instruments & Instrumentation; Physics GA 399FR UT WOS:000262786300021 ER PT J AU Murphy, E Allen, DG AF Murphy, Elizabeth Allen, David G. TI Why did the NHE inhibitor clinical trials fail? SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID NA+-H+ EXCHANGE; CARDIAC PURKINJE-FIBER; ISOLATED RAT-HEART; MYOCARDIAL-INFARCTION; INTRACELLULAR NA+; VENTRICULAR MYOCYTES; EARLY REPERFUSION; SODIUM CURRENT; ISCHEMIA; CARIPORIDE C1 [Murphy, Elizabeth] NHLBI, NIH, Bethesda, MD 20892 USA. [Allen, David G.] Univ Sydney, Sch Med Sci & Bosch Inst F13, Sydney, NSW 2006, Australia. RP Murphy, E (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 40 TC 25 Z9 25 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD FEB PY 2009 VL 46 IS 2 BP 137 EP 141 DI 10.1016/j.yjmcc.2008.09.715 PG 5 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 398BY UT WOS:000262707500004 PM 19027021 ER PT J AU Creson, TK Yuan, PX Manji, HK Chen, G AF Creson, Thomas K. Yuan, Peixiong Manji, Husseini K. Chen, Guang TI Evidence for Involvement of ERK, PI3K, and RSK in Induction of Bcl-2 by Valproate SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Valproate; bcl-2; ERK; PI3K; RSK ID SIGNAL-REGULATED KINASE; NERVE GROWTH-FACTOR; GLYCOGEN-SYNTHASE KINASE-3; MOOD STABILIZER; HISTONE DEACETYLASE; NEUROTROPHIC FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; INOSITOL BIOSYNTHESIS; TRANSCRIPTION FACTOR; PHOSPHORYLATED CREB AB Valproate, an anticonvulsant and mood stabilizer, up-regulates Bcl-2, a neurotrophic/neuroprotective protein. In this study, we investigated the molecular mechanism through which Bcl-2 is up-regulated by valproate using cultured human neuron-like cells. Valproate, within therapeutically relevant ranges, induced time- and concentration-dependent up-regulations of both Bcl-2 messenger RNA and protein implicating an underlying gene transcriptional-mediated mechanism. Bcl-2 up-regulations were associated with ERK1/2 and PI3K pathway activations and elevated levels of activated phospho-RSK and phospho-CREB, convergent targets of the ERK1/2 and PI3K pathways. Valproate increased transcriptional activity of a human bcl-2 promoter-reporter gene construct. This effect was attenuated, but not blocked, by mutation of a CREB DNA binding site, a CRE site in the human bcl-2 promoter sequence. ERK and/or PI3K pathway inhibitors and RSK1 small hairpin RNA knockdown reduced, but did not abolish, baseline and valproate-induced promoter activities and lowered Bcl-2 protein levels. These data collectively suggest that valproate induces Bcl-2 regulation partially through activations of the ERK and PI3K cascades and their convergent kinase, RSK, although other unknown mechanism(s) are likely involved. Given the known roles of Bcl-2 in the central nervous system, the current findings offer a partial yet complex molecular mechanistic explanation for the known neurobiological effects of valproate including neurite growth, neuronal survival, and neurogenesis. C1 [Creson, Thomas K.; Yuan, Peixiong; Manji, Husseini K.; Chen, Guang] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Chen, G (reprint author), NIMH, Mol Pathophysiol Lab, NIH, 35 Convent Dr,Bldg 35,Rm 1C-912, Bethesda, MD 20892 USA. EM guangchen@mail.nih.gov RI Chen, Guang/A-2570-2017 FU NIMH intramural program; NARSAD research award FX This work was supported by the NIMH intramural program (Manji and Chen) and a NARSAD research award (Chen). NR 51 TC 44 Z9 44 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD FEB PY 2009 VL 37 IS 2 BP 123 EP 134 DI 10.1007/s12031-008-9122-2 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 387SG UT WOS:000261971300003 PM 18677583 ER PT J AU Park, J Koshimizu, H Loh, Y AF Park, Joshua J. Koshimizu, Hisatsugu Loh, Y. Peng TI Biogenesis and Transport of Secretory Granules to Release Site in Neuroendocrine Cells SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Biogenesis of peptidergic secretory granules; Chromogranin A; Expression of inhibitor of protein Nexin-1; Carboxypeptidase E or cytoplasmic tail; Post-Golgi transport; Dynactin; Microtubule-based motors ID TRANSCRIPTIONAL REPRESSOR REST; TYROSINE-HYDROXYLASE GENE; CHROMOGRANIN-A; CARBOXYPEPTIDASE-E; PC12 CELLS; BETA-CELLS; CYTOPLASMIC DYNEIN; TARGETED ABLATION; PROTEIN; EXPRESSION AB Biogenesis and post-Golgi transport of peptidergic secretory granules to the release site are crucial for secretion of neuropeptides from neuroendocrine cells. Recent studies have uncovered multilevel molecular mechanisms for the regulation of secretory granule biogenesis. Insulinoma-associated protein 2 (ICA512/IA-2), polypyrimidine-tract binding protein, and chromogranin A have been identified to regulate secretory granule biogenesis at the transcriptional, posttranscriptional, and posttranslational levels, respectively, by increasing granule protein levels, which in turn drives granule formation after stimulation. Post-Golgi transport of secretory granules is microtubule-based and mediated by transmembrane carboxypeptidase E (CPE). The cytoplasmic tail of CPE anchors secretory granules to the microtubule motors, kinesin-2 and -3, or dynein, via interaction with the adaptor, dynactin, to mediate anterograde and retrograde transport, respectively. C1 [Park, Joshua J.; Koshimizu, Hisatsugu; Loh, Y. Peng] NICHHD, Cellular Neurobiol Sect, Dev Neurobiol Program, NIH, Bethesda, MD 20892 USA. RP Loh, Y (reprint author), NICHHD, Cellular Neurobiol Sect, Dev Neurobiol Program, NIH, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov RI Koshimizu, Hisatsugu/G-5536-2010 FU National Institute of Child Health and Human Development; National Institutes of Health FX This research is supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 49 TC 17 Z9 18 U1 1 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD FEB PY 2009 VL 37 IS 2 BP 151 EP 159 DI 10.1007/s12031-008-9098-y PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 387SG UT WOS:000261971300006 PM 18607778 ER PT J AU Wu, MX Yu, KF Liu, AY AF Wu, Mi-Xia Yu, Kai F. Liu, Aiyi TI Exact inference on contrasts in means of intraclass correlation models with missing responses SO JOURNAL OF MULTIVARIATE ANALYSIS LA English DT Article DE Contrast; Exact test; Intraclass correlation model; Linear mixed model; Simultaneous confidence intervals ID CONFIDENCE-INTERVALS AB Intraclass correlation models with missing data at random are considered. With a properly reduced model, a general method, which allows repeated observations with missing data in a non-monotone pattern, is proposed to construct exact test statistics and simultaneous confidence intervals for linear contrasts in the means. Simulation results are given to compare exact and asymptotic simultaneous confidence intervals. A real example is provided for the illustration of the proposed method. Published by Elsevier Inc. C1 [Wu, Mi-Xia; Yu, Kai F.; Liu, Aiyi] NICHHD, Biometry & Math Stat Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, Rockville, MD 20852 USA. [Wu, Mi-Xia] Beijing Univ Technol, Coll Appl Sci, Beijing 100022, Peoples R China. RP Wu, MX (reprint author), NICHHD, Biometry & Math Stat Branch, Div Epidemiol Stat & Prevent Res, NIH,DHHS, 6100 Execut Blvd, Rockville, MD 20852 USA. EM wumixia@gmail.com OI Liu, Aiyi/0000-0002-6618-5082 FU Intramural NIH HHS [Z01 HD002535-09] NR 10 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0047-259X J9 J MULTIVARIATE ANAL JI J. Multivar. Anal. PD FEB PY 2009 VL 100 IS 2 BP 301 EP 308 DI 10.1016/j.jmva.2008.05.002 PG 8 WC Statistics & Probability SC Mathematics GA 382BN UT WOS:000261580000005 PM 20126283 ER PT J AU Fitch, RW Sturgeon, GD Patel, SR Spande, TF Garraffo, HM Daly, JW Blaauw, RH AF Fitch, Richard W. Sturgeon, Gordon D. Patel, Shaun R. Spande, Thomas F. Garraffo, H. Martin Daly, John W. Blaauw, Richard H. TI Epiquinamide: A Poison That Wasn't from a Frog That Was SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID INDOLIZIDINE ALKALOIDS; RAY-ANALYSIS; (+)-EPIQUINAMIDE; DENDROBATIDAE; TRICOLOR; 223G AB In 2003, we reported the isolation, structure elucidation, and pharmacology of epiquinamide (1), a novel alkaloid isolated from an Ecuadoran poison frog, Epipedobates tricolor. Since then, several groups, including ours, have undertaken synthetic efforts to produce this compound, which appeared initially to be a novel, beta 2-selective nicotinic acetylcholine receptor agonist. Based on prior chiral GC analysis of synthetic and natural samples, the absolute structure of this alkaloid was established as (1S,9aS)-1-acetamidoquinolizidine. We have synthesized the (1R*,9aS*)-isomer (epi-epiquinamide) using an iminium ion nitroaldol reaction as the key step. We have also synthesized ent-1 semisynthetically from (-)-lupinine. Synthetic epiquinamide is inactive at nicotinic receptors, in accord with recently published reports. We have determined that the activity initially reported is due to cross-contamination from co-occurring epibatidine in the isolated material. C1 [Fitch, Richard W.; Sturgeon, Gordon D.] Indiana State Univ, Dept Chem, Terre Haute, IN 47809 USA. [Patel, Shaun R.] Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. [Spande, Thomas F.; Garraffo, H. Martin; Daly, John W.] NIDDK, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Blaauw, Richard H.] Chiralix BV, NL-6503 CB Nijmegen, Netherlands. RP Fitch, RW (reprint author), Indiana State Univ, Dept Chem, 600 Chestnut St,Sci S35E, Terre Haute, IN 47809 USA. EM rfitch@indstate.edu FU Department of Chemistry and College of Arts and Sciences at Indiana State University [12030168]; Indiana State University Promising Scholar Award; National Science Foundation [CHE0521075]; NIDDK FX K. J. Lipscomb and R. J. Tucker are acknowledged for performing exploratory experiments. A generous gift of HEK cells expressing various subunit combinations for nicotinic receptors by Drs. K. J. Kellar and Y. Xiao of Georgetown University Medical School is gratefully acknowledged. This work was performed with funds from the Department of Chemistry and College of Arts and Sciences at Indiana State University (startup funding to R.W.F. and summer stipend to G.D.S.), as well as a Sigma Xi Grant-in-aid (12030168 to K.J.L.), the Lilly Endowment (Wabash College Indiana Internship Initiative summer stipend to S.R.P. and Indiana State University Promising Scholar Award to R.W.F.), and the National Science Foundation (CHE0521075 for a 400 MHz NMR spectrometer at Indiana State University). Work performed at NIH was supported by the intramural program of NIDDK. NR 32 TC 27 Z9 27 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2009 VL 72 IS 2 BP 243 EP 247 DI 10.1021/np8005452 PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 413BR UT WOS:000263768400011 PM 19245264 ER PT J AU Benninger, DH Thees, S Kollias, SS Bassetti, CL Waldvogel, D AF Benninger, David H. Thees, Sebastian Kollias, Spyros S. Bassetti, Claudio L. Waldvogel, Daniel TI Morphological differences in Parkinson's disease with and without rest tremor SO JOURNAL OF NEUROLOGY LA English DT Article DE Parkinson's disease; voxel-based morphometry; tremor akinetic-rigid syndrome ID MULTIPLE SYSTEM ATROPHY; THALAMIC-STIMULATION; LONG-TERM; MOTOR CORTEX; PEDUNCULOPONTINE NUCLEUS; DEPRESSION INVENTORY; MOVEMENT-DISORDERS; PROGNOSTIC FACTORS; METABOLIC ANATOMY; CEREBRAL ATROPHY AB Rest tremor is a hallmark of Parkinson's disease (PD), but its pathogenesis remains incompletely understood. Nigro-striatal dopamine deficiency correlates best with bradykinesia, but not with tremor. Oscillating neurons in one or multiple localizations within the basal gangliathalamo-cortical loop may cause rest tremor, and an active contribution of the cerebellum and the cerebello-thalamo-cortical projections has been postulated. To compare the pattern of grey matter volume in PD patients with and without tremor to identify structural correlates of rest tremor. Voxel-based morphometry (VBM) of a high-resolution 3 Tesla, T1-weighted MR images, pre-processed according to an optimized protocol using SPM2, was performed in 24 patients with mild to moderate PD comparing local grey matter volume in patients with (n = 14) and without rest tremor (n = 10). Grey matter volume is decreased in the right quadrangular lobe and declive of the cerebellum in PD with tremor compared to those without (PFDR < 0.05). These results demonstrate for the first time morphological changes in the cerebellum in PD patients with rest tremor and highlight the involvement of the cerebellum and cerebello- thalamo-cortical circuit in the pathogenesis of parkinsonian rest tremor. C1 [Benninger, David H.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Benninger, David H.; Bassetti, Claudio L.; Waldvogel, Daniel] Univ Zurich Hosp, Dept Neurol, CH-8091 Zurich, Switzerland. [Thees, Sebastian; Kollias, Spyros S.] Univ Zurich Hosp, Dept Neuroradiol, CH-8091 Zurich, Switzerland. RP Benninger, DH (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N240 MSC1428,Ctr Dr, Bethesda, MD 20892 USA. EM benningerd@ninds.nih.gov RI Kollias, Spyros/J-9276-2012; Benninger, David/A-8157-2015 OI Benninger, David/0000-0002-1049-9533 NR 67 TC 46 Z9 50 U1 1 U2 4 PU DR DIETRICH STEINKOPFF VERLAG PI HEIDELBERG PA TIERGARTENSTRASSE 17, 69121 HEIDELBERG, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD FEB PY 2009 VL 256 IS 2 BP 256 EP 263 DI 10.1007/s00415-009-0092-2 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 418VE UT WOS:000264176700014 PM 19219572 ER PT J AU Foltynie, T Cheeran, B Williams-Gray, CH Edwards, MJ Schneider, SA Weinberger, D Rothwell, JC Barker, RA Bhatia, KP AF Foltynie, T. Cheeran, B. Williams-Gray, C. H. Edwards, M. J. Schneider, S. A. Weinberger, D. Rothwell, J. C. Barker, R. A. Bhatia, K. P. TI BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID ACTIVITY-DEPENDENT SECRETION; AGE-OF-ONSET; NEUROTROPHIC FACTOR; L-DOPA; MOTOR COMPLICATIONS; SYNAPTIC PLASTICITY; BRAIN; POLYMORPHISM; EXPRESSION; ASSOCIATION AB Background: Levodopa induced dyskinesias (LID) are a common problem which ultimately limit the effective treatment of patients with Parkinson's disease (PD). There is accumulating evidence that LID develop due to abnormal synaptic plasticity, which is in turn influenced by the release of brain derived neurotrophic factor (BDNF). Methods: The influence of a common functional polymorphism of the BDNF gene on the risk of developing dyskinesias in a large cohort of patients with PD (n = 315), who were independently and variably treated with levodopa and/or other dopaminergic treatments, was investigated. Results: Patients with the met allele of BDNF, associated with lower activity dependent secretion of BDNF, were at significantly higher risk of developing dyskinesias earlier in the course of treatment with dopaminergic agents (hazard ratio for each additional met allele 2.12, p = 0.001), which persisted following adjustment for potential confounding variables. Conclusion: This functional polymorphism may help predict which individuals are most at risk of LID and is consistent with the known actions of BDNF on synaptic plasticity in the striatum. C1 [Foltynie, T.; Cheeran, B.; Edwards, M. J.; Schneider, S. A.; Rothwell, J. C.; Bhatia, K. P.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Foltynie, T.; Williams-Gray, C. H.] Cambridge Ctr Brian Repair, Cambridge, England. [Weinberger, D.] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Foltynie, T (reprint author), UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, Queen Sq, London WC1N 3BG, England. EM T.Foltynie@ion.ucl.ac.uk RI Edwards, Mark/F-1052-2012; OI Rothwell, John/0000-0003-1367-6467; Cheeran, Binith/0000-0002-3442-1044 FU Wellcome Trust FX The Wellcome Trust provided financial support to TF through a Clinical Training Fellowship during the collection of the data used in this study. NR 36 TC 60 Z9 63 U1 1 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD FEB PY 2009 VL 80 IS 2 BP 141 EP 144 DI 10.1136/jnnp.2008.154294 PG 4 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 396HH UT WOS:000262582300007 PM 18977816 ER PT J AU Micsenyi, MC Dobrenis, K Stephney, G Pickel, J Vanier, MT Slaugenhaupt, SA Walkley, SU AF Micsenyi, Matthew C. Dobrenis, Kostantin Stephney, Gloria Pickel, James Vanier, Marie T. Slaugenhaupt, Susan A. Walkley, Steven U. TI Neuropathology of the Mcoln1(-/-) Knockout Mouse Model of Mucolipidosis Type IV SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Axonal spheroids; Bis(monoacylglycero) phosphate; Gangliosides; Lysosomal disease; Mucolipin 1; P62/Sequestosome 1 ID NEURONAL-CEROID-LIPOFUSCINOSIS; LYSOSOMAL STORAGE DISORDERS; LYSOBISPHOSPHATIDIC ACID; CULTURED FIBROBLASTS; CATION CHANNEL; DISEASE; AUTOPHAGY; ACCUMULATION; P62/SQSTM1; GENE AB The recently developed Mcoln1(-/-) knockout mouse provides a novel model for analyzing mucolipin 1 function and mucolipidosis type IV disease. Here we characterize the neuropathology of Mcoln1(-/-) mouse at the end stage. Evidence of ganglioside accumulation, including increases in GM2, GM3, and GD3 and redistribution of GM1, was found throughout the central nervous system (CNS) independent of significant cholesterol accumulation. Unexpectedly, colocalization studies using immunofluorescence confocal microscopy revealed that GM1 and GM2 were present in separate vesicles within individual neurons. While GM2 was significantly colocalized with LAMP2, consistent with late-endosomal/lysosomal processing, some GIM2-immunoreactivity occurred in LAMP2-negative sites, suggesting involvement of other vesicular systems. P62/Sequestosome 1 (P62/SQSTM1) inclusions were also identified in the CNS of the Mcoln1(-/-) mouse, Suggesting deficiencies in protein degradation. Glial cell activation was increased in brain, and there was evidence of reduced myelination in cerebral and cerebellar white matter tracts. Autofluorescent material accumulated throughout the brains of the knockout mice. Finally, axonal spheroids were prevalent in white matter tracts and Purkinje cell axons. This neuropathological characterization of the Mcoln1(-/-) mouse provides an important step in understanding how mucolipin I loss of function affects the CNS and contributes to mucolipidosis type IV disease. C1 [Micsenyi, Matthew C.; Dobrenis, Kostantin; Walkley, Steven U.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Rose Kennedy Ctr Res Mental Retardat & Human Dev, Bronx, NY 10461 USA. [Pickel, James] NIMH, NIH, Bethesda, MD 20892 USA. [Vanier, Marie T.] Laennec Med Sch, INSERM, Lyon, France. [Vanier, Marie T.] Lyon Univ, Lyon, France. [Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Slaugenhaupt, Susan A.] Harvard Univ, Sch Med, Boston, MA USA. RP Walkley, SU (reprint author), Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Rose Kennedy Ctr Res Mental Retardat & Human Dev, 1410 Pelham Pkwy S,Room 618, Bronx, NY 10461 USA. EM walkley@accom.yu.edu FU NICHD NIH HHS [P30 HD001799, R01 HD045561]; NINDS NIH HHS [R01 NS039995, R01 NS39995] NR 48 TC 38 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD FEB PY 2009 VL 68 IS 2 BP 125 EP 135 PG 11 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 402KN UT WOS:000263012700002 PM 19151629 ER PT J AU Gonzalez-Islas, C Chub, N Wenner, P AF Gonzalez-Islas, Carlos Chub, Nikolai Wenner, Peter TI NKCC1 and AE3 Appear to Accumulate Chloride in Embryonic Motoneurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SPONTANEOUS NETWORK ACTIVITY; SPONTANEOUS RHYTHMIC ACTIVITY; RAT NEOCORTICAL NEURONS; CHICK SPINAL-CORD; INTRACELLULAR CHLORIDE; RETINAL NEURONS; LUMBAR MOTONEURONS; NERVOUS-SYSTEM; IONIC BASIS; COTRANSPORTER AB Gonzalez-Islas C, Chub N, Wenner P. NKCC1 and AE3 appear to accumulate chloride in embryonic motoneurons. J Neurophysiol 101: 507-518, 2009. First published November 26, 2008; doi: 10.1152/jn.90986.2008. During early development, gamma-aminobutyric acid (GABA) depolarizes and excites neurons, contrary to its typical function in the mature nervous system. As a result, developing networks are hyperexcitable and experience a spontaneous network activity that is important for several aspects of development. GABA is depolarizing because chloride is accumulated beyond its passive distribution in these developing cells. Identifying all of the transporters that accumulate chloride in immature neurons has been elusive and it is unknown whether chloride levels are different at synaptic and extrasynaptic locations. We have therefore assessed intracellular chloride levels specifically at synaptic locations in embryonic motoneurons by measuring the GABAergic reversal potential (E-GABA) for GABA(A) miniature postsynaptic currents. When whole cell patch solutions contained 17-52 mM chloride, we found that synaptic E GABA was around -30 mV. Because of the low HCO3- permeability of the GABA(A) receptor, this value of E-GABA corresponds to approximately 50 mM intracellular chloride. It is likely that synaptic chloride is maintained at levels higher than the patch solution by chloride accumulators. We show that the Na+-K+-2Cl (-) cotransporter, NKCC1, is clearly involved in the accumulation of chloride in motoneurons because blocking this transporter hyperpolarized E-GABA and reduced nerve potentials evoked by local application of a GABA(A) agonist. However, chloride accumulation following NKCC1 block was still clearly present. We find physiological evidence of chloride accumulation that is dependent on HCO3- and sensitive to an anion exchanger blocker. These results suggest that the anion exchanger, AE3, is also likely to contribute to chloride accumulation in embryonic motoneurons. C1 [Gonzalez-Islas, Carlos; Wenner, Peter] Emory Univ, Sch Med, Dept Physiol, Atlanta, GA 30322 USA. [Chub, Nikolai] NINDS, Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Wenner, P (reprint author), Emory Univ, Sch Med, Dept Physiol, Room 601,Whitehead Bldg, Atlanta, GA 30322 USA. EM pwenner@emory.edu OI Wenner, Peter/0000-0002-7072-2194 FU National Institute of Neurological Disorders and Stroke (NINDS) [NS-046510]; National Science Foundation [0616097] FX This research was supported by National Institute of Neurological Disorders and Stroke (NINDS) Grant NS-046510 and National Science Foundation Grant 0616097 to P. Wenner and by the intramural program of the NINDS. NR 47 TC 47 Z9 47 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2009 VL 101 IS 2 BP 507 EP 518 DI 10.1152/jn.90986.2008 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 403ZK UT WOS:000263120300002 PM 19036864 ER PT J AU Bell, AH Hadj-Bouziane, F Frihauf, JB Tootell, RBH Ungerleider, LG AF Bell, Andrew H. Hadj-Bouziane, Fadila Frihauf, Jennifer B. Tootell, Roger B. H. Ungerleider, Leslie G. TI Object Representations in the Temporal Cortex of Monkeys and Humans as Revealed by Functional Magnetic Resonance Imaging SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID POSTERIOR INFEROTEMPORAL CORTEX; HUMAN EXTRASTRIATE CORTEX; MACAQUE CEREBRAL-CORTEX; SURFACE-BASED ANALYSIS; MIDDLE FUSIFORM GYRUS; FACE PERCEPTION; TOPOGRAPHICAL DISORIENTATION; ACQUIRED PROSOPAGNOSIA; RESPONSE PATTERNS; INDIVIDUAL FACES AB Bell AH, Hadj-Bouziane F, Frihauf JB, Tootell RB, Ungerleider LG. Object representations in the temporal cortex of monkeys and humans as revealed by functional magnetic resonance imaging. J Neurophysiol 101: 688-700, 2009. First published December 3, 2008; doi:10.1152/jn.90657.2008. Increasing evidence suggests that the neural processes associated with identifying everyday stimuli include the classification of those stimuli into a limited number of semantic categories. How the neural representations of these stimuli are organized in the temporal lobe remains under debate. Here we used functional magnetic resonance imaging (fMRI) to identify correlates for three current hypotheses concerning object representations in the inferior temporal (IT) cortex of monkeys and humans: representations based on animacy, semantic categories, or visual features. Subjects were presented with blocked images of faces, body parts (animate stimuli), objects, and places (inanimate stimuli), and multiple overlapping contrasts were used to identify the voxels most selective for each category. Stimulus representations appeared to segregate according to semantic relationships. Discrete regions selective for animate and inanimate stimuli were found in both species. These regions could be further subdivided into regions selective for individual categories. Notably, face-selective regions were contiguous with body-part-selective regions, and object-selective regions were contiguous with placeselective regions. When category-selective regions in monkeys were tested with blocks of single exemplars, individual voxels showed preferences for visually dissimilar exemplars from the same category and voxels with similar preferences tended to cluster together. Our results provide some novel observations with respect to how stimulus representations are organized in IT cortex. In addition, they further support the idea that representations of complex stimuli in IT cortex are organized into multiple hierarchical tiers, encompassing both semantic and physical properties. C1 [Bell, Andrew H.; Hadj-Bouziane, Fadila; Frihauf, Jennifer B.; Tootell, Roger B. H.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Tootell, Roger B. H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Bell, AH (reprint author), NIMH, Lab Brain & Cognit, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM bellah@mail.nih.gov RI Hadj-Bouziane, Fadila/A-1180-2013; OI Bell, Andrew/0000-0001-8420-4622 FU National Institutes of Health [R01MH-67529, R01 EY-017081] FX This work was supported by grants from the National Institutes of Health (R01MH-67529 and R01 EY-017081 to R. B. H. Tootell, the Athinoula A. Martinos Center for Biomedical Imaging, the National Center for Research Resources, and the National Institute of Mental Health Intramural Research Program to A. H. Bell, F. Hadj-Bouziane, J. B. Frihauf, and L. G. Ungerleider. NR 88 TC 90 Z9 91 U1 1 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2009 VL 101 IS 2 BP 688 EP 700 DI 10.1152/jn.90657.2008 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 403ZK UT WOS:000263120300018 PM 19052111 ER PT J AU Bredfeldt, CE Read, JCA Cumming, BG AF Bredfeldt, C. E. Read, J. C. A. Cumming, B. G. TI A Quantitative Explanation of Responses to Disparity-Defined Edges in Macaque V2 SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID MONKEY VISUAL-CORTEX; RECEPTIVE-FIELD SIZE; AREA V2; V1 NEURONS; NEURAL MECHANISMS; BORDER OWNERSHIP; SIMPLE CELLS; SELECTIVITY; REPRESENTATION; ORGANIZATION AB Bredfeldt CE, Read JCA, Cumming BG. A quantitative explanation of responses to disparity-defined edges in macaque V2. J Neurophysiol 101: 701-713, 2009. First published December 10, 2008; doi:10.1152/jn.00729.2007. Previous experiments have shown that V2 neurons respond to complex stimuli such as cyclopean edges (edges defined purely by binocular disparity), angles, and motion borders. It is currently unknown whether these responses are a simple consequence of converging inputs from a prior stage of processing (V1). Alternatively, they may identify edges in a way that is invariant across a range of visual cues defining the edge, in which case they could provide a neuronal substrate for scene segmentation. Here, we examine the ability of a simple feedforward model that combines two V1-like inputs to describe the responses of V2 neurons to cyclopean edges. A linear feedforward model was able to qualitatively reproduce the major patterns of response enhancement for cyclopean edges seen in V2. However, quantitative fitting revealed that this model usually predicts response suppression by some edge configurations and such suppression was rarely seen in the data. This problem was resolved by introducing a squaring nonlinearity at the output of the individual inputs prior to combination. The extended model produced extremely good fits to most of our data. We conclude that the responses of V2 neurons to complex stimuli such as cyclopean edges can be adequately explained by a simple convergence model and do not necessarily represent the development of sophisticated mechanisms that signal scene segmentation, although they probably constitute a step toward this goal. C1 [Bredfeldt, C. E.; Cumming, B. G.] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. [Read, J. C. A.] Univ Newcastle, Inst Neurosci, Newcastle Upon Tyne, Tyne & Wear, England. RP Cumming, BG (reprint author), 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. EM bgc@nei.nih.gov RI Read, Jenny/A-7493-2013 OI Read, Jenny/0000-0002-9029-5185 FU National Institutes of Health, National Eye Institute; Royal Society University Research Fellowship [UF041260] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Eye Institute, and by Royal Society University Research Fellowship Grant UF041260 awarded to J. C. A. Read. NR 28 TC 5 Z9 6 U1 1 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2009 VL 101 IS 2 BP 701 EP 713 DI 10.1152/jn.00729.2007 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 403ZK UT WOS:000263120300019 PM 19073795 ER PT J AU Bouret, S Richmond, BJ AF Bouret, Sebastien Richmond, Barry J. TI Relation of Locus Coeruleus Neurons in Monkeys to Pavlovian and Operant Behaviors SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID REWARD SCHEDULES; PHASIC ACTIVATION; CERULEUS NEURONS; VENTRAL STRIATUM; CENTRAL NUCLEUS; CORTEX; NOREPINEPHRINE; RETRIEVAL; ATTENTION; RESPONSES AB Bouret S, Richmond BJ. Relation of locus coeruleus neurons in monkeys to Pavlovian and operant behaviors. J Neurophysiol 101: 898-911, 2009. First published December 17, 2008; doi: 10.1152/jn.91048.2008. Noradrenaline is released throughout the forebrain from locus coeruleus (LC) projections in close temporal proximity to emotional and goal-directed events. To examine interactive influences of these processes on LC neuronal activity, we used a task where Pavlovian and operant processes vary and can be easily identified. We recorded 69 single LC neurons from two monkeys performing a task where cues indicate the progression through schedules of one, two, or three operant trials. Pavlovian responses and phasic LC activations occur following the appearance of conditioned visual cues (54/69 neurons), especially those at the beginning of new schedules, whether the current trial will be rewarded (single trial schedule) or not (2 or 3 trial schedules), and after visual imperative signals eliciting the operant response (64/69 neurons), whether the current trial will be rewarded or not. The modulation of LC responses seems to be relatively independent of attention or motivation, because the responses do not covary with operant performance in the task. The magnitude of LC responses across the schedules varied in close relation to the intensity of Pavlovian behavior but these responses were also modulated by operant processes. Our conclusion is that LC activation occurs when task-relevant stimuli evoke a conditioned instinctive (Pavlovian) response, with the strength of the activation also being modulated by goal-directed processes. Thus locus coeruleus neurons broadcast information about stimulus-elicited primitive and goal-directed behaviors to forebrain structures important for executive functions and emotions. C1 [Bouret, Sebastien; Richmond, Barry J.] NIMH, Neuropsychol Lab, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, Natl Inst Hlth, Dept Hlth & Human Serv, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov RI Bouret, Sebastien/J-9383-2013 OI Bouret, Sebastien/0000-0003-2279-6161 FU Intramural Research Program of the National Institute of Mental Health; Fondation Fyssen FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. S. Bouret was partially supported by the Fondation Fyssen. NR 35 TC 26 Z9 26 U1 1 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2009 VL 101 IS 2 BP 898 EP 911 DI 10.1152/jn.91048.2008 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 403ZK UT WOS:000263120300036 PM 19091919 ER PT J AU Shen, H Luo, Y Kuo, CC Deng, XL Chang, CF Harvey, BK Hoffer, BJ Wang, Y AF Shen, Hui Luo, Yu Kuo, Chi-Chung Deng, Xiaolin Chang, Chen-Fu Harvey, Brandon K. Hoffer, Barry J. Wang, Yun TI 9-Cis-Retinoic Acid Reduces Ischemic Brain Injury in Rodents Via Bone Morphogenetic Protein SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE retinoic acid; BMP7; stroke; neuroprotection ID MIDDLE CEREBRAL-ARTERY; RETINOID-X-RECEPTOR; NEURAL DIFFERENTIATION; DOCOSAHEXAENOIC ACID; OSTEOGENIC PROTEIN-1; INDUCED APOPTOSIS; BMP-7 EXPRESSION; NUCLEAR RECEPTOR; OXIDATIVE STRESS; STROKE RATS AB Retinoic acid (RA), a biologically active derivative of vitamin A, has protective effects against damage caused by H(2)O(2) or oxygen-glucose deprivation in mesangial and PC12 cells. In cultured human osteosarcoma cells, RA enhances the expression of bone morphogenetic protein-7 (BMP7), a trophic factor that reduces ischemia- or neurotoxin-mediated neurodegeneration in vivo. The purpose of this study is to examine whether RA reduces ischemic brain injury through a BMP7 mechanism. We found that intracerebroventricular administration of 9-cis-retinoic acid (9cRA) enhanced BMP7 mRNA expression, detected by RT-PCR, in rat cerebral cortex at 24 hr after injection. Rats were also subjected to transient focal ischemia induced by ligation of the middle cerebral artery (MCA) at 1 day after 9cRA injection. Pretreatment with 9cRA increased locomotor activity and attenuated neurological deficits 2 days after MCA ligation. 9cRA also reduced cerebral infarction and TUNEL labeling. These protective responses were antagonized by the BMP antagonist noggin given 1 day after 9cRA injection. Taken together, our data suggest that 9cRA has protective effects against ischemia-induced injury, and these effects involve BMPs. (c) 2008 Wiley-Liss, Inc. C1 [Wang, Yun] Natl Inst Drug Abuse, Intramural Res Program, Neural Protect & Regenerat Sect, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Neural Protect & Regenerat Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov RI Harvey, Brandon/A-5559-2010; luo, Yu (Agnes)/E-4446-2010 FU IRP of NIDA, NIH, DHHS FX Contract grant sponsor: IRP of NIDA, NIH, DHHS. NR 43 TC 20 Z9 23 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD FEB 1 PY 2009 VL 87 IS 2 BP 545 EP 555 DI 10.1002/jnr.21865 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 403JQ UT WOS:000263079300025 PM 18803283 ER PT J AU Lonser, RR Butman, JA Kiringoda, R Song, D Oldfield, EH AF Lonser, Russell R. Butman, John A. Kiringoda, Ruwan Song, Debbie Oldfield, Edward H. TI Pituitary stalk hemangioblastomas in von Hippel-Lindau disease SO JOURNAL OF NEUROSURGERY LA English DT Article DE hemangioblastoma; pituitary stalk; treatment options; tumor incidence; von Hippel-Lindau disease ID CENTRAL-NERVOUS-SYSTEM; MORBID HEARING-LOSS; OF-THE-LITERATURE; SUPRASELLAR HEMANGIOBLASTOMA; ENDOLYMPHATIC SAC; INTRASELLAR HEMANGIOBLASTOMA; NATURAL-HISTORY; TUMORS; RADIOSURGERY; RESECTION AB Object. Pituitary stalk hemangioblastomas are rare. and information on them is limited to a small number of case reports. To gain insight into the incidence, clinical effects, and management of pituitary stalk hemangioblastomas, the authors analyzed a series of patients with von Hippel-Lindau (VHL) disease. Methods. Patients with VHL disease who were enrolled in a prospective National Institutes of Health natural history study were included. Clinical, imaging, and laboratory findings were analyzed. Results. Two hundred fifty patients were included in the study (120 male and 130 female patients). In 8 patients (3%) 8 pituitary stalk hemangioblastomas were identified on MR imaging. This anatomical location was the most common supratentorial site for these lesions; 29% of all supratentorial hemangioblastomas were found there. The mean (+/- standard deviation) pituitary stalk hemangioblastoma volume was 0.5 +/- 0.9 cm(3) (range 0.08-2.8 cm(3)). Results. of endocrine laboratory profiles were normal in all patients. All patients remained asymptomatic and none required treatment during the follow-up period (mean duration 41.4 +/- 14.4 months). Conclusions. The pituitary stalk is the most common site for the development of supratentorial hemangioblastomas in patients with VHL disease. Pituitary stalk hemangioblastomas often remain asymptomatic and do not require treatment. These findings indicate that pituitary stalk hemangioblastomas in patients with VHL disease may be managed with observation and that surgery for them can be reserved until associated signs or symptoms occur. (DOI: 10.3171/2008.4.17532) C1 [Lonser, Russell R.; Kiringoda, Ruwan; Song, Debbie; Oldfield, Edward H.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Butman, John A.] Ctr Clin, Neuroradiol Sect, Dept Diagnost Radiol, NIH, Bethesda, MD USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Butman, John/A-2694-2008; Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the NIH FX The Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the NIH supported this research. NR 25 TC 16 Z9 17 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD FEB PY 2009 VL 110 IS 2 BP 350 EP 353 DI 10.3171/2008.4.17532 PG 4 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 399GI UT WOS:000262788000021 PM 18834262 ER PT J AU Budde, MD Frank, JA AF Budde, Matthew D. Frank, Joseph A. TI Magnetic Tagging of Therapeutic Cells for MRI SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE molecular imaging; MRI; magnetic cellular tagging; immune cells; stem cells ID MESENCHYMAL STEM-CELLS; IN-VIVO MRI; RESONANCE TRACKING; CELLULAR THERAPY; CONTRAST AGENT; NANOPARTICLES; REPORTER; MODEL; EXPRESSION; REJECTION AB Transplantation of stem cells or immune cells has shown promise for the treatment of several diseases. Monitoring magnetically la beled cells with MRI has furthered our understanding of cellular migration and the pathophysiology of diseases in experimental models. These studies should pave the way for guiding clinical trials using cell-based therapies. This review briefly describes the various methods used to label and track cells with MRI and the potential for such methods to translate to human applications. C1 [Budde, Matthew D.; Frank, Joseph A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Budde, MD (reprint author), NIH, Ctr Clin, Bldg 10,Room B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. EM buddem@cc.nih.gov FU Intramural Research Program of the Clinical Center at the National Institutes of Health FX This work was supported by the Intramural Research Program of the Clinical Center at the National Institutes of Health. NR 33 TC 49 Z9 52 U1 1 U2 4 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2009 VL 50 IS 2 BP 171 EP 174 DI 10.2967/jnumed.108.053546 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 409EA UT WOS:000263487800018 PM 19164242 ER PT J AU Crosier, MD Booth, SL Peter, I Dawson-Hughes, B Price, PA O'Donnell, CJ Hoffmann, U Williamson, MK Ordovas, JM AF Crosier, Michael D. Booth, Sarah L. Peter, Inga Dawson-Hughes, Bess Price, Paul A. O'Donnell, Christopher J. Hoffmann, Udo Williamson, Matthew K. Ordovas, Jose M. TI Matrix Gla Protein Polymorphisms are Associated with Coronary Artery Calcification in Men SO JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY LA English DT Article DE matrix gla protein; coronary artery calcification; polymorphism; vitamin K; atherosclerosis ID COMPUTED-TOMOGRAPHY; RISK-FACTORS; ATHEROSCLEROSIS; DISEASE; SERUM; GENE; RAT AB Matrix Gla protein (MGP) is a key regulator of vascular calcification. Genetic variation at the MGP locus could modulate the development of coronary artery calcification (CAC). Our aim was to examine the cross-sectional association between MGP single nucleotide polymorphisms (SNPs) [rs1800802 (T-138C), rs1800801 (G-7A), and rs4236 (Ala102Thr)] and CAC. CAC was measured by multidetector computed tomography (MDCT), in older men and women of European descent. (n=386; 60 to 80 3, of age). Serum MGP was measured by radioimmunoassay. Linear, Tobit and Ordinal regression analyses all revealed that in men, homozygous carriers of the minor allele of rs1800802, rs1800801. or rs4236 (minor allele frequency: 21, 38, and 40%. respectively) were associated with a decreased quantity of CAC. relative to major allele carriers. This association was not found in women. Although genetic variation in MGP was associated with serum MGP concentrations, there were no associations between serum MGP and CAC. The results of this study suggest a role for MGP genetic variants in coronary atherosclerosis among men that is not reflected in serum MGP concentrations. C1 [Crosier, Michael D.; Booth, Sarah L.; Dawson-Hughes, Bess; Ordovas, Jose M.] Tufts Univ, Human Nutr Res Ctr Aging, USDA, Boston, MA 02111 USA. [Peter, Inga] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Price, Paul A.; Williamson, Matthew K.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Donnell, Christopher J.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiovasc CT Core Lab, Boston, MA 02114 USA. RP Booth, SL (reprint author), Tufts Univ, Human Nutr Res Ctr Aging, USDA, 711 Washington St, Boston, MA 02111 USA. EM sarah.booth@tufts.edu OI Ordovas, Jose/0000-0002-7581-5680 FU U.S. Department of Agriculture, Agricultural Research Service under Cooperative Agreement [58-1950-7-707]; National Institute of Aging [AG14759, HL69272, NIDDK T32DK62032] FX Based upon work supported by the U.S. Department of Agriculture, Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707, National Institute of Aging (AG14759, HL69272 and NIDDK T32DK62032). Any opinions. findings, conclusions or recommendations expressed in this publication are those of the authors, and do not necessarily reflect the view of the U.S. Department of Agriculture. NR 27 TC 28 Z9 31 U1 0 U2 0 PU CENTER ACADEMIC PUBL JAPAN PI TOKYO PA 2-4-16 YAYOI, BUNKYO-KU, TOKYO, 113-0032, JAPAN SN 0301-4800 J9 J NUTR SCI VITAMINOL JI J. Nutr. Sci. Vitaminol. PD FEB PY 2009 VL 55 IS 1 BP 59 EP 65 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 413BF UT WOS:000263767200008 PM 19352064 ER PT J AU Capitini, CM Derdak, J Hughes, MS Love, CP Baird, K Mackall, CL Fry, TJ AF Capitini, Christian M. Derdak, Joanne Hughes, Marybeth S. Love, Cynthia P. Baird, Kristin Mackall, Crystal L. Fry, Terry J. TI Unusual Sites of Extraskeletal Metastases of Ewing Sarcoma After Allogeneic Hematopoietic Stem Cell Transplantation SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE Ewing sarcoma; allogeneic stem cell transplant; metastasis ID TUMORS; BRAIN AB Allogeneic stein cell transplantation (SCT) for solid tumors remains under investigation. We report a case of extended disease stability after a nonmyeloablative peripheral blood SCT for metastatic, refractory Ewing sarcoma. Of note, the patient developed metastatic disease to 2 unusual sites-the brain and small intestine. The allogeneic SCT environment may alter typical metastatic patterns, and may represent an ideal platform to manipulate and enhance the antitumor immune response. Further clinical trials are needed to evaluate the role for allogeneic SCT for this disease. C1 [Capitini, Christian M.; Derdak, Joanne; Love, Cynthia P.; Baird, Kristin; Mackall, Crystal L.; Fry, Terry J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hughes, Marybeth S.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Fry, Terry J.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. RP Capitini, CM (reprint author), NCI, Pediat Oncol Branch, NIH, 10 Ctr Dr,Room 1W-5832, Bethesda, MD 20892 USA. EM capitinic@mail.nih.gov OI Capitini, Christian/0000-0002-2276-6731 FU Intramural NIH HHS [Z99 CA999999] NR 15 TC 6 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD FEB PY 2009 VL 31 IS 2 BP 142 EP 144 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 404FA UT WOS:000263135100015 PM 19194203 ER PT J AU Maran, RRM Thomas, A Roth, M Sheng, ZH Esterly, N Pinson, D Gao, X Zhang, YW Ganapathy, V Gonzalez, FJ Guo, GL AF Maran, Rengasamy R. M. Thomas, Ann Roth, Megan Sheng, Zhonghua Esterly, Noriko Pinson, David Gao, Xin Zhang, Yawei Ganapathy, Vadivel Gonzalez, Frank J. Guo, Grace L. TI Farnesoid X Receptor Deficiency in Mice Leads to Increased Intestinal Epithelial Cell Proliferation and Tumor Development SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID SMALL HETERODIMER PARTNER; BILE-ACID RECEPTOR; NUCLEAR RECEPTOR; COLON-CANCER; BETA-CATENIN; ADENOMATOUS POLYPOSIS; BINDING-PROTEIN; BREAST-CANCER; EXPRESSION; GROWTH AB Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-regulation in the expression of genes involved in cell cycle progression and inflammation, including cyclin D1 and interleukin-6. Most importantly, FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polyposis coli mutant mice. Furthermore, after treatment with a colon carcinogen, azoxymethane, FXR deficiency increased the adenocarcinoma multiplicity and size in colon and rectum of C57BL/6 mice. Loss of FXR function also increased the intestinal lymphoid nodule numbers in the intestine. Taken together, the current study is the first to show that FXR deficiency promotes cell proliferation, inflammation, and tumorigenesis in the intestine, suggesting that activation of FXR by nonbile acid ligands may protect against intestinal carcinogenesis. C1 [Maran, Rengasamy R. M.; Thomas, Ann; Roth, Megan; Sheng, Zhonghua; Esterly, Noriko; Guo, Grace L.] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Pinson, David] Univ Kansas, Med Ctr, Dept Pathol, Kansas City, KS 66160 USA. [Pinson, David] Univ Kansas, Med Ctr, Dept Lab Anim Resources, Kansas City, KS 66160 USA. [Gao, Xin] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Ganapathy, Vadivel] Med Coll Georgia, Dept Biochem, Augusta, GA 30912 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Guo, GL (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM lguo@kumc.edu OI Roth, Megan/0000-0002-6657-9292 FU Intramural Research Program of the National Institutes of Health National Cancer Institute; National Institutes of Health [R01-DK81343, K12-HD052027, P20-RR015563, P20-RR021940]; Kansas Masonic Cancer Research Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health National Cancer Institute; by the National Institutes of Health [ Grants R01-DK81343, K12-HD052027, P20-RR015563, P20-RR021940]; and by the Kansas Masonic Cancer Research Institute. NR 37 TC 87 Z9 90 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2009 VL 328 IS 2 BP 469 EP 477 DI 10.1124/jpet.108.145409 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 396WZ UT WOS:000262623600012 PM 18981289 ER PT J AU Zhao, CX Xu, XZ Cui, YH Wang, PH Wei, X Yang, SL Edin, ML Zeldin, DC Wang, DW AF Zhao, Chun Xia Xu, Xizhen Cui, Yinghua Wang, Peihua Wei, Xin Yang, Shilin Edin, Matthew L. Zeldin, Darryl C. Wang, Dao Wen TI Increased Endothelial Nitric-Oxide Synthase Expression Reduces Hypertension and Hyperinsulinemia in Fructose-Treated Rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PROTEIN-KINASE-B; INDUCED INSULIN-RESISTANCE; DIABETES-MELLITUS; GENE-THERAPY; SIGNALING PATHWAYS; METABOLIC SYNDROME; MUSCLE; ACTIVATION; ANGIOGENESIS; MECHANISMS AB Endothelial dysfunction and decreased production of nitric oxide (NO) by endothelial NO synthase (eNOS) are implicated in the pathogenesis of hypertension and insulin resistance. Because the potential influence of increased eNOS expression/activity on these parameters is unclear, the present study examined the effects of eNOS gene therapy on insulin resistance and blood pressure alterations in a fructose-induced hypertension model in rats. As predicted, 2 weeks of fructose consumption in the drinking water resulted in elevated systolic blood pressure and insulin resistance. These and other physiologic alterations were reversed within 2 weeks after a single intravenous injection of a vector containing the human eNOS cDNA (pcDNA3.1-eNOS), whereas injection of an empty vector (pcDNA3.1) was without effect. In support of the beneficial effects of pcDNA3.1-eNOS treatment being because of enhanced eNOS expression and activity, increased eNOS protein levels were documented in aorta, liver, kidney, and heart of fructose-treated rats injected with pcDNA3.1-eNOS, and corresponding elevations in nitrite/nitrate and cGMP concentrations were observed in urine. Furthermore, pcDNA3.1-eNOS treatment prevented fructose-induced decreases in expression levels of insulin receptor substrate-1, the p110 catalytic subunit of phosphatidylinositol 3-kinase, phosphorylated Akt, and phosphorylated AMP-activated protein kinases in liver, aorta, and skeletal muscle. The results of this study cumulatively indicate that gene therapy with human eNOS decreased fructose-induced hypertension and insulin resistance in rats and suggest potential signaling pathways that mediate these effects. These data highlight the potential utility of eNOS gene therapy in the treatment of hypertension and insulin resistance. C1 [Zhao, Chun Xia; Xu, Xizhen; Cui, Yinghua; Wang, Peihua; Wei, Xin; Yang, Shilin; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. [Zhao, Chun Xia; Xu, Xizhen; Cui, Yinghua; Wang, Peihua; Wei, Xin; Yang, Shilin; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Inst Hypertens, Wuhan 430030, Peoples R China. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn OI Edin, Matthew/0000-0002-7042-500X FU Intramural NIH HHS NR 41 TC 37 Z9 40 U1 1 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2009 VL 328 IS 2 BP 610 EP 620 DI 10.1124/jpet.108.143396 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 396WZ UT WOS:000262623600028 PM 19008412 ER PT J AU Perdivara, I Petrovich, R Allinquant, B Deterding, LJ Tomer, KB Przybylski, M AF Perdivara, Irina Petrovich, Robert Allinquant, Bernadette Deterding, Leesa J. Tomer, Kenneth B. Przybylski, Michael TI Elucidation of O-Glycosylation Structures of the beta-Amyloid Precursor Protein by Liquid Chromatography-Mass Spectrometry Using Electron Transfer Dissociation and Collision Induced Dissociation SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE beta-Amyloid; amyloid-precursor protein; Alzheimer's disease; O-glycosylation; tandem-mass spectrometry; electron transfer-dissociation; collision-induced dissociation ID TRANSFER ION/ION REACTIONS; HAMSTER OVARY CELLS; QUADRUPOLE ION-TRAP; CAPTURE DISSOCIATION; ALZHEIMERS-DISEASE; SECRETASE CLEAVAGE; SIDE-CHAIN; IDENTIFICATION; PEPTIDES; LOCALIZATION AB Accumulation and deposition of beta-amyloid peptide, a major constituent in neuritic plaques are hallmarks of Alzheimer's disease (AD) and AD-related neurodegenerative diseases. beta-Amyloid (A beta) is derived from the proteolytic cleavage of amyloid precursor protein (APP), a transmembrane protein present in three major isoforms in brain comprising 695, 751 and 770 amino acids, respectively. Among other post-translational modifications, APP is modified during maturation by N- and O-glycosylation, which are thought to be responsible for its expression and secretion. Unlike N-glycosylation, no sites of O-glycosylation of APP have previously been reported. We report here the identification of three specific O-glycosylation sites of the secreted APP695 (sAPP695) produced in CHO cells, using a combination of high-performance liquid chromatography and electrospray-tandem mass spectrometry. With the use of electron transfer dissociation and collision induced dissociation (ETD and CID), we identified type, composition and structures of the Core 1 type O-linked glycans attached at the residues Thr 291, Thr 292 and Thr 576 of the full-length APP695. The glycosylations comprise multiple short glycans, containing N-acetyl galactosamine (GalNAc), Gal-GalNAc and sialic acid terminated structures. The presence of the glycopeptides in the tryptic mixture was identified using the CID-generated sugar oxonium ions. ETD proved to be valuable for the unambiguous identification of the modified sites as ETD fragmentation occurred along the peptide backbone with little or no cleavage of the glycans. Thus, the combination of the CID and ETD techniques in LC-MS is shown here, as a powerful tool for de novo identification of O-glycosylations at unknown modification sites in proteins. C1 [Perdivara, Irina; Petrovich, Robert; Deterding, Leesa J.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Przybylski, Michael] Univ Konstanz, Dept Chem, Lab Analyt Chem & Biopolymer Struct Anal, D-78457 Constance, Germany. [Allinquant, Bernadette] Univ Paris 05, U894, INSERM, F-75014 Paris, France. RP Przybylski, M (reprint author), Univ Konstanz, Dept Chem, Lab Analyt Chem & Biopolymer Struct Anal, D-78457 Constance, Germany. EM tomer@niehs.nih.gov; Michael.Przybylski@uni-konstanz.de RI Tomer, Kenneth/E-8018-2013 FU NIH; National Institute of Environmental Health Sciences; University of Konstanz; Deutsche Forschungsgemeinschaft FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. This work has been supported in part by the University of Konstanz, and by the Deutsche Forschungsgemeinschaft (Biopolymer-MS and FG-753). The authors would like to thank Ms. Katina Johnson and Dr. Jason Williams for the help provided with the Agilent software, as well as Dr. Lake Paul for the help provided with the Western blot experiments. NR 44 TC 70 Z9 71 U1 2 U2 35 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2009 VL 8 IS 2 SI SI BP 631 EP 642 DI 10.1021/pr800758g PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 405AC UT WOS:000263193300023 PM 19093876 ER PT J AU Reilly, KJ Moore, CA AF Reilly, Kevin J. Moore, Christopher A. TI Respiratory Movement Patterns During Vocalizations at 7 and 11 Months of Age SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE respiration; speech; infant; motor development; physiology ID CHEST-WALL COMPLIANCE; RIB CAGE; LUNG-VOLUME; FULL-TERM; INFANTS; DIAPHRAGM; SPEECH; CHILDREN; KINEMATICS; NEWBORN AB Purpose: The present investigation was designed to study the modulation of abdomen and rib cage movements during vocalization over a period of development associated with rapid decreases in the compliance of the chest wall. Method: Rib cage and abdominal kinematics were recorded during spontaneous vocalizations in 7- and 11-month old infants. Principal component analysis was used to represent each infant's abdomen and rib cage traces as the weighted sum of a small number of principal component (PC) waveforms. Results: The fundamental periods of infants' PC waveforms in the 11-month group were significantly shorter than those in the 7-month group. In addition, the variance contributed by PCs describing unidirectional patterns of respiratory movement decreased in the 11-month group, whereas the variances contributed by PCs describing modulated patterns of movement increased. Lastly, the extent to which abdomen and rib cage movements predicted the duration of corresponding vocalizations also increased significantly in the 11-month group compared with the 7-month group. Conclusions: The findings of the present study were consistent with the hypothesis that decreases in the compliance of the chest wall result in more rapid modulation of chest wall movements and greater control of those movements by the developing neuromuscular system. C1 [Reilly, Kevin J.] Northeastern Univ, Dept Speech Language Pathol & Audiol, Boston, MA 02115 USA. [Moore, Christopher A.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RP Reilly, KJ (reprint author), Northeastern Univ, Dept Speech Language Pathol & Audiol, 360 Huntington Ave, Boston, MA 02115 USA. EM k.reilly@neu.edu FU NIDCD NIH HHS [F31 DC000295, F31 DC00295, R01 DC000822, R01 DC00822, T32 DC000033, T32 DC00033] NR 40 TC 5 Z9 5 U1 0 U2 2 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD FEB 1 PY 2009 VL 52 IS 1 BP 223 EP 239 DI 10.1044/1092-4388(2008/06-0215) PG 17 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 400EJ UT WOS:000262850500016 PM 18695025 ER PT J AU Appaneal, RN Levine, BR Perna, FM Roh, JL AF Appaneal, Renee Newcomer Levine, Beverly Rockhill Perna, Frank M. Roh, Joni L. TI Measuring Postinjury Depression Among Male and Female Competitive Athletes SO JOURNAL OF SPORT & EXERCISE PSYCHOLOGY LA English DT Article DE measurement; major depressive disorder; mental health; sport injury; psychological response ID STRUCTURED INTERVIEW GUIDE; SEASON-ENDING INJURIES; HAMILTON RATING-SCALE; SPORT INJURY; IMMUNE FUNCTION; ADOLESCENTS; RESPONSES; ISSUES; RISK; PREVENTION AB Depression is common among athletes following sport injury, yet few studies have explored the severity of postinjury depression. Among those studies, only one examined gender differences although women in the general population are more likely than men to experience depression. No research to date has used interviews to assess depression despite their standard use among mental health professionals. In a quasi-experimental design, we used a self-report checklist and a clinical interview to compare depression among male and female athletes at I week, I month, and 3 months postinjury. Results revealed significant effects of group (injured vs. control) and time (since injury), and these effects were different for the two depression measures. We also explored the sensitivity and specificity of the user-rated checklist in identifying severely depressed athletes compared with the interview. Findings underscore the importance of multimodal approaches and clinical judgment when evaluating athletes' postinjury depression symptoms. C1 [Appaneal, Renee Newcomer] Univ N Carolina, Dept Exercise & Sport Sci, Greensboro, NC 27412 USA. [Levine, Beverly Rockhill] Univ N Carolina, Dept Publ Hlth Educ, Greensboro, NC 27412 USA. [Perna, Frank M.] NCI, Behav Res Proram, Hlth Promot Res Branch, Bethesda, MD 20892 USA. [Roh, Joni L.] Calif Univ Penn, Dept Hlth Sci & Sport Studies, California, PA USA. RP Appaneal, RN (reprint author), Univ N Carolina, Dept Exercise & Sport Sci, Greensboro, NC 27412 USA. FU West Virginia University Office of Research; National Athletic Trainers' Association FX This research was supported by grants to Dr. Perna (PI) from the West Virginia University Office of Research and the National Athletic Trainers' Association. NR 56 TC 23 Z9 24 U1 3 U2 20 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 0895-2779 J9 J SPORT EXERCISE PSY JI J. Sport Exerc. Psychol. PD FEB PY 2009 VL 31 IS 1 BP 60 EP 76 PG 17 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 411MV UT WOS:000263654600005 PM 19325188 ER PT J AU Stevens, HE Leckman, JF Coplan, JMD Suomi, SJ AF Stevens, Hanna E. Leckman, James F. Coplan, Jere My D. Suomi, Stephen J. TI Risk and Resilience: Early Manipulation of Macaque Social Experience and Persistent Behavioral and Neurophysiological Outcomes SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE primates; maternal care; attachment; hypothalamic-pituitary-adrenal axis; neurophysiology ID CORTICOTROPIN-RELEASING-FACTOR; TRANSPORTER GENE VARIATION; INFANT RHESUS-MONKEYS; CEREBROSPINAL-FLUID CONCENTRATIONS; VARIABLE FORAGING DEMAND; EARLY REARING CONDITIONS; BIOGENIC-AMINE ACTIVITY; EARLY-LIFE STRESSORS; SEROTONIN TRANSPORTER; NONHUMAN-PRIMATES AB Objective: To review the contributions of research on nonhuman primates, specifically macaque monkeys, to the understanding of early social stress and its effects on behavior and neurophysiology. Method: Review and synthesis of two bodies of work on macaque monkeys and early social manipulation: peer rearing and variable foraging demands. The literature was searched with Medline using key terms macaque, variable foraging, and peer rearing. The reference lists of these articles were also used to generate potential studies for review. Results: Nonhuman primate macaques show similarities to humans in their social development and functioning. Peer rearing of young macaques and rearing of young macaques with mothers experiencing variable foraging conditions both result in increased anxious, impulsive, and aggressive temperament and behavior; more reactive stress physiology; altered neurotransmitter functioning; and immune and metabolic changes. Functional variants of specific genes that code for neuromodulators are mediators of these effects. Conclusions: Disrupted social relations during macaque rearing contribute to the risk for developing emotional and neurophysiological disturbance. In the face of such disruption, certain genotypes contribute to resilience. This can be alternately stated that, for animals of high-risk genotypes, resilience is conferred by quality relationships during rearing. This interaction of genetics with early social environment also applies to child mental health, implicating biological mediators identified in macaques as contributing to more complex outcomes in humans. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(2):114-127. C1 [Stevens, Hanna E.; Leckman, James F.] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06520 USA. [Suomi, Stephen J.] NICHHD, Comparat Ethol Lab, Bethesda, MD USA. RP Stevens, HE (reprint author), Yale Univ, Sch Med, Yale Child Study Ctr, 230 S Frontage Rd, New Haven, CT 06520 USA. EM hanna.stevens@yale.edu RI Stevens, Hanna/M-4104-2016 FU Yale Child Study Center FX Financial support was provided by Yale Child Study Center Albert J. Solnit Integrated Training Program. NR 80 TC 56 Z9 56 U1 0 U2 39 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2009 VL 48 IS 2 BP 114 EP 127 DI 10.1097/CHI.0b013e318193064c PG 14 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 397XO UT WOS:000262695900004 PM 19127170 ER PT J AU Kennard, BD Silva, SG Tonev, S Rohde, P Hughes, JL Vitiello, B Kratochvil, CJ Curry, JF Emslie, GJ Reinecke, M Nlkrch, J AF Kennard, Betsy D. Silva, Susan G. Tonev, Simon Rohde, Paul Hughes, Jennifer L. Vitiello, Benedetto Kratochvil, Christopher J. Curry, John F. Emslie, Graham J. Reinecke, Mark Nlkrch, John TI Remission and Recovery in the Treatment for Adolescents With Depression Study (TADS): Acute and Long-Term Outcomes SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE adolescent depression; remission; residual symptoms; recovery ID COGNITIVE-BEHAVIORAL TREATMENT; PLACEBO-CONTROLLED TRIAL; RESIDUAL SYMPTOMS; PSYCHOTHERAPY TRIAL; MAJOR DEPRESSION; CLINICAL-TRIAL; DISORDER; THERAPY; CHILDREN; RELAPSE AB Objective: We examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS). Method: The TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder to 12 weeks of treatment with fluoxetine, cognitive-behavioral therapy, their combination, or pill placebo. The pill placebo group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at weeks 12 (acute phase remitters) and 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission. Results: At week 36, the estimated remission rates for intention-to-treat cases were as follows: combination, 60%; fluoxetine, 55%; cognitive-behavioral therapy, 64%; and overall, 60%. Paired comparisons reveal that, at week 24, all active treatments converge on remission outcomes. The recovery rate at week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36. Conclusions: Most depressed adolescents in all three treatment modalities achieved remission at the end of 9 months of treatment. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(2):186-195. C1 [Kennard, Betsy D.; Hughes, Jennifer L.; Emslie, Graham J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Silva, Susan G.; Tonev, Simon] Duke Univ, Med Ctr, Clin Res Inst, Durham, NC 27706 USA. [Rohde, Paul] Oregon Res Inst, Albuquerque, NM USA. [Vitiello, Benedetto] NIH, Div Serv & Intervent Res, Bethesda, MD USA. [Kratochvil, Christopher J.] Univ Nebraska Med Ctr, Omaha, NE USA. [Curry, John F.; Reinecke, Mark] Northwestern Univ, Evanston, IL 60208 USA. RP Kennard, BD (reprint author), Univ Texas SW Med Ctr Dallas, 53233 Harry Hines Blvd, Dallas, TX 75390 USA. EM Beth.kennard@utsouthwestern.edu FU National Institute of Mental Health to Duke University Medical Center [N01 MH80008] FX The Treatment for Adolescents with Depression Study (TADS) is supported by contract N01 MH80008 from the National Institute of Mental Health to Duke University Medical Center (Dr. March, Principal Investigator). NR 41 TC 64 Z9 65 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2009 VL 48 IS 2 BP 186 EP 195 DI 10.1097/CHI.0b013e31819176f9 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 397XO UT WOS:000262695900011 PM 19127172 ER PT J AU Katz, KA Roseman, JE Roseman, RL Katz, SI AF Katz, Kenneth A. Roseman, Julie E. Roseman, Robert L. Katz, Stephen I. TI Dermatitis herpetiformis flare associated with use of triiodomethane packing strips for alveolar osteitis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter ID IODINE C1 [Roseman, Julie E.] Emory Univ, Atlanta, GA 30322 USA. [Roseman, Robert L.] Vitreo Retinal Associates, Gainesville, FL USA. [Katz, Stephen I.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Katz, KA (reprint author), 1360 Mission St,Ste 401, San Francisco, CA 94103 USA. EM kenneth.katz@gmail.com FU Intramural NIH HHS [Z01 SC003657-33, Z99 AR999999] NR 7 TC 5 Z9 5 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2009 VL 60 IS 2 BP 352 EP 353 DI 10.1016/j.jaad.2008.08.041 PG 2 WC Dermatology SC Dermatology GA 396UW UT WOS:000262617700031 PM 19150286 ER PT J AU Powell, AC Casey, K Liewehr, DJ Hayanga, A James, TA Cherr, GS AF Powell, Anathea C. Casey, Kathleen Liewehr, David J. Hayanga, Awori James, Ted A. Cherr, Gregory S. TI Results of a National Survey of Surgical Resident Interest in International Experience, Electives, and Volunteerism SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID COUNTRIES; SURGERY AB BACKGROUND: Data are emerging about the essential nature of sustainable global surgical care and interest among North American surgeons. Currently, there is no formal mechanism for US surgical residents to participate in international training opportunities. A small, single-institution survey found that general surgery residents at New York University are highly motivated to pursue international training. But little research has addressed the attitudes of North American residents about international training. The goal of this study was to acquire a broader understanding of surgical resident interest in international training. STUDY DESIGN: A structured questionnaire was administered anonymously and voluntarily to all American College of Surgeons resident members. RESULTS: Seven hundred twenty-four residents completed surveys. Ninety-four percent of respondents planned careers in general surgery. Ninety-two percent of respondents were interested in an international elective, and 82% would prioritize the experience over all or some other electives. Fifty-four percent and 73% of respondents would be willing to use vacation and participate even if cases were not counted for graduation requirements, respectively. Educational indebtedness was high among respondents (50% of respondents carried >= $100,000 debt). Despite debt, 85% of respondents plan to volunteer while in practice. The most frequent barriers identified by respondents were financial (61%) and logistic (66%). CONCLUSIONS: American College of Surgeons resident members are highly motivated to acquire international training experience, with many planning to volunteer in the future. A consensus among stake-holders in North American surgical education is needed to further explore international training within surgical residency. (J Am Coll Surg 2009;208:304-312. (C) 2009 by the American College of Surgeons) C1 [Powell, Anathea C.] NYU, Sch Med, Dept Surg, New York, NY 10016 USA. [Hayanga, Awori] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [James, Ted A.] Univ Vermont, Dept Surg, Burlington, VT 05405 USA. [Powell, Anathea C.; Casey, Kathleen] Amer Coll Surg, Operat Giving Back & Educ Comm, Chicago, IL USA. [Powell, Anathea C.; Hayanga, Awori; James, Ted A.; Cherr, Gregory S.] Amer Coll Surg, Resident Associate Soc, Chicago, IL USA. [Liewehr, David J.] NCI, Biostat & Data Management Sect, Off Clin Director, CCR, Bethesda, MD 20892 USA. [Cherr, Gregory S.] SUNY Buffalo, Dept Surg, Buffalo, NY 14260 USA. [Cherr, Gregory S.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Powell, AC (reprint author), NYU, Sch Med, Dept Surg, New York, NY 10016 USA. EM powela@1enyumc.org NR 18 TC 67 Z9 67 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD FEB PY 2009 VL 208 IS 2 BP 304 EP 312 DI 10.1016/j.jamcollsurg.2008.10.025 PG 9 WC Surgery SC Surgery GA 407TP UT WOS:000263387500019 PM 19228545 ER PT J AU Rovner, AJ Nansel, TR Gellar, L AF Rovner, Alisha J. Nansel, Tonja R. Gellar, Lauren TI The Effect of a Low-Glycemic Diet vs a Standard Diet on Blood Glucose Levels and Macronutrient Intake in Children with Type 1 Diabetes SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID INDEX FOODS; OBESITY; ADVICE; YOUTH AB A low-glycemic index (GI) diet may lower postprandial hyperglycemia and decrease the risk for postabsorptive hypoglycemia in people with type 1 diabetes. However, insufficient evidence exists on the efficacy of a low-GI diet to support practice recommendations. The goal of this study was to examine the blood glucose response to and the macronutrient composition of low-GI meals vs usual meals consumed ad libitum at home in children with type 1 diabetes. A within-subject, crossover design was employed. Twenty-three participants were recruited between June and August 2006. Participants wore a continuous blood glucose monitoring system and completed diet diaries on 2 days. On 1 day, participants consumed their usual meal; on another day, participants consumed low-GI meals ad libidum. Order of the 2 days was counterbalanced. The mean GI was 34 +/- 6 for the low-GI day and 57 6 for the usual meal day (P<0.0001). During the low-GI day, mean daytime blood glucose values (125 +/- 28 mg/dL [6.9 +/- 1.5 nmol/L] vs 185 +/- 58 mg/dL [10.3 +/- 3.2 nmol/L], P<0.001), blood glucose area above 180 mg/dL (4,486 +/- 6,138 vs 26,707 +/- 25,038, P<0.006), and high blood glucose index (5.1 +/- 5.1 vs 13.6 +/- 7.6, P<0.001) were lower compared to the usual mean day. During the low-GI day, subjects consumed more fiber (24.5 +/- 12.3 g vs 14.5 +/- 6.1 g, P<0.007) and less fat (45.7 +/- 12.2 g vs 76.8 +/- 32.4 g, P<0.005); however, there were no differences in energy, carbohydrate, or protein intake. In this pilot study, a low-GI diet was associated with improved diet quality and a reduction in hyperglycemia. C1 [Rovner, Alisha J.; Nansel, Tonja R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gellar, Lauren] Univ Manchester, Sch Med, Clin & Populat Hlth Res Div, Worcester, MA USA. RP Rovner, AJ (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, 6100 Execut Blvd,Room 7B13R,MSC 7500, Bethesda, MD 20892 USA. EM rouneral@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595 FU Intramural NIH HHS [Z01 HD008805-01] NR 24 TC 20 Z9 22 U1 0 U2 4 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD FEB PY 2009 VL 109 IS 2 BP 303 EP 307 DI 10.1016/j.jada.2008.10.047 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 401CI UT WOS:000262915500016 PM 19167958 ER PT J AU Wright, RM Roumani, YF Boudreau, R Newman, AB Ruby, CM Studenski, SA Shorr, RI Bauer, DC Simonsick, EM Hilmer, SN Hanlon, JT AF Wright, Rollin M. Roumani, Yazan F. Boudreau, Robert Newman, Anne B. Ruby, Christine M. Studenski, Stephanie A. Shorr, Ronald I. Bauer, Douglas C. Simonsick, Eleanor M. Hilmer, Sarah N. Hanlon, Joseph T. CA Hlth Aging & Body Composition Stud TI Effect of Central Nervous System Medication Use on Decline in Cognition in Community-Dwelling Older Adults: Findings from the Health, Aging and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE cognition; aged; medications ID BENZODIAZEPINE USE; ELDERLY PERSONS; INFLAMMATORY MARKERS; FUNCTIONAL DECLINE; PREDICTIVE MODEL; RISK-FACTORS; DRUG-USE; DELIRIUM; IMPAIRMENT; PERFORMANCE AB To evaluate whether combined use of multiple central nervous system (CNS) medications over time is associated with cognitive change. Longitudinal cohort study. Pittsburgh, Pennsylvania, and Memphis, Tennessee. Two thousand seven hundred thirty-seven healthy adults (aged >= 65) enrolled in the Health, Aging and Body Composition study without baseline cognitive impairment (modified Mini-Mental State Examination (3MS) score >= 80). CNS medication (benzodiazepine- and opioid-receptor agonists, antipsychotics, antidepressants) use, duration, and dose were determined at baseline (Year 1) and Years 3 and 5. Cognitive function was measured using the 3MS at baseline and Years 3 and 5. The outcome variables were incident cognitive impairment (3MS score < 80) and cognitive decline (>= 5-point decline on 3MS). Multivariable interval-censored survival analyses were conducted. By Year 5, 7.7% of subjects had incident cognitive impairment; 25.2% demonstrated cognitive decline. CNS medication use increased from 13.9% at baseline to 15.3% and 17.1% at Years 3 and 5, respectively. It was not associated with incident cognitive impairment (adjusted hazard ratio (adj HR)=1.11, 95% confidence interval (CI)=0.73-1.69) but was associated with cognitive decline (adj HR 1.37, 95% CI=1.11-1.70). Longer duration (adj HR=1.39, CI=1.08-1.79) and higher doses (> 3 standardized daily doses) (adj HR=1.87, 95% CI=1.25-2.79) of CNS medications suggested greater risk of cognitive decline than with nonuse. Combined use of CNS medications, especially at higher doses, appears to be associated with cognitive decline in older adults. Future studies must explore the effect of combined CNS medication use on vulnerable older adults. C1 [Wright, Rollin M.; Roumani, Yazan F.; Newman, Anne B.; Studenski, Stephanie A.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr, Pittsburgh, PA 15213 USA. [Boudreau, Robert; Newman, Anne B.] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Ruby, Christine M.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15213 USA. [Studenski, Stephanie A.; Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res, Pittsburgh, PA USA. [Studenski, Stephanie A.; Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. [Shorr, Ronald I.] N Florida S Georgia Vet Hlth Syst, Ctr Geriatr Res Educ & Clin, Gainesville, FL USA. [Bauer, Douglas C.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Simonsick, Eleanor M.] Johns Hopkins Univ, Inst Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Simonsick, Eleanor M.; Hilmer, Sarah N.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Hilmer, Sarah N.] Univ Sydney, Sydney, NSW 2006, Australia. [Hilmer, Sarah N.] Royal N Shore Hosp, Sydney, NSW, Australia. RP Wright, RM (reprint author), Univ Pittsburgh, Dept Med Geriatr, Kaufmann Med Bldg,Suite 500,3471 5th Ave, Pittsburgh, PA 15213 USA. EM rmw27@pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Hilmer, Sarah/0000-0002-5970-1501; Boudreau, Robert/0000-0003-0162-5187 FU National Institutes of Health (NIH), National Institute on Aging; NIH c [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01AG027017]; Pittsburgh Claude D. Pepper Older Americans Independence Center [P30AG024827]; John A. Hartford Foundation Center FX Sponsors' Roles: The organizations that funded this study did not influence the interpretation of the data or the development of this manuscript. NR 53 TC 37 Z9 38 U1 2 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2009 VL 57 IS 2 BP 243 EP 250 DI 10.1111/j.1532-5415.2008.02127.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 399WE UT WOS:000262829200008 PM 19207141 ER PT J AU Cesari, M Kritchevsky, SB Newman, AB Simonsick, EM Harris, TB Penninx, BW Brach, JS Tylavsky, FA Satterfield, S Bauer, DC Rubin, SM Visser, M Pahor, M AF Cesari, Matteo Kritchevsky, Stephen B. Newman, Anne B. Simonsick, Eleanor M. Harris, Tamara B. Penninx, Brenda W. Brach, Jennifer S. Tylavsky, Frances A. Satterfield, Suzanne Bauer, Doug C. Rubin, Susan M. Visser, Marjolein Pahor, Marco CA Hlth Aging & Body Composition Stud TI Added Value of Physical Performance Measures in Predicting Adverse Health-Related Events: Results from the Health, Aging and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE Short Physical Performance Battery; functional limitation; death; hospitalization; usual gait speed ID LOWER-EXTREMITY FUNCTION; SUBSEQUENT DISABILITY; FUNCTIONAL DEPENDENCE; ELDERLY PEOPLE; WOMENS HEALTH; WALKING SPEED; OLDER WOMEN; GAIT SPEED; MORTALITY; RELIABILITY AB To determine how three different physical performance measures (PPMs) combine for added utility in predicting adverse health events in elders. Prospective cohort study. Health, Aging and Body Composition Study. Three thousand twenty-four well-functioning older persons (mean age 73.6). Timed gait, repeated chair stands, and balance (semi- and full-tandem, and single leg stands each held for 30 seconds) tests were administered at baseline. Usual gait speed was categorized to distinguish high- and low-risk participants using the previously established 1-m/s cutpoint. The same population-percentile (21.3%) was used to identify cutpoints for the repeated chair stands (17.1 seconds) and balance (53.0 seconds) tests. Cox proportional hazard analyses were performed to evaluate the added value of PPMs in predicting mortality, hospitalization, and (severe) mobility limitation events over 6.9 years of follow-up. Risk estimates for developing adverse health-related events were similarly large for each of the three high-risk groups considered separately. Having more PPM scores at the high-risk level was associated with a greater risk of developing adverse health-related events. When all three PPMs were considered, having only one poor performance was sufficient to indicate a highly significantly higher risk of (severe) lower extremity and mortality events. Although gait speed is considered to be the most important predictor of adverse health events, these findings demonstrate that poor performance on other tests of lower extremity function are equally prognostic. This suggests that chair stand and standing balance performance may be adequate substitutes when gait speed is unavailable. C1 [Cesari, Matteo; Pahor, Marco] Univ Florida, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL 32611 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27103 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Brach, Jennifer S.] Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Tylavsky, Frances A.; Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Bauer, Doug C.; Rubin, Susan M.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Bauer, Doug C.; Rubin, Susan M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Visser, Marjolein] Vrije Univ Amsterdam, Fac Earth & Life Sci, Inst Hlth Sci, Amsterdam, Netherlands. RP Cesari, M (reprint author), Univ Florida, Inst Aging, Dept Aging & Geriatr Res, 210 E Mowry Rd, Gainesville, FL 32611 USA. EM macesari@gmail.com RI Cesari, Matteo/A-4649-2008; Newman, Anne/C-6408-2013; OI Cesari, Matteo/0000-0002-0348-3664; Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging (NIA) [N01-AG-6-2106, N01-AG-6-2101, N01-AG-6-2103]; University of Florida Institute on Aging; Claude D. Pepper Older Americans Independence Center (National Institutes of Health (NIH) [1P30AG028740] FX Sponsor's Role: None. NR 26 TC 144 Z9 149 U1 3 U2 14 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2009 VL 57 IS 2 BP 251 EP 259 DI 10.1111/j.1532-5415.2008.02126.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 399WE UT WOS:000262829200009 PM 19207142 ER PT J AU Vestergaard, S Patel, KV Walkup, MP Pahor, M Marsh, AP Espeland, MA Studenski, S Gill, TM Church, T Guralnik, JM AF Vestergaard, Sonja Patel, Kushang V. Walkup, Michael P. Pahor, Marco Marsh, Anthony P. Espeland, Mark A. Studenski, Stephanie Gill, Thomas M. Church, Timothy Guralnik, Jack M. TI Stopping to Rest During a 400-Meter Walk and Incident Mobility Disability in Older Persons with Functional Limitations SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE mobility disability; aging; physical performance test ID PERIPHERAL ARTERIAL-DISEASE; LIFE-STYLE INTERVENTIONS; PHYSICAL PERFORMANCE BATTERY; LOWER-EXTREMITY FUNCTION; SELF-EFFICACY; INDEPENDENCE; ADULTS; ASSOCIATION; MORTALITY; EXERCISE AB To examine the association between stopping to rest during a 400-m usual-pace walk test (400-MWT) and incident mobility disability in older persons with functional limitations. Prospective cohort study. Community based. Four hundred twenty-four participants in the Lifestyle Intervention and Independence for Elders Pilot (LIFE-P) Study aged 70 to 89 with functional limitations (summary score <= 9 on the Short Physical Performance Battery (SPPB)) but able to complete the 400-MWT within 15 minutes. Rest stops during the 400-MWT were recorded. The onset of mobility disability, defined as being unable to complete the 400-MWT or taking more than 15 minutes to do so, was recorded at Months 6 and 12. Fifty-four (12.7%) participants rested during the 400-MWT at baseline, of whom 37.7% experienced mobility disability during follow-up, versus 8.6% of those not stopping to rest. Performing any rest stop was strongly associated with incident mobility disability at follow-up (odds ratio (OR)=5.4, 95% confidence interval (CI)=2.7-10.9) after adjustment for age, sex, and clinic site. This association was weaker, but remained statistically significant, after further adjusting for SPPB and time to complete the 400-MWT simultaneously (OR=2.6, 95% CI=1.2-5.9). Stopping to rest during the 400-MWT is strongly associated with incident mobility disability in nondisabled older persons with functional limitations. Given the prognostic value, rest stops should be recorded as part of the standard assessment protocol for the 400-MWT. C1 [Vestergaard, Sonja; Patel, Kushang V.; Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Walkup, Michael P.; Espeland, Mark A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Marsh, Anthony P.] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [Pahor, Marco] Univ Florida, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL USA. [Studenski, Stephanie] Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA USA. [Gill, Thomas M.] Yale Univ, Dept Internal Med Geriatr, New Haven, CT USA. [Church, Timothy] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Vestergaard, S (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, 7201 Wisconsin Ave,Suite 3C309, Bethesda, MD 20892 USA. EM vestergaards@mail.nih.gov FU Cooperative Agreement with the National Institute on Aging (NIA) [UO1 AG022376]; National Institutes of Health; NIA [K24AG021507, AG024827, AG023641] FX Sponsor's Role: The granting institutions named above did not interfere in any way with the design, methods, participant recruitment, data collection or analysis, or preparation of the manuscript. NR 18 TC 9 Z9 9 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2009 VL 57 IS 2 BP 260 EP 265 DI 10.1111/j.1532-5415.2008.02097.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 399WE UT WOS:000262829200010 PM 19170785 ER PT J AU Yeganova, L Comeau, DC Kim, W Wilbur, WJ AF Yeganova, Lana Comeau, Donald C. Kim, Won Wilbur, W. John TI How to Interpret PubMed Queries and Why It Matters SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article ID OF-THE-LITERATURE; INFORMATION-SCIENCE; RELEVANCE; FRAMEWORK; THINKING; SYSTEMS; NOTION AB A significant fraction of queries in PubMed (TM) are multiterm queries without parsing instructions. Generally, search engines interpret such queries as collections of terms, and handle them as a Boolean conjunction of these terms. However, analysis of queries in PubMed (TM) indicates that many such queries are meaningful phrases, rather than simple collections of terms. In this study, we examine whether or not it makes a difference, in terms of retrieval quality, if such queries are interpreted as a phrase or as a conjunction of query terms. And, if it does, what is the optimal way of searching with such queries. To address the question, we developed an automated retrieval evaluation method, based on machine learning techniques, that enables us to evaluate and compare various retrieval outcomes. We show that the class of records that contain all the search terms, but not the phrase, qualitatively differs from the class of records containing the phrase. We also show that the difference is systematic, depending on the proximity of query terms to each other within the record. Based on these results, one can establish the best retrieval order for the records. Our findings are consistent with studies in proximity searching. C1 [Yeganova, Lana; Comeau, Donald C.; Kim, Won; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bethesda, MD 20894 USA. RP Yeganova, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM yeganova@mail.nih.gov; comeau@mail.nih.gov; wonkim@mail.nih.gov; wilbur@mail.nih.gov FU National Institutes of Health-National Librarv of Medicine(TM) FX The authors are Supported by the Intramural Research Program of the National Institutes of Health-National Librarv of Medicine (TM). NR 14 TC 8 Z9 8 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1532-2882 J9 J AM SOC INF SCI TEC JI J. Am. Soc. Inf. Sci. Technol. PD FEB PY 2009 VL 60 IS 2 BP 264 EP 274 DI 10.1002/asi.20979 PG 11 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 404FK UT WOS:000263136200005 ER PT J AU Jackson, SN Dutta, S Woods, AS AF Jackson, Shelley N. Dutta, Sucharita Woods, Amina S. TI The Use of ECD/ETD to Identify the Site of Electrostatic Interaction in Noncovalent Complexes SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; CAPTURE DISSOCIATION; MECHANISM; PEPTIDE AB Electrostatic interactions play an important role in the formation of noncovalent complexes. Our previous work has highlighted the role of certain amino acid residues, Such as arginine, glutamate, aspartate, and phosphorylated/sulfated residues, in the formation of salt bridges resulting in noncovalent complexes between peptides. Tandem mass spectrometry (MS) studies of these complexes using collision-induced dissociation (CID) have provided information on their relative stability. However, product-ion spectra produced by CID have been unable to assign specifically the site of interaction for the complex. In this work, tandem MS experiments were conducted on noncovalent complexes using both electron capture dissociation (ECD) and electron-transfer dissociation (ETD). The resulting spectra were dominated by intramolecular fragments of the complex with the electrostatic interaction site intact. Based upon these data, we were able to assign the binding site for the peptides forming the noncovalent complex. (J Am Soc Mass Spectrom 2009, 20, 176-179) (C) 2009 Published by Elsevier Inc. on behalf of American Society for Mass Spectrometry C1 [Jackson, Shelley N.; Woods, Amina S.] NIDA, IRP, NIH, Baltimore, MD 21224 USA. [Dutta, Sucharita] Thermo Fisher Sci, San Jose, CA USA. RP Woods, AS (reprint author), NIDA, IRP, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 15 TC 23 Z9 23 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD FEB PY 2009 VL 20 IS 2 BP 176 EP 179 DI 10.1016/j.jasms.2008.08.021 PG 4 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 402HJ UT WOS:000263004500002 PM 18835725 ER PT J AU Olson, MT Yergey, AL AF Olson, Matthew T. Yergey, Alfred L. TI Calculation of the Isotope Cluster for Polypeptides by Probability Grouping SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID RESONANCE MASS-SPECTROMETRY; FOURIER-TRANSFORM; ABUNDANCE CALCULATIONS; DISTRIBUTIONS; SPECTRA; DECONVOLUTION; PROTEOMICS; REDUCTION; PATTERNS; PEAKS AB This paper presents a novel theoretical basis for accurately calculating the isotope cluster of polypeptides. In contrast to previous approaches to this problem, which consider exhaustive or near exhaustive combinations of isotopic species, the program, Neutron Cluster, groups probabilities to yield highly accurate information without elucidating any fine structure within a nominal mass unit. This is a fundamental difference from any previously described algorithm for calculating the isotope cluster. As a result of this difference, the accurate isotope clusters for high molecular weight polypeptides can be calculated rapidly without any pruning. When applied to isotope enriched polypeptides, the algorithm introduces "grouping error", which is described, quantified, and avoided by using probability partitioning. 0 Am Soc Mass Spectrom 2009, 20, 295-302) (C) 2009 Published by Elsevier Inc. on behalf of American Society for Mass Spectrometry C1 [Olson, Matthew T.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. [Olson, Matthew T.; Yergey, Alfred L.] NICHHD, Sect Metab & Mass Spectrometry, NIH, Baltimore, MD USA. RP Olson, MT (reprint author), Johns Hopkins Med Inst, Dept Pathol, Carnegie 400,600 N Wolfe St, Baltimore, MD 21287 USA. EM Molson8@jhmi.edu FU National Institute of Child Health and Human Development FX The authors acknowledge support for this research by the Intramural Research Program of the National Institute of Child Health and Human Development. The authors gratefully acknowledge the helpful comments and discussion of Jonathan A. Epstein (OSD/NICHD/NIH). NR 27 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD FEB PY 2009 VL 20 IS 2 BP 295 EP 302 DI 10.1016/j.jasms.2008.10.007 PG 8 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 402HJ UT WOS:000263004500015 PM 19026561 ER PT J AU Sanchez-Nino, MD Sanz, AB Ihalmo, P Lassila, M Holthofer, H Mezzano, S Aros, C Groop, PH Saleem, MA Mathieson, PW Langham, R Kretzler, M Nair, V Lemley, KV Nelson, RG Mervaala, E Mattinzoli, D Rastaldi, MP Ruiz-Ortega, M Martin-Ventura, JL Egido, J Ortiz, A AF Dolores Sanchez-Nino, Maria Belen Sanz, Ana Ihalmo, Pekka Lassila, Markus Holthofer, Harry Mezzano, Sergio Aros, Claudio Groop, Per-Henrik Saleem, Moin A. Mathieson, Peter W. Langham, Robert Kretzler, Matthias Nair, Viji Lemley, Kevin V. Nelson, Robert G. Mervaala, Eero Mattinzoli, Deborah Rastaldi, Maria Pia Ruiz-Ortega, Marta Luis Martin-Ventura, Jose Egido, Jesus Ortiz, Alberto TI The MIF Receptor CD74 in Diabetic Podocyte Injury SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MIGRATION INHIBITORY FACTOR; TUBULAR EPITHELIAL-CELLS; ACTIVATED PROTEIN-KINASES; PROGRESSIVE RENAL INJURY; HUMAN GLOMERULONEPHRITIS; NEPHROPATHY; EXPRESSION; P38; APOPTOSIS; INTERFERON AB Although metabolic derangement plays a central role in diabetic nephropathy, a better understanding of secondary mediators of injury may lead to new therapeutic strategies. Expression of macrophage migration inhibitory factor (MIF) is increased in experimental diabetic nephropathy, and increased tubulointerstitial mRNA expression of its receptor, CD74, has been observed in human diabetic nephropathy. Whether CD74 transduces MIF signals in podocytes, however, is unknown. Here, we found glomerular and tubulointerstitial CD74 mRNA expression to be increased in Pima Indians with type 2 diabetes and diabetic nephropathy. Immunohistochemistry confirmed the increased glomerular and tubular expression of CD74 in clinical and experimental diabetic nephropathy and localized glomerular CD74 to podocytes. In cultured human podocytes, CD74 was expressed at the cell surface, was upregulated by high concentrations of glucose and TNF-alpha, and was activated by MIF, leading to phosphorylation of extracellular signal-regulated kinase 1/2 and p38. High glucose also induced CD74 expression in a human proximal tubule cell line (HK2). In addition, MIF induced the expression of the inflammatory mediators TRAIL and monocyte chemoattractant protein 1 in podocytes and HK2 cells in a p38-dependent manner. These data suggest that CD74 acts as a receptor for MIF in podocytes and may play a role in the pathogenesis of diabetic nephropathy. C1 [Dolores Sanchez-Nino, Maria; Belen Sanz, Ana; Ruiz-Ortega, Marta; Luis Martin-Ventura, Jose; Egido, Jesus; Ortiz, Alberto] Univ Autonoma Madrid, Fdn Jimenez Diaz, Fdn Renal Inigo Alvarez de Toledo, Madrid 28040, Spain. [Ihalmo, Pekka; Groop, Per-Henrik] Univ Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Ihalmo, Pekka; Groop, Per-Henrik] Univ Helsinki, Cent Hosp, Dept Med, Div Nephrol, Helsinki, Finland. [Lassila, Markus] Univ Helsinki, Haartman Inst, Dept Bacteriol & Immunol, FIN-00014 Helsinki, Finland. [Holthofer, Harry] Dublin City Univ, Ctr Bioanalyt Sci, Dublin 9, Ireland. [Mezzano, Sergio; Aros, Claudio] Univ Austral Chile, Div Nephrol, Valdivia, Chile. [Saleem, Moin A.; Mathieson, Peter W.] Univ Bristol, Acad & Childrens Renal Unit, Bristol, Avon, England. [Langham, Robert] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic 3010, Australia. [Kretzler, Matthias; Nair, Viji] Univ Michigan, Div Nephrol, Ann Arbor, MI 48109 USA. [Lemley, Kevin V.] Childrens Hosp Los Angeles, Div Nephrol, Los Angeles, CA 90027 USA. [Nelson, Robert G.] NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. [Mervaala, Eero] Univ Helsinki, Inst Biomed Pharmacol, FIN-00014 Helsinki, Finland. [Mattinzoli, Deborah; Rastaldi, Maria Pia] Fdn DAmico Ric Malattie Renali, Milan, Italy. RP Ortiz, A (reprint author), Univ Autonoma Madrid, Fdn Jimenez Diaz, Fdn Renal Inigo Alvarez de Toledo, Avda Reyes Catolicos 2, Madrid 28040, Spain. EM aortiz@fjd.es RI Nelson, Robert/B-1470-2012; Ruiz-Ortega, Marta/D-3584-2012; OI Ruiz-Ortega, Marta/0000-0002-1495-6535; Sanchez-Nino, Maria Dolores/0000-0001-7110-6409; ruiz-ortega, marta/0000-0002-1403-2690 FU ADDNET [FIS 06/0046, SAF03/884, LSHB-CT-2004-6]; DIALOK [LSHB-CT-2007-036644]; Sociedad Espanola de Nefrologia; ISCIII-RETIC [REDinREN/RD06/0016]; Comunidad de Madrid [FRACM/S-BIO0283/2006]; National Institute of Diabetes and Digestive and Kidney Diseases FX This Study was Supported by grant FIS 06/0046, SAF03/884, LSHB-CT-2004-6 (ADDNET), LSHB-CT-2007-036644 (DIALOK), Sociedad Espanola de Nefrologia, ISCIII-RETIC REDinREN/RD06/0016, and Comunidad de Madrid/FRACM/S-BIO0283/2006. Salary support was provided by FIS to A.B.S., MEC to M.D.S.N., Programa Intensificacion Actividad Investigadora (ISCIII/Agencia LainEntralgo/CM) to A.O., and the Finnish Kidney Foundation and the Kyllikki and Uolevi Lehikoinen Foundation for P.I. Fondecyt 1080083 to S.M. This research was supported, in part, by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases.; Anneli von Behr is acknowledged for technical assistance and Mar Gonzalez Garcia-Parreno and Alberto Puime for technical help. NR 33 TC 62 Z9 65 U1 3 U2 6 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2009 VL 20 IS 2 BP 353 EP 362 DI 10.1681/ASN.2008020194 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 406HE UT WOS:000263284800018 PM 18842989 ER PT J AU Gonzales, PA Pisitkun, T Hoffert, JD Tchapyjnikov, D Star, RA Kleta, R Wang, NS Knepper, MA AF Gonzales, Patricia A. Pisitkun, Trairak Hoffert, Jason D. Tchapyjnikov, Dmitry Star, Robert A. Kleta, Robert Wang, Nam Sun Knepper, Mark A. TI Large-Scale Proteomics and Phosphoproteomics of Urinary Exosomes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID TANDEM MASS-SPECTRA; VACUOLAR H+-ATPASE; PHOSPHORYLATION ANALYSIS; HYPOKALEMIC ALKALOSIS; COTRANSPORTER NKCC2; BARTTERS-SYNDROME; CL COTRANSPORTER; IDENTIFICATION; BIOMARKERS; PHYSIOLOGY AB Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular bodies from every renal epithelial cell type facing the urinary space. Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. Overall, the analysis identified 1132 proteins unambiguously, including 177 that are represented on the Online Mendelian Inheritance in Man database of disease-related genes, suggesting that exosome analysis is a potential approach to discover urinary biomarkers. We extended the proteomic analysis to phospho-proteomic profiling using neutral loss scanning, and this yielded multiple novel phosphorylation sites, including serine-811 in the thiazide-sensitive Na-Cl co-transporter, NCC. To demonstrate the potential use of exosome analysis to identify a genetic renal disease, we carried out immunoblotting of exosomes from urine samples of patients with a clinical diagnosis of Bartter syndrome type 1, showing an absence of the sodium-potassium-chloride co-transporter 2, NKCC2. The proteomic data are publicly accessible at http://dir.nhlbi.nih.gov/papers/lkem/exosome/. C1 [Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. [Star, Robert A.] NIDDK, Renal Diagnost & Therapeut Unit, Bethesda, MD USA. [Kleta, Robert] NHGRI, Sect Human Biomed Genet, Med Genet Branch, Bethesda, MD 20892 USA. [Kleta, Robert] NIH, Off Rare Dis, Off Director, Bethesda, MD USA. [Gonzales, Patricia A.; Wang, Nam Sun] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. [Kleta, Robert] UCL, Ctr Nephrol, London Epithelial Grp, London, England. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,MSC-1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov RI Wang, Nam Sun/E-4253-2016; OI Pisitkun, Trairak/0000-0001-6677-2271 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 28 TC 242 Z9 250 U1 8 U2 46 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2009 VL 20 IS 2 BP 363 EP 379 DI 10.1681/ASN.2008040406 PG 17 WC Urology & Nephrology SC Urology & Nephrology GA 406HE UT WOS:000263284800019 PM 19056867 ER PT J AU Vines, AI Baird, DD AF Vines, Anissa I. Baird, Donna D. TI Stress of Caring for Children: The Role of Perceived Racism SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE race/ethnicity; racism; children/adolescents ID AFRICAN-AMERICAN; MENTAL-HEALTH; DISCRIMINATION; WOMEN; RACE; SOCIALIZATION; EXPERIENCES AB Purpose: Regardless of race, most mothers experience stress related to concerns about their children. African American mothers may experience the additional stress of their child(ren) experiencing racism. We describe the stress that African American women have about their children experiencing racism. Methods: The Telephone-Ad ministered Perceived Racism Scale (TPRS) was administered to 476 African American women ages 36 to 53 who were members of a prepaid health plan. The 8-item Concern for Children scale, I of the 5 TPRS scales, was completed by 382 women and assessed the level of concern women have about their children experiencing racism. The responses ranged from "not at all concerned" to "very concerned." Results: For 6 of the 8 items, more than 60% reported being "very concerned" for their children. Items of highest concern involved institutionalized racism with more than 70% reported being very concerned about their children being harmed or harassed by the police or getting stopped in a predominantly white neighborhood. Respondents were less concerned about their children being considered less attractive than their white counterparts and/or being excluded from social events, activities, or groups. Level of concern was not related to income or education. Unsurprisingly, respondents who reported high levels of perceived racism also reported greater concern for their child(ren). Conclusions: These findings highlight an additional stressor related to childrearing in a "race-conscious" society. Future research on stress and African American women's health should include this additional stressor. C1 [Vines, Anissa I.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Vines, Anissa I.] Ethn Culture & Hlth Outcomes ECHO Program, Chapel Hill, NC USA. [Baird, Donna D.] Natl Inst Environm Hlth Sci, Dept Epidemiol, Res Triangle Pk, NC USA. RP Vines, AI (reprint author), Univ N Carolina, 266 Rosenau Hall,CB 7435, Chapel Hill, NC 27599 USA. EM avines@email.unc.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU University of North Carolina; National Institute of Child Health and Human Development; National Institutes of Health Office of the Director; Office of Research on Women's Health; National Institute of Environmental Health Sciences (NIEHS); National Institute of Mental Health [1-RO3-MH61057] FX The final preparation of this article was supported in part by the University of North Carolina at Chapel Hill K 12 Building Interdisciplinary Careers in Women's Health Research program funded by the National Institute of Child Health and Human Development, the National Institutes of Health Office of the Director, Office of Research on Women's Health and the National Institute of Environmental Health Sciences (NIEHS). The conceptualization of the study, data collection, and analyses for this project were supported by the Intramural Research Training Program at the NIEHS and by the National Institute of Mental Health (grant 1-RO3-MH61057 to A.I.V.). NR 16 TC 3 Z9 3 U1 2 U2 6 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD FEB PY 2009 VL 101 IS 2 BP 156 EP 160 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 425XW UT WOS:000264672300010 PM 19378633 ER PT J AU Jackson, WM Aragon, AB Djouad, F Song, Y Koehler, SM Nesti, LJ Tuan, RS AF Jackson, W. M. Aragon, A. B. Djouad, F. Song, Y. Koehler, S. M. Nesti, L. J. Tuan, R. S. TI Mesenchymal progenitor cells derived from traumatized human muscle SO JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE LA English DT Article DE mesenchymal stem cells; multipotent progenitor cells; muscle stem cells; heterotopic ossification; regenerative medicine; orthopaedic trauma ID HUMAN BONE-MARROW; HUMAN TRABECULAR BONE; HUMAN SYNOVIAL-MEMBRANE; ADULT STEM-CELLS; STROMAL CELLS; HETEROTOPIC OSSIFICATION; IN-VITRO; UMBILICAL-CORD; DIFFERENTIATION; TISSUE AB Mesenchymal stem cells (MSCs) derived from adult tissues are an important candidate cell type for cell-based tissue engineering and regenerative medicine. Currently, clinical applications for MSCs require additional surgical procedures to harvest the autologous MSCs (i.e. from bone marrow) or commercial allogeneic alternatives. We have recently identified a population of mesenchymal progenitor cells (MPCs) in traumatized muscle tissue that has been surgically debrided from traumatic orthopaedic extremity wounds. The purpose of this study was to evaluate whether MPCs derived from traumatized muscle may provide a clinical alternative to bone-marrow MSCs, by comparing their morphology, proliferation capacity, cell surface epitope profile and differentiation capacity. After digesting the muscle tissue with collagenase, the MPCs were enriched by a direct plating technique. The morphology and proliferation rate of the muscle-derived MPCs was similar to bone-marrow derived MSCs. Both populations expressed cell surface markers characteristic for MSCs (CD 73, CD 90 and CD105), and did not express markers typically absent on MSCs (CD14, CD34 and CD45). After 21 days in specific differentiation media, the histological staining and gene expression of the MPCs and MSCs was characteristic for differentiation into osteoblasts, chondrocytes and adipocytes, but not into myoblasts. Our findings demonstrate that traumatized muscle-derived MPCs exhibit a similar phenotype and resemble MSCs derived from the bone marrow. MPCs harvested from traumatized muscle tissue may be considered for applications in tissue engineering and regenerative medicine following orthopaedic trauma requiring circumferential debridement. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Jackson, W. M.; Aragon, A. B.; Djouad, F.; Song, Y.; Koehler, S. M.; Nesti, L. J.; Tuan, R. S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Aragon, A. B.; Nesti, L. J.] Walter Reed Army Med Ctr, Integrated Dept Orthopaed & Rehabil, Washington, DC 20307 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, 50 S Dr,Room 1140,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov OI Djouad, Farida/0000-0001-8248-6822 FU WRAMC [P05-A011]; NIH NIAMS Intramural Research Program [Z01 AR41131] FX This study was supported by the Military Amputee Research Program at WRAMC (Grant No. P05-A011) and the NIH NIAMS Intramural Research Program (Grant No. Z01 AR41131). FACS data were collected at the NIAMS Flow Cytometry Section with the expert assistance of Jim Simone. Portions of this work were performed at the Naval Surgical Research laboratory in the National Naval Medical Center. The authors would like to thank Michael K. Sracic and James R. Bailey for their assistance in performing the differentiation experiments in this study. NR 53 TC 40 Z9 44 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1932-6254 J9 J TISSUE ENG REGEN M JI J. Tissue Eng. Regen. Med. PD FEB PY 2009 VL 3 IS 2 BP 129 EP 138 DI 10.1002/term.149 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Engineering, Biomedical SC Cell Biology; Biotechnology & Applied Microbiology; Engineering GA 421VA UT WOS:000264385200008 PM 19170141 ER PT J AU Lockenhoff, CE Terracciano, A Patriciu, NS Eaton, WW Costa, PT AF Loeckenhoff, Corinna E. Terracciano, Antonio Patriciu, Nicholas S. Eaton, William W. Costa, Paul T., Jr. TI Self-Reported Extremely Adverse Life Events and Longitudinal Changes in Five-Factor Model Personality Traits in an Urban Sample SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; EPIDEMIOLOGIC CATCHMENT-AREA; YOUNG ADULTHOOD; NEO-PI; TEMPORAL STABILITY; MAJOR DEPRESSION; TRAUMATIC EVENTS; WORK EXPERIENCES; FOLLOW-UP; PREDICTORS AB This study examined longitudinal personality change in response to extremely adverse life events in a sample (N= 458) drawn from the First Baltimore Epidemiologic Catchment Area study Five factor model personality traits were assessed twice over art average interval of 8 years. Twenty-five percent of the participants reported air extremely horrifying or frightening event within 2 years before the second personality assessment. Relative to the rest of the sample, they showed increases in neuroticism, decreases in tire compliance facet of agreeableness, and decreases in openness to values. Baseline personality was unrelated to future events, but among participants who reported extreme events, lower extraversion and/or conscientiousness at baseline as well as longitudinal increases in neuroticism predicted lower mental health at follow-up. C1 [Loeckenhoff, Corinna E.; Terracciano, Antonio; Patriciu, Nicholas S.; Costa, Paul T., Jr.] NIA, Lab Personal & Cognit, NIH, DHHS, Baltimore, MD 21224 USA. [Eaton, William W.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. RP Lockenhoff, CE (reprint author), NIA, NIH, Biomed Res Ctr, IRR 251 Bayview Blvd,Suite 100,Room 04B323, Baltimore, MD 21224 USA. EM Loeckenhoff@gmail.com RI terracciano, antonio/B-1884-2008; OI Loeckenhoff, Corinna/0000-0003-1605-1323; Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000197-03, ZIA AG000197-04]; NIDA NIH HHS [R01 DA026652, R01 DA026652-16A1]; NIMH NIH HHS [K23 MH064543, MH 47447, MH 50616, MH64543, R01 MH047447, R01 MH047447-15, R01 MH050616] NR 43 TC 50 Z9 51 U1 7 U2 20 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD FEB PY 2009 VL 22 IS 1 BP 53 EP 59 DI 10.1002/jts.20385 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 414TQ UT WOS:000263888500008 PM 19230009 ER PT J AU Robinson, JM Shavers, V AF Robinson, J. M. Shavers, V. TI The Role of Health Insurance Coverage in Cancer Screening Utilization SO JOURNAL OF UROLOGY LA English DT Article C1 [Robinson, J. M.] NCI, Canc Prevent & Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. NCI, Off Educ & Special Initiat, Bethesda, MD 20892 USA. RP Robinson, JM (reprint author), NCI, Canc Prevent & Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. 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 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2009 VL 181 IS 2 BP 793 EP 793 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 394BJ UT WOS:000262419900179 ER PT J AU Duda, A Lee-Turner, L Fox, J Robinson, N Dustan, S Kaye, S Fryer, H Carrington, M McClure, M Mclean, AR Fidler, S Weber, J Phillips, RE Frater, AJ AF Duda, A. Lee-Turner, L. Fox, J. Robinson, N. Dustan, S. Kaye, S. Fryer, H. Carrington, M. McClure, M. Mclean, A. R. Fidler, S. Weber, J. Phillips, R. E. Frater, A. J. CA SPARTAC Trail Investigators TI HLA-Associated Clinical Progression Correlates with Epitope Reversion Rates in Early Human Immunodeficiency Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL RESPONSES; PRIMARY HIV-INFECTION; IN-VIVO; LYMPHOCYTE RESPONSES; VIRAL LOAD; DISEASE PROGRESSION; IMMUNE-RESPONSES; TYPE-1; ESCAPE; AIDS AB Human immunodeficiency virus type 1 (HIV-1) can evade immunity shortly after transmission to a new host but the clinical significance of this early viral adaptation in HIV infection is not clear. We present an analysis of sequence variation from a longitudinal cohort study of HIV adaptation in 189 acute seroconverters followed for up to 3 years. We measured the rates of variation within well-defined epitopes to determine associations with the HLA-linked hazard of disease progression. We found early reversion across both the gag and pol genes, with a 10-fold faster rate of escape in gag (2.2 versus 0.27 forward mutations/1,000 amino acid sites). For most epitopes (23/34), variation in the HLA-matched and HLA-unmatched controls was similar. For a minority of epitopes (8/34, and generally associated with HLA class I alleles that confer clinical benefit), new variants appeared early and consistently over the first 3 years of infection. Reversion occurred early at a rate which was HLA-dependent and correlated with the HLA class 1-associated relative hazard of disease progression and death (P = 0.0008), reinforcing the association between strong cytotoxic T-lymphocyte responses, viral fitness, and disease status. These data provide a comprehensive overview of viral adaptation in the first 3 years of infection. Our findings of HLA-dependent reversion suggest that costs are borne by some escape variants which may benefit the host, a finding contrary to a simple immune evasion paradigm. These epitopes, which are both strongly and frequently recognized, and for which escape involves a high cost to the virus, have the potential to optimize vaccine design. C1 [Duda, A.; Lee-Turner, L.; Robinson, N.; Phillips, R. E.; Frater, A. J.] Univ Oxford, Nuffield Dept Clin Med, Oxford OX1 3SY, England. [Duda, A.; Lee-Turner, L.; Robinson, N.; Fryer, H.; Mclean, A. R.; Phillips, R. E.; Frater, A. J.] James Martin 21st Century Sch, Oxford OX1 3SY, England. [Fox, J.; Dustan, S.; Kaye, S.; McClure, M.; Fidler, S.; Weber, J.] Univ London Imperial Coll Sci Technol & Med, Div Med, Wright Fleming Inst, St Marys Hosp, London W2 1PG, England. [Fryer, H.; Mclean, A. R.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Carrington, M.] NCI, Basic Res Program, SAIC Frederick, Lab Genom Div, Frederick, MD 21701 USA. RP Phillips, RE (reprint author), Dept Clin Med, Peter Medawar Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. EM rodney.phillips@ndm.ox.ac.uk RI Beral, Valerie/B-2979-2013; OI Frater, John/0000-0001-7163-7277 FU Wellcome Trust (United Kingdom) FX A. D. and J. F. are supported by the MRC. J.W. and R.E.P. are supported by the Wellcome Trust (United Kingdom). NR 47 TC 32 Z9 32 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 1 PY 2009 VL 83 IS 3 BP 1228 EP 1239 DI 10.1128/JVI.01545-08 PG 12 WC Virology SC Virology GA 392TR UT WOS:000262325600007 PM 19019964 ER PT J AU Davis, KL Bibollet-Ruche, F Li, H Decker, JM Kutsch, O Morris, L Salomon, A Pinter, A Hoxie, JA Hahn, BH Kwong, PD Shaw, GM AF Davis, Katie L. Bibollet-Ruche, Frederic Li, Hui Decker, Julie M. Kutsch, Olaf Morris, Lynn Salomon, Aidy Pinter, Abraham Hoxie, James A. Hahn, Beatrice H. Kwong, Peter D. Shaw, George M. TI Human Immunodeficiency Virus Type 2 (HIV-2)/HIV-1 Envelope Chimeras Detect High Titers of Broadly Reactive HIV-1 V3-Specific Antibodies in Human Plasma SO JOURNAL OF VIROLOGY LA English DT Review ID HUMAN MONOCLONAL-ANTIBODIES; CORECEPTOR-BINDING-SITE; PRINCIPAL NEUTRALIZING DOMAIN; EPITOPE FINE SPECIFICITY; SUBTYPE-C INFECTION; V3 LOOP; SOLUBLE CD4; CROSS-REACTIVITY; VACCINE DESIGN; CRYPTIC NATURE AB Deciphering antibody specificities that constrain human immunodeficiency virus type 1 (HIV-1) envelope (Env) diversity, limit virus replication, and contribute to neutralization breadth and potency is an important goal of current HIV/AIDS vaccine research. Transplantation of discrete HIV-1 neutralizing epitopes into HIV-2 scaffolds may provide a sensitive, biologically functional context by which to quantify specific antibody reactivities even in complex sera. Here, we describe a novel HIV-2 proviral scaffold (pHIV-2(KR.X7)) into which we substituted the complete variable region 3 (V3) of the env gene of HIV-1(YU2) or HIV-1(Ccon) to yield the chimeric proviruses pHIV-2(KR.X7) YU2 V3 and pHIV-2(KR.X7) Ccon V3. These HIV-2/HIV-1 chimeras were replication competent and sensitive to selective pharmacological inhibitors of virus entry. V3 chimeric viruses were resistant to neutralization by HIV-1 monoclonal antibodies directed against the CD4 binding site, coreceptor binding site, and gp41 membrane proximal external region but exhibited striking sensitivity to HIV-1 V3-specific monoclonal antibodies, 447-52D and F425 B4e8 (50% inhibitory concentration of [IC(50)] <0.005 mu g/ml for each). Plasma specimens from 11 HIV-1 clade B- and 10 HIV-1 clade C-infected subjects showed no neutralizing activity against HIV-2 but exhibited high-titer V3-specific neutralization against both HIV-2/HIV-1 V3 chimeras with IC(50) measurements ranging from 1: 50 to greater than 1:40,000. Neutralization titers of B clade plasmas were as much as 1,000-fold lower when tested against the primary HIV-1(YU2) virus than with the HIV-2(KR.X7) YU2 V3 chimera, demonstrating highly effective shielding of V3 epitopes in the native Env trimer. This finding was replicated using a second primary HIV-1 strain (HIV-1(BORI)) and the corresponding HIV-2(KR.X7) BORI V3 chimera. We conclude that V3 is highly immunogenic in vivo, eliciting antibodies with substantial breadth of reactivity and neutralizing potential. These antibodies constrain HIV-1 Env to a structure(s) in which V3 epitopes are concealed prior to CD4 engagement but do not otherwise contribute to neutralization breadth and potency against most primary virus strains. Triggering of the viral spike to reveal V3 epitopes may be required if V3 immunogens are to be components of an effective HIV-1 vaccine. C1 [Davis, Katie L.; Kutsch, Olaf; Hahn, Beatrice H.; Shaw, George M.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Bibollet-Ruche, Frederic; Li, Hui; Decker, Julie M.; Kutsch, Olaf; Hahn, Beatrice H.; Shaw, George M.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Morris, Lynn] Natl Inst Communicable Dis, AIDS Virus Res Unit, Johannesburg, South Africa. [Salomon, Aidy; Pinter, Abraham] Publ Hlth Res Inst, Newark, NJ 07103 USA. [Salomon, Aidy; Pinter, Abraham] Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. [Hoxie, James A.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Kwong, Peter D.] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Shaw, GM (reprint author), Univ Alabama, Dept Med, 720 20th St S, Birmingham, AL 35294 USA. EM gshaw@uab.edu OI , Lynn/0000-0003-3961-7828 FU Bill and Melinda Gates Foundation [37874, 38619, 38631]; NIH [AI 67854, AI 27767, AI 46238] FX This work was supported by grants from the Bill and Melinda Gates Foundation (37874, 38619, and 38631) and the NIH (AI 67854, AI 27767, and AI 46238). NR 108 TC 43 Z9 43 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 1 PY 2009 VL 83 IS 3 BP 1240 EP 1259 DI 10.1128/JVI.01743-08 PG 20 WC Virology SC Virology GA 392TR UT WOS:000262325600008 PM 19019969 ER PT J AU Chen, Z DeSalle, R Schiffman, M Herrero, R Burk, RD AF Chen, Zigui DeSalle, Rob Schiffman, Mark Herrero, Rolando Burk, Robert D. TI Evolutionary Dynamics of Variant Genomes of Human Papillomavirus Types 18, 45, and 97 SO JOURNAL OF VIROLOGY LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; GENITAL HUMAN-PAPILLOMAVIRUS; GRADE CERVICAL LESIONS; VIRUS-POSITIVE WOMEN; AMINO-ACID SITES; DIVERSIFYING SELECTION; WORLDWIDE PERSPECTIVE; PHYLOGENETIC ANALYSIS; NATURAL-HISTORY; OVERLAPPING PCR AB Human papillomavirus type 18 (HPV18) and HPV45 account for approximately 20% of all cervix cancers. We show that HPV18, HPV45, and the recently discovered HPV97 comprise a clade sharing a most recent common ancestor within HPV alpha 7 species. Variant lineages of these HPV types were classified by sequence analysis of the upstream regulatory region/E6 region among cervical samples from a population-based study in Costa Rica, and 27 representative genomes from each major variant lineage were sequenced. Nucleotide variation within HPV18 and HPV45 was 3.82% and 2.39%, respectively, and amino acid variation was 4.73% and 2.87%, respectively. Only 18 nucleotide variations, of which 10 were nonsynonymous, were identified among three HPV97 genomes. Full-genome comparisons revealed maximal diversity between HPV18 African and non-African variants (2.6% dissimilarity), whereas HPV18 Asian-American [E1 (AA)] and European (E2) variants were closely related ( less than 0.5% dissimilarity); HPV45 genomes had a maximal difference of 1.6% nucleotides. Using a Bayesian Markov chain Monte Carlo (MCMC) method, the divergence times of HPV18, -45, and -97 from their most recent common ancestors indicated that HPV18 diverged approximately 7.7 million years (Myr) ago, whereas HPV45 and HPV97 split off around 5.7 Myr ago, in a period encompassing the divergence of the great ape species. Variants within the HPV18/45/97 lineages were estimated to have diverged from their common ancestors in the genus Homo within the last 1 Myr (<0.7 Myr). To investigate the molecular basis of HPV18, HPV45, and HPV97 evolution, regression models of codon substitution were used to identify lineages and amino acid sites under selective pressure. The E5 open reading frame (ORF) of HPV18 and the E4 ORFs of HPV18, HPV45, and HPV18/45/97 had nonsynonymous/ synonymous substitution rate ratios (dN/dS) over 1 indicative of positive Darwinian selection. The L1 ORF of HPV18 genomes had an increased proportion of nonsynonymous substitutions (4.93%; average dN/dS ratio [M3] = 0.3356) compared to HPV45 (1.86%; M3 = 0.1268) and HPV16 (2.26%; M3 = 0.1330) L1 ORFs. In contrast, HPV18 and HPV16 genomes had similar amino acid substitution rates within the E1 ORF (2.89% and 3.24%, respectively), while HPV45 E1 was highly conserved (amino acid substitution rate was 0.77%). These data provide an evolutionary history of this medically important clade of HPVs and identify an unexpected divergence of the L1 gene of HPV18 that may have clinical implications for the long-term use of an L1-virus-like particle-based prophylactic vaccine. C1 [Chen, Zigui; Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Burk, Robert D.] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. [DeSalle, Rob] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD USA. [Herrero, Rolando] Costa Rica Fdn Hlth Sci, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Burk, Robert D.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womans Hlth, Bronx, NY 10461 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. RP Burk, RD (reprint author), Albert Einstein Coll Med, Dept Microbiol & Immunol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM burk@aecom.yu.edu RI Chen, Zigui/E-8490-2017 FU National Cancer Institute [CA78527] FX This work was supported in part by Public Health Service award CA78527 from the National Cancer Institute. R. D. thanks the Louis and Dorothy Cullman Program in Molecular Systematics at the American Museum of Natural History for support. NR 51 TC 45 Z9 48 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 1 PY 2009 VL 83 IS 3 BP 1443 EP 1455 DI 10.1128/JVI.02068-08 PG 13 WC Virology SC Virology GA 392TR UT WOS:000262325600027 PM 19036820 ER PT J AU Mason, RD Alcantara, S Peut, V Loh, L Lifson, JD De Rose, R Kent, SJ AF Mason, Rosemarie D. Alcantara, Sheilajen Peut, Viv Loh, Liyen Lifson, Jeffrey D. De Rose, Robert Kent, Stephen J. TI Inactivated Simian Immunodeficiency Virus-Pulsed Autologous Fresh Blood Cells as an Immunotherapy Strategy SO JOURNAL OF VIROLOGY LA English DT Article ID CD8(+) T-CELLS; DENDRITIC CELLS; FUNCTIONAL IMPAIRMENT; PROTECTIVE EFFICACY; VIRAL LOAD; VACCINE; RESPONSES; HIV; MACAQUES; INFECTION AB Practical immunotherapies for human immunodeficiency virus infection are needed. We evaluated inactivated simian immunodeficiency virus (SIV) pulsed onto fresh peripheral blood mononuclear cells in 12 pigtail macaques with chronic SIV(mac251) infection for T-cell immunogenicity in a randomized cross-over design study. The immunotherapy was safe and convincingly induced high levels of SIV-specific CD4(+) T-cell responses ( mean, 5.9% +/- 1.3% of all CD4(+) T cells) and to a lesser extent SIV-specific CD8(+) T-cell responses (mean, 0.7% +/- 0.4%). Responses were primarily directed toward Gag and less frequently toward Env but not Pol or regulatory/accessory SIV proteins. T-cell responses against Gag were generally broad and polyfunctional, with a mean of 2.7 CD4(+) T-cell epitopes mapped per animal and more than half of the SIV Gag-specific CD4(+) T cells expressing three or more effector molecules. The immunogenicity was comparable to that found in previous studies of peptide-pulsed blood cells. Despite the high-level immunogenicity, no reduction in viral load was observed in the chronically viremic macaques. This contrasts with our studies of immunization with peptide- pulsed blood cells during early SIV infection in macaques. Future studies of inactivated virus-pulsed blood cell immunotherapy during early infection of patients receiving antiretroviral therapy are warranted. C1 [Mason, Rosemarie D.; Alcantara, Sheilajen; Peut, Viv; Loh, Liyen; De Rose, Robert; Kent, Stephen J.] Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic 3010, Australia. [Lifson, Jeffrey D.] SAIC Frederick Inc, AIDS & Canc Virus Program, Natl Canc Inst, Frederick, MD 21792 USA. RP Kent, SJ (reprint author), Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic 3010, Australia. EM skent@unimelb.edu.au OI De Rose, Robert/0000-0003-4316-3910; Kent, Stephen/0000-0002-8539-4891 FU Australian Centre for HIV and Hepatitis Research; Canadian Institutes of Health Research; Australian National Health and Medical Research Council; National Cancer Institute; NIH [N01-CO-12400, HHSN266200400088C] FX This work was supported by the Australian Centre for HIV and Hepatitis Research, the Canadian Institutes of Health Research, Australian National Health and Medical Research Council grants, and by the National Cancer Institute, NIH, under contracts N01-CO-12400 and HHSN266200400088C (J.D.L.). NR 34 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 1 PY 2009 VL 83 IS 3 BP 1501 EP 1510 DI 10.1128/JVI.02119-08 PG 10 WC Virology SC Virology GA 392TR UT WOS:000262325600033 PM 19019966 ER PT J AU Schowalter, RM Chang, A Robach, JG Buchholz, UJ Dutch, RE AF Schowalter, Rachel M. Chang, Andres Robach, Jessica G. Buchholz, Ursula J. Dutch, Rebecca Ellis TI Low-pH Triggering of Human Metapneumovirus Fusion: Essential Residues and Importance in Entry SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; VESICULAR STOMATITIS-VIRUS; CLATHRIN-MEDIATED ENDOCYTOSIS; PARAMYXOVIRUS MEMBRANE-FUSION; SMALL HYDROPHOBIC SH; INFLUENZA HEMAGGLUTININ; F-PROTEIN; VERO CELLS; PARAINFLUENZA VIRUS-5; ENVELOPE GLYCOPROTEIN AB Human metapneumovirus (HMPV) is a significant respiratory pathogen classified in the Pneumovirinae subfamily of the paramyxovirus family. Recently, we demonstrated that HMPV F protein-promoted cell-cell fusion is stimulated by exposure to low pH, in contrast to what is observed for other paramyxovirus F proteins. In the present study, we examined the potential role of histidine protonation in HMPV F fusion and investigated the role of low pH in HMPV viral entry. Mutagenesis of the three ectodomain histidine residues of the HMPV F protein demonstrated that the mutation of a histidine in the heptad repeat B linker domain (H435) ablated fusion activity without altering cell surface expression or proteolytic processing significantly. Modeling of the HMPV F protein revealed several basic residues surrounding this histidine residue, and the mutation of these residues also reduced fusion activity. These results suggest that electrostatic repulsion in the heptad repeat B linker region may contribute to the triggering of HMPV F. In addition, we examined the effect of inhibitors of endosomal acidification or endocytosis on the entry of a recombinant green fluorescent protein-expressing HMPV. Interestingly, chemicals that raise the pH of endocytic vesicles resulted in a 30 to 50% decrease in HMPV infection, while the inhibitors of endocytosis reduced infection by as much as 90%. These data suggest that HMPV utilizes an endocytic entry mechanism, in contrast to what has been hypothesized for most paramyxoviruses. In addition, our results indicate that HMPV uses the low pH of the endocytic pathway to enhance infectivity, though the role of low pH likely differs from classically described mechanisms. C1 [Schowalter, Rachel M.; Chang, Andres; Dutch, Rebecca Ellis] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. [Robach, Jessica G.] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. [Buchholz, Ursula J.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Dutch, RE (reprint author), Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Biomed Biol Sci Res Bldg,741 South Limestone, Lexington, KY 40536 USA. EM rdutc2@uky.edu FU Great Rivers affiliate of the American Heart Association [0715355B]; March of Dimes; National Institutes of Health. [1R21AI074783-01] FX This study was supported by predoctoral fellowship 0715355B from the Great Rivers affiliate of the American Heart Association, a research grant from the March of Dimes, and research grant 1R21AI074783-01 from the National Institutes of Health. NR 67 TC 50 Z9 54 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 1 PY 2009 VL 83 IS 3 BP 1511 EP 1522 DI 10.1128/JVI.01381-08 PG 12 WC Virology SC Virology GA 392TR UT WOS:000262325600034 PM 19036821 ER PT J AU Gill, JM Szanton, S Taylor, TJ Page, GG Campbell, JC AF Gill, Jessica M. Szanton, S. Taylor, T. J. Page, G. G. Campbell, J. C. TI Medical Conditions and Symptoms Associated with Posttraumatic Stress Disorder in Low-Income Urban Women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID INTIMATE PARTNER VIOLENCE; ADMINISTERED PTSD SCALE; PRIMARY-CARE PATIENTS; SELF-REPORTED HEALTH; AFRICAN-AMERICANS; ADOLESCENT GIRLS; PHYSICAL HEALTH; SUBSTANCE-ABUSE; TRAUMA EXPOSURE; MENTAL-HEALTH AB Background: Epidemiological studies have consistently reported rates of posttraumatic stress disorder (PTSD) in women that are twice that of men. In men and women, PTSD has been associated with comorbid medical conditions, medical symptoms and lower self-rating of health. In low-income urban women, rates of PTSD are even more elevated than in suburban women and may be related to observed health disparities. Methods: In this study, 250 women seeking healthcare at an urban clinic were interviewed for a PTSD diagnosis, major depressive disorder (MDD), the experience of traumatic events, the experience of current and past common medical conditions and symptoms, and subjective rating of health. A chart review was used to assess healthcare use in the past year. Results: More current (5.2 vs. 3.8, p < 0.05) and past medical conditions (4.6 vs. 3.3, p < 0.05) were reported by women with a lifetime history of PTSD than by women without this history, after controlling for demographics and current depression. Women with lifetime PTSD also had more annual clinic appointments (5.9 vs. 3.8 p < 0.03) and were 2.4 times (p < 0.05) more likely to report lower appraisal of their physical health. Conclusions: These findings suggest that urban health-seeking women with PTSD experience health impairments that may cause increased morbidity and that healthcare providers should consider the health ramifications of PTSD when providing medical care to women. C1 [Gill, Jessica M.; Taylor, T. J.] Natl Inst Nursing Res, NIH, Bethesda, MD USA. [Szanton, S.; Page, G. G.; Campbell, J. C.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. RP Gill, JM (reprint author), Natl Inst Natl Certificate, NIH, 10 Ctr Dr,10-CRC 2-1339, Bethesda, MD 20892 USA. EM gillj@mail.nih.gov FU National Institutes of Health, National Institute of Nursing Research (NINR) [8326927]; Individual National Research Service Award (NRSA) funded through NINR [F31 NR009166]; Institutional Training grant funded through NINR [T32 NR 07968]; Fear Shanon Davies Memorial Grant FX Funding was provided by the National Institutes of Health, National Institute of Nursing Research (NINR) postdoctoral fellowship 8326927; Individual National Research Service Award (NRSA) F31 NR009166 funded through NINR; Institutional Training grant funded through NINR T32 NR 07968; Health Disparities in Underserved Populations; and The Freedom from Fear Shanon Davies Memorial Grant. NR 51 TC 10 Z9 10 U1 4 U2 7 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD FEB PY 2009 VL 18 IS 2 BP 261 EP 267 DI 10.1089/jwh.2008.0914 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 402HE UT WOS:000263004000017 PM 19183098 ER PT J AU Sierra, F AF Sierra, Felipe TI Biology of Aging Summit Report Foreword SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material C1 NIA, Div Aging Biol, NIH, Bethesda, MD 20892 USA. RP Sierra, F (reprint author), NIA, Div Aging Biol, NIH, Bethesda, MD 20892 USA. EM sierraf@nia.nih.gov NR 0 TC 6 Z9 6 U1 0 U2 0 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2009 VL 64 IS 2 BP 155 EP 156 DI 10.1093/gerona/gln069 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 419AB UT WOS:000264190400001 PM 19228781 ER PT J AU Morrell, CH Brant, LJ Ferrucci, L AF Morrell, Christopher H. Brant, Larry J. Ferrucci, Luigi TI Model Choice Can Obscure Results in Longitudinal Studies SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mixed-effects models; Multilevel modeling; Observational study; Recruitment bias; Regression ID MIXED-EFFECTS MODELS; OLDER MEXICAN-AMERICANS; REGRESSION-MODELS; SELECTION BIAS; HIP FRACTURE; DECLINE; DISEASE; WOMEN AB Background. This article examines how different parameterizations of age and time in modeling observational longitudinal data can affect results. Methods. When individuals of different ages at study entry are considered, it becomes necessary to distinguish between longitudinal and cross-sectional differences to overcome possible selection biases. Results. Various models were fitted using data from longitudinal studies with participants with different ages and different follow-up lengths. Decomposing age into two components-age at entry into the study (first age) and the longitudinal follow-up (time) compared with considering age alone-leads to different conclusions. Conclusions. In general, models using both first age and time terms performed better, and these terms are usually necessary to correctly analyze longitudinal data C1 [Morrell, Christopher H.; Brant, Larry J.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Morrell, Christopher H.] Loyola Coll, Dept Math Sci, Baltimore, MD 21210 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Harbor Hosp, Baltimore, MD 21224 USA. RP Brant, LJ (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM larry_brant@nih.gov FU National Institutes of Health; National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging NR 36 TC 28 Z9 28 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2009 VL 64 IS 2 BP 215 EP 222 DI 10.1093/gerona/gln024 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 419AB UT WOS:000264190400017 PM 19196902 ER PT J AU Vasunilashorn, S Coppin, AK Patel, KV Lauretani, F Ferrucci, L Bandinelli, S Guralnik, JM AF Vasunilashorn, Sarinnapha Coppin, Antonia K. Patel, Kushang V. Lauretani, Fulvio Ferrucci, Luigi Bandinelli, Stefania Guralnik, Jack M. TI Use of the Short Physical Performance Battery Score to Predict Loss of Ability to Walk 400 Meters: Analysis From the InCHIANTI Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mobility; 400 m walk; Incidence of disability; Functional limitation; Aging ID LOWER-EXTREMITY FUNCTION; OLDER-ADULTS; MOBILITY LIMITATION; SUBSEQUENT DISABILITY; FUNCTIONAL MOBILITY; OBJECTIVE-MEASURE; ELDERLY PERSONS; RISK-FACTORS; TAI-CHI; EXERCISE AB Background. Early detection of mobility limitations remains an important goal for preventing mobility disability. The purpose of this study was to examine the association between the Short Physical Performance Battery (SPPB) and the loss of ability to walk 400 m, an objectively assessed mobility outcome increasingly used in clinical trials. Methods. The study sample consisted of 542 adults from the InCHIANTI ("Invecchiare in Chianti," aging in Chianti area) study aged 65 and older, who completed the 400 m walk at baseline and had evaluations on the SPPB and 400 m walk at baseline and 3-year follow-up. Multiple logistic regression models were used to determine whether SPPB scores predict the loss of ability to walk 400 m at follow-up among persons able to walk 400 m at baseline. Results. The 3-year incidence of failing the 400 m walk was 15.5%. After adjusting for age, sex, education, body mass index, Mini-Mental State Examination, number of medical conditions, and 400 m walk gait speed at baseline, SPPB score was significantly associated with loss of ability to walk 400 m after 3 years. Participants with SPPB scores of 10 or lower at baseline had significantly higher odds of mobility disability at follow-up ( odds ratio [ OR] = 3.38, 95% confidence interval [ CI]: 1.32-8.65) compared with those who scored 12, with a graded response across the range of SPPB scores ( OR = 26.93, 95% CI: 7.51-96.50; OR = 7.67, 95% CI: 2.26-26.04; OR = 8.28, 95% CI: 3.32-20.67 for SPPB = 7, SPPB 8, and SPPB 9, respectively). Conclusions. The SPPB strongly predicts loss of ability to walk 400 m. Thus, using the SPPB to identify older persons at high risk of lower body functional limitations seems a valid means of recognizing individuals who would benefit most from preventive interventions. C1 [Vasunilashorn, Sarinnapha] Univ So Calif, Davis Sch Gerontol, Los Angeles, CA 90089 USA. [Lauretani, Fulvio] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Lauretani, Fulvio] Tuscany Hlth Reg Agcy, Florence, Italy. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. RP Vasunilashorn, S (reprint author), Univ So Calif, Davis Sch Gerontol, 3715 McClintock Ave, Los Angeles, CA 90089 USA. EM vasunila@usc.edu RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Italian Ministry of Health [ICS 110.1/RS97.71]; National Institutes of Health (NIH); National Institute on Aging [N01-AG-1-2111, T32AG000037-27] FX The InCHIANTI study was supported as a "targeted project" (ICS 110.1/ RS97.71) by the Italian Ministry of Health and in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging ( contract N01-AG-1-2111). This research was supported in part by grants from the National Institute on Aging (T32AG000037-27) and in part by the Intramural Research Program, National Institute on Aging, NIH. Eileen Crimmins and Merril Silverstein provided helpful suggestions on previous drafts of the article. NR 44 TC 74 Z9 76 U1 2 U2 7 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2009 VL 64 IS 2 BP 223 EP 229 DI 10.1093/gerona/gln022 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 419AB UT WOS:000264190400018 PM 19182232 ER PT J AU Viljanen, A Kaprio, J Pyykko, I Sorri, M Pajala, S Kauppinen, M Koskenvuo, M Rantanen, T AF Viljanen, Anne Kaprio, Jaakko Pyykko, Ilmari Sorri, Martti Pajala, Satu Kauppinen, Markku Koskenvuo, Markku Rantanen, Taina TI Hearing as a Predictor of Falls and Postural Balance in Older Female Twins SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Hearing; Postural balance; Fall; Twin study; Heritability; Aging ID ENVIRONMENTAL-INFLUENCES; ELDERLY-PEOPLE; WOMEN; RISK; PERFORMANCE; DYSFUNCTION; POPULATION; NEED; GAIT AB Background. The purpose of the present study was to examine, first, whether hearing acuity predicts falls and whether the potential association is explained by postural balance and, second, to examine whether shared genetic or environmental effects underlie these associations. Methods. Hearing was measured using a clinical audiometer as a part of the Finnish Twin Study on Aging in 103 monozygotic and 114 dizygotic female twin pairs aged 63-76 years. Postural balance was indicated as a center of pressure (COP) movement in semitandem stance, and participants filled in a fall-calendar daily for an average of 345 days after the baseline. Results. Mean hearing acuity (better ear hearing threshold level at 0.5-4 kHz) was 21 dB (standard deviation [SD] 12). Means of the COP velocity moment for the best to the poorest hearing quartiles increased linearly from 40.7 mm(2)/s ( SD 24.4) to 52.8 mm(2)/s (SD 32.0) (p value for the trend = .003). Altogether 199 participants reported 437 falls. Age-adjusted incidence rate ratios (IRRs) for falls, with the best hearing quartile as a reference, were 1.2 (95% confidence interval [CI] = 0.4-3.8) in the second, 4.1 (95% CI = 1.1-15.6) in the third, and 3.4 (95% CI = 1.0-11.4) in the poorest hearing quartiles. Adjustment for COP velocity moment decreased IRRs markedly. Twin analyses showed that the association between hearing acuity and postural balance was not explained by genetic factors in common for these traits. Conclusion. People with poor hearing acuity have a higher risk for falls, which is partially explained by their poorer postural control. Auditory information about environment may be important for safe mobility. C1 [Viljanen, Anne; Kauppinen, Markku; Rantanen, Taina] Univ Jyvaskyla, Finnish Ctr Interdisciplinary Gerontol, Dept Hlth Sci, FIN-40014 Jyvaskyla, Finland. [Kaprio, Jaakko; Koskenvuo, Markku] Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. [Kaprio, Jaakko] Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. [Pyykko, Ilmari] Tampere Univ Hosp, Dept Otorhinolaryngol & Head & Neck Surg, Tampere, Finland. [Sorri, Martti] Univ Oulu, Dept Otorhinolaryngol, Oulu, Finland. [Pajala, Satu] NIA, LEBD, NIH, Bethesda, MD 20892 USA. RP Viljanen, A (reprint author), Univ Jyvaskyla, Finnish Ctr Interdisciplinary Gerontol, Dept Hlth Sci, POB 35 Viveca, FIN-40014 Jyvaskyla, Finland. EM anne.viljanen@sport.jyu.fi RI Kaprio, Jaakko/A-1820-2008; Rantanen, Taina/O-6579-2016; OI Rantanen, Taina/0000-0002-1604-1945; Viljanen, Anne/0000-0002-8428-3604; Kaprio, Jaakko/0000-0002-3716-2455 FU Academy of Finland; Ministry of Education, Finland; GENOMEUTWIN; EU [QLG2-CT-2002-01254] FX This study was funded from grants by the Academy of Finland, the Ministry of Education, Finland, and the GENOMEUTWIN project (EU grant no. QLG2-CT-2002-01254). S. P. was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. We are indebted to all the participants for their commitment to the study. NR 35 TC 53 Z9 56 U1 0 U2 7 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2009 VL 64 IS 2 BP 312 EP 317 DI 10.1093/gerona/gln015 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 419AB UT WOS:000264190400031 PM 19182227 ER PT J AU Moeller, HB Knepper, MA Fenton, RA AF Moeller, Hanne B. Knepper, Mark A. Fenton, Robert A. TI Serine 269 phosphorylated aquaporin-2 is targeted to the apical membrane of collecting duct principal cells SO KIDNEY INTERNATIONAL LA English DT Article DE phosphorylation; vasopressin; endocytosis; exocytosis; immunohistochemistry; aquaporin water channel ID WATER CHANNEL; VASOPRESSIN TREATMENT; EPITHELIAL-CELLS; PLASMA-MEMBRANE; RAT-KIDNEY; AQP2; TRAFFICKING; EXPRESSION; PERMEABILITY; ENDOCYTOSIS AB Trafficking of the water channel aquaporin-2 to the apical plasma membrane of the collecting duct is mediated by arginine vasopressin, rendering the cell permeable to water. We recently identified a novel form of aquaporin-2 that is phosphorylated at serine-269 (pS269-AQP2). Using antibodies specific for this form of the water channel, we detected rat and mouse pS269-AQP2 in the connecting tubule and throughout the collecting duct system. Using confocal immunofluorescence microscopy with organelle-specific markers and immunogold electron microscopy, we found that pS269-AQP2 was found only on the apical plasma membrane of principal cells. In vasopressin-deficient Brattleboro rats, pS269-AQP2 was undetectable but dramatically increased in abundance after these rats were treated with [deamino-Cys-1, d-Arg8] vasopressin (dDAVP). This increase occurred only at the apical plasma membrane, even after long-term dDAVP treatment. Following dDAVP there was a time-dependent redistribution of total aquaporin-2 from predominantly intracellular vesicles to the apical plasma membrane, clathrin-coated vesicles, early endosomal compartments, and lysosomes. However, pS269-AQP2 was found only on the apical plasma membrane at any time. Our results show that S269 phosphorylated aquaporin-2 is exclusively associated with the apical plasma membrane, where it escapes endocytosis to remain at the cell surface. C1 [Moeller, Hanne B.; Fenton, Robert A.] Univ Aarhus, Inst Anat, Water & Salt Res Ctr, DK-8000 Aarhus, Denmark. [Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Fenton, RA (reprint author), Univ Aarhus, Inst Anat, Water & Salt Res Ctr, Bldg 1233, DK-8000 Aarhus, Denmark. EM rofe@ana.au.dk FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21, Z01 HL001285-22, ZIA HL001285-23, ZIA HL001285-24]; NHLBI NIH HHS [Z01 HL001285, Z01-HL001285] NR 27 TC 54 Z9 54 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2009 VL 75 IS 3 BP 295 EP 303 DI 10.1038/ki.2008.505 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 394YP UT WOS:000262489400009 PM 18843259 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD FEB PY 2009 VL 38 IS 2 BP 47 EP 47 DI 10.1038/laban0209-47 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 406KO UT WOS:000263294400005 PM 19165188 ER PT J AU Schnabel, RB Sullivan, LM Levy, D Pencina, M Massaro, JM D'Agostino, RB Newton-Cheh, C Yamamoto, JF Magnani, JW Tadros, TM Kannel, WB Wang, TJ Ellinor, PT Wolf, PA Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Sullivan, Lisa M. Levy, Daniel Pencina, Michael Massaro, Joseph M. D'Agostino, Ralph B., Sr. Newton-Cheh, Christopher Yamamoto, Jennifer F. Magnani, Jared W. Tadros, Thomas M. Kannel, William B. Wang, Thomas J. Ellinor, Patrick T. Wolf, Philip A. Vasan, Ramachandran S. Benjamin, Emelia J. TI Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study SO LANCET LA English DT Article ID OLDER-ADULTS; PHYSICAL-ACTIVITY; PREVENTION; OBESITY; HEALTH; METAANALYSIS; PREVALENCE; PREDICTION; MORTALITY; SURVIVAL AB Background Atrial fibrillation contributes to substantial increases in morbidity and mortality. We aimed to develop a risk score to predict individuals' absolute risk of developing the condition, and to provide a framework for researchers to assess new risk markers. Methods We assessed 4764 participants in the Framingham Heart Study from 8044 examinations (55% women, 45-95 years of age) undertaken between June, 1968, and September, 1987. Thereafter, participants were monitored for the first event of atrial fibrillation for a maximum of 10 years. Multivariable Cox regression identified clinical risk factors associated with development of atrial fibrillation in 10 years. Secondary analyses incorporated routine echocardiographic measurements (5152 participants, 7156 examinations) to reclassify the risk of atrial fibrillation and to assess whether these measurements improved risk prediction. Findings 457 (10%) of the 4764 participants developed atrial fibrillation. Age, sex, body-mass index, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, and heart failure were associated with atrial fibrillation and incorporated in a risk score (p<0.05, except body-mass index p=0.08), clinical model C statistic 0.78 (95% Cl 0.76-0.80). Risk of atrial fibrillation in 10 years varied with age: more than 15% risk was recorded in 53 (1%) participants younger than 65 years, compared with 783 (27%) older than 65 years. Additional incorporation of echocardiographic measurements to enhance the risk prediction model only slightly improved the C statistic from 0.78 (95% CI 0.75-0.80) to 0.79 (0.77-0.82), p=0.005. Echocardiographic measurements did not improve risk reclassification (p=0.18). Interpretation From clinical factors readily accessible in primary care, our risk score could help to identify risk of atrial fibrillation for individuals in the community; assess technologies or markers for improvement of risk prediction, and target high-risk individuals for preventive measures. C1 [Benjamin, Emelia J.] Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA 01702 USA. [Sullivan, Lisa M.; Pencina, Michael; Massaro, Joseph M.; Yamamoto, Jennifer F.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kannel, William B.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Mem Dept Med, Boston, MA 02118 USA. [Levy, Daniel; Massaro, Joseph M.; Tadros, Thomas M.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Evans Mem Dept Med, Boston, MA 02118 USA. [Levy, Daniel; Kannel, William B.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Evans Mem Dept Med, Boston, MA 02118 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Newton-Cheh, Christopher] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Dept Med 2, Mainz, Germany. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM emelia@bu.edu RI Schnabel, Renate/F-6527-2014; OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU US National Institutes of Health (NIH)/National Heart, Lung and Blood Institute [N01-HC-25195]; NIH [HL076784, AG028321, AG029451, HL092577, HL080124, HL077477, HL71039, HL093328, R01 NS 17950, 2K24 HL04334]; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/1-1]; Doris Duke Charitable Foundation Clinical Scientist Development Award [HL080025]; Burroughs Wellcome Fund Career Award for Medical Scientists FX Supported by US National Institutes of Health (NIH)/National Heart, Lung and Blood Institute contract N01-HC-25195 and NIH grants HL076784, AG028321. and AG029451 (E)B) HL092577 (EJB, PTE); HL080124, HL077477, HL71039, and HL093328 (RSV); R01 NS 17950 (PAW). NIH Research Career Award 2K24 HL04334 (RSV); Deutsche Forschungsgemeinschaft (German Research Foundation) Research Fellowship SCHN 1149/1-1 (RBS); HL080025, Doris Duke Charitable Foundation Clinical Scientist Development Award, and Burroughs Wellcome Fund Career Award for Medical Scientists (CN-C). NR 35 TC 395 Z9 408 U1 3 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD FEB-MAR PY 2009 VL 373 IS 9665 BP 739 EP 745 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 412LD UT WOS:000263725400033 PM 19249635 ER PT J AU Hacke, W Furlan, AJ Al-Rawi, Y Davalos, A Fiebach, JB Gruber, F Kaste, M Lipka, LJ Pedraza, S Ringleb, PA Rowley, HA Schneider, D Schwamm, LH Leal, JS Sooehngen, M Teal, PA Wilhelm-Ogunbiyi, K Wintermark, M Warach, S AF Hacke, Werner Furlan, Anthony J. Al-Rawi, Yasir Davalos, Antoni Fiebach, Jochen B. Gruber, Franz Kaste, Markku Lipka, Leslie J. Pedraza, Salvador Ringleb, Peter A. Rowley, Howard A. Schneider, Dietmar Schwamm, Lee H. Leal, Joaquin Serena Soehngen, Mariola Teal, Phil A. Wilhelm-Ogunbiyi, Karin Wintermark, Max Warach, Steven TI Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study SO LANCET NEUROLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; ACUTE HEMISPHERIC STROKE; CONTROLLED-TRIAL; ALTEPLASE; THROMBOLYSIS; ECASS; ATLANTIS; ONSET AB Background Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). Methods In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (11:1) to 90 mu g/kg desmoteplase, 125 mu g/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Findings Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 mu g/kg desmoteplase; 66 received 125 mu g/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 mu g/kg desmoteplase, 36% (24 of 66) for 125 mu g/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 mu g/kg desmoteplase 14.0% (0.5 cm(3)); 125 mu g/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 mu g/kg desmoteplase, 4.5% (3 of 66) for 125 mu g/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% 13 of 571 for 90 mu g/kg desmoteplase; 21% [14 of 66] for 125 mu g/kg desmoteplase; and 6% [4 of 63] for placebo). Interpretation The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. ne high response rate in the placebo group could be explained by the mild strokes recorded (low base-line NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. C1 [Hacke, Werner; Ringleb, Peter A.] Univ Heidelberg, Dept Neurol, D-69120 Heidelberg, Germany. [Furlan, Anthony J.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Neurol Inst, Dept Neurol, Cleveland, OH USA. [Al-Rawi, Yasir] MEGA Pharma Solut FZE, Rak, U Arab Emirates. [Davalos, Antoni] Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurosci, Barcelona, Spain. [Fiebach, Jochen B.] Dept Neurol, Berlin, Germany. [Fiebach, Jochen B.] Berlin Neuroimaging Ctr, Berlin, Germany. [Gruber, Franz] Gen Hosp Linz, Dept Neurol & Psychiat, Neuro ICU, Linz, Austria. [Kaste, Markku] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Lipka, Leslie J.] Forest Labs Inc, Jersey City, NJ USA. [Leal, Joaquin Serena] Hosp Univ Dr Josep Trueta Girona, Dept Neurol, Girona, Spain. [Pedraza, Salvador] Hosp Univ Dr Josep Trueta Girona, Dept Radiol, Girona, Spain. [Rowley, Howard A.] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. [Schneider, Dietmar] Univ Leipzig, Neurol ICU, Leipzig, Germany. [Schneider, Dietmar] Univ Leipzig, Stroke Unit, Leipzig, Germany. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Soehngen, Mariola; Wilhelm-Ogunbiyi, Karin] PAION AG, Aachen, Germany. [Ringleb, Peter A.] Univ British Columbia, Vancouver Gen Hosp, Div Neurol, Vancouver, BC V5Z 1M9, Canada. [Wintermark, Max] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Warach, Steven] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Hacke, W (reprint author), Univ Heidelberg, Dept Neurol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany. EM werner.hacke@med.uni-heidelberg.de OI Ringleb, Peter/0000-0002-5473-8671; Fiebach, Jochen B./0000-0002-7936-6958; Schwamm, Lee/0000-0003-0592-9145; Wintermark, Max/0000-0002-6726-3951; Kaste, Markku/0000-0001-6557-6412 FU PAION Deutschland GmbH; Forest Laboratories FX Funding PAION Deutschland GmbH; Forest Laboratories. NR 18 TC 316 Z9 330 U1 0 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD FEB PY 2009 VL 8 IS 2 BP 141 EP 150 DI 10.1016/S1474-4422(08)70267-9 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 398SO UT WOS:000262752000012 PM 19097942 ER PT J AU Greenberg, SM Vernooij, MW Cordonnier, C Viswanathan, A Salman, RAS Warach, S Launer, LJ Van Buchem, MA Breteler, MMB AF Greenberg, Steven M. Vernooij, Meike W. Cordonnier, Charlotte Viswanathan, Anand Salman, Rustorn Al-Shahi Warach, Steven Launer, Lenore J. Van Buchem, Mark A. Breteler, Monique M. B. CA Microbleed Study Grp TI Cerebral microbleeds: a guide to detection and interpretation SO LANCET NEUROLOGY LA English DT Review ID T2-ASTERISK-WEIGHTED MR-IMAGES; GRADIENT-ECHO MRI; INTRACEREBRAL HEMORRHAGE; AMYLOID ANGIOPATHY; ASYMPTOMATIC MICROBLEEDS; INTRACRANIAL HEMORRHAGE; CAVERNOUS MALFORMATIONS; HEMOSIDERIN SPOTS; LOBAR HEMORRHAGE; RISK-FACTORS AB Cerebral microbleeds (CMBs) are increasingly recognised neuroimaging findings in individuals with cerebrovascular disease and dementia, and in normal ageing. There has been substantial progress in the understanding of CMBs in recent years, particularly in the development of newer MRI methods for the detection of CMBs and the application of these techniques to population-based samples of elderly people. In this Review, we focus on these recent developments and their effects on two main questions: how CMBs are detected, and how CMBs should be interpreted. The number of CMBs detected depends on MRI characteristics, such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength, and image post-processing, emphasising the importance of taking into account MRI technique in the interpretation of study results. Recent investigations with sensitive MRI techniques have indicated a high prevalence of CMBs in community-dwelling elderly people. We propose a procedural guide for identification of CMBs and suggest possible future approaches for elucidating the role of these common lesions as markers for, and contributors to, small-vessel brain disease. C1 [Greenberg, Steven M.; Viswanathan, Anand] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Vernooij, Meike W.] Univ Med Ctr, Erasmus MC, Dept Radiol, Rotterdam, Netherlands. [Vernooij, Meike W.; Breteler, Monique M. B.] Univ Med Ctr, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Cordonnier, Charlotte] Lille Univ Hosp, Dept Neurol, Stroke Dept, Lille, France. [Salman, Rustorn Al-Shahi] Univ Edinburgh, Western Gen Hosp, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Warach, Steven] Natl Inst Neurol Disorders & Stroke, Stroke Branch, Bethesda, MD USA. [Launer, Lenore J.] NIA, Lab Epidemiol Biometry & Demog, Bethesda, MD 20892 USA. [Van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. RP Greenberg, SM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM sgreenberg@partners.org RI Breteler, Monique /J-5058-2014; Vernooij, Meike/E-4061-2016; Gurol, Edip/J-2279-2014; OI Gurol, Edip/0000-0002-2169-4457; Al-Shahi Salman, Rustam/0000-0002-2108-9222 FU sundry research funds; Massachusetts General Hospital Hemorrhagic Stroke Research Program FX Other members of the Microbleed Study Group who participated in the Cerebral Microbleeds: Detection and Definition conference and contributed valuable discussions and criticisms for this paper were M A Ikram, M J Bos, M M F Poets (Rotterdam, Netherlands), I van der Grond (Leiden, Netherlands), M E Gurol, and R N K Nandigam (Boston, USA). The conference was held by the Microbleed Study Group on April 12, 2008 in Chicago, USA and was supported by sundry research funds provided by individual donors to the Massachusetts General Hospital Hemorrhagic Stroke Research Program without commercial interests or contributions from industry. NR 71 TC 534 Z9 561 U1 6 U2 68 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD FEB PY 2009 VL 8 IS 2 BP 165 EP 174 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 398SO UT WOS:000262752000015 PM 19161908 ER PT J AU Dierov, J Sanchez, PV Burke, BA Padilla-Nash, H Putt, ME Ried, T Carroll, M AF Dierov, J. Sanchez, P. V. Burke, B. A. Padilla-Nash, H. Putt, M. E. Ried, T. Carroll, M. TI BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold SO LEUKEMIA LA English DT Article DE BCR/ABL; chronic myeloid leukemia; etoposide; spectral karyotyping (SKY); genomic instability ID CHRONIC MYELOID-LEUKEMIA; DOUBLE-STRAND BREAKS; BCR-ABL; HEMATOPOIETIC-CELLS; CLONAL EVOLUTION; TYROSINE KINASE; DNA-DAMAGE; EXPRESSION; APOPTOSIS; ABERRATIONS AB Earlier reports have suggested that the BCR/ABL oncogene, associated with chronic myeloid leukemia, induces a mutator phenotype; however, it is unclear whether this leads to long-term changes in chromosomes and whether the phenotype is found in primary chronic myelogeneous leukemia (CML) cells. We have addressed both these issues. BCR/ABL-expressing cell lines show an increase in DNA breaks after treatment with etoposide as compared to control cells. However, although BCR/ABL-expressing cell lines have an equivalent cell survival, they have an increase in chromosomal translocations after DNA repair as compared to control cells. This demonstrates that BCR/ABL expression decreases the fidelity of DNA repair. To see whether this is true in primary CML samples, normal CD34+ progenitor cells and CML progenitor cells were treated with etoposide. CML progenitor cells have equivalent survival but have an increase in DNA double-strand breaks (DSBs). Spectral karyotyping demonstrates new chromosomal translocations in CML cells, but not normal progenitor cells, consistent with error-prone DNA repair. Taken together, these data demonstrate that BCR/ABL enhances the accumulation of DSBs and alters the apoptotic threshold in CML leading to error-prone DNA repair. C1 [Dierov, J.; Sanchez, P. V.; Burke, B. A.; Carroll, M.] Univ Penn, Div Hematol & Oncol, Dept Med, Philadelphia, PA 19104 USA. [Padilla-Nash, H.; Ried, T.] NCI, Sect Canc Gen, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Putt, M. E.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Carroll, M (reprint author), Univ Penn, Div Hematol & Oncol, Dept Med, BRB 2-3 Room 708,421 Curie Blvd, Philadelphia, PA 19104 USA. EM carroll2@mail.med.upenn.edu FU Leukemia Lymphoma Society; NCI [R01CA100885]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX MC is a Clinical Scholar of the Leukemia Lymphoma Society and is supported by NCI R01CA100885. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank Tomasz Skorski and colleagues for sharing data prior to publication. JD, PVS, BAB and HP-N performed experiments. MEP performed statistical analysis. TR provided reagents and expertise. MC supervised the experiments and wrote the papers. NR 29 TC 21 Z9 21 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2009 VL 23 IS 2 BP 279 EP 286 DI 10.1038/leu.2008.308 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 406RJ UT WOS:000263312300008 PM 19020542 ER PT J AU Ullmannova-Benson, V Guan, M Zhou, X Tripathi, V Yang, XY Zimonjic, DB Popescu, NC AF Ullmannova-Benson, V. Guan, M. Zhou, X. Tripathi, V. Yang, X-Y Zimonjic, D. B. Popescu, N. C. TI DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway SO LEUKEMIA LA English DT Article DE multiple myeloma; DLC1; tumor suppressor gene; promoter methylation; migration; invasion ID HEPATOCELLULAR-CARCINOMA; ACTIVATING PROTEIN; PROMOTER HYPERMETHYLATION; PROSTATE-CANCER; METHYLATION; METASTASIS; EXPRESSION; PATHOGENESIS; ASSOCIATION; PROFILES AB DLC1 (deleted in liver cancer 1), a tumor suppressor gene that encodes a RhoGTPase-activating protein, is recurrently downregulated or silenced in various solid tumors and hematological malignancies because of epigenetic modifications or genomic deletion. Here, we identified DLC1 promoter hypermethylation in 43 out of 44 multiple myeloma (MM) cell lines, which resulted in downregulation or silencing of DLC1 in 41 samples. High frequency of tumor-specific methylation and attenuation or silencing of DLC1 expression could serve as an independent diagnostic marker for MM. Combined treatment with demethylating and acetylating agents significantly elevated the expression of DLC1 and suppressed MM cell proliferation. Two cell lines exhibiting complete promoter methylation and the absence of DLC1 expression were transduced by an adenoviral vector containing DLC1 cDNA. In both cell lines, the reexpression of DLC1 inhibited myeloma cell invasion and migration, reduced RhoA activity and resulted in the reorganization of actin cytoskeleton. These results provide the first evidence for the antiproliferative effect of DLC1 in a hematological cancer and implicate RhoA pathway in suppression of MM migration and invasion. Given the myeloma cells sensitivity to the reactivation of DLC1 function, the potential for molecular targeted therapy of DLC1-mediated pathways as well as epigenetic therapies hold prospects. C1 [Ullmannova-Benson, V.; Guan, M.; Zhou, X.; Tripathi, V.; Yang, X-Y; Zimonjic, D. B.; Popescu, N. C.] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Expt Carcinogenesis Lab, Bldg 37,Room 4128,37 Convent Dr,MSC 4262, Bethesda, MD 20892 USA. EM popescun@mail.nih.gov RI yang, xuyu/D-1414-2012; Benson, Veronika/D-9942-2014 OI Benson, Veronika/0000-0003-4770-9909 FU National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the National Cancer Institute, NIH. We thank Dr Michael Kuehl (Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA) for providing DNA and RNA samples isolated from multiple myeloma cell lines, critical reading of the manuscript and most helpful suggestions. We also thank to Dr Sheng Chen for kindly providing plasma cells samples from healthy donors. NR 49 TC 22 Z9 27 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2009 VL 23 IS 2 BP 383 EP 390 DI 10.1038/leu.2008.285 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 406RJ UT WOS:000263312300020 PM 18923442 ER PT J AU Lee, KM Ward, MH Han, S Ahn, HS Kang, HJ Choi, HS Shin, HY Koo, HH Seo, JJ Choi, JE Ahn, YO Kang, D AF Lee, Kyoun -Mu Ward, Mary H. Han, Sohee Ahn, Hyo Seop Kang, Hyoung Jin Choi, Hyung Soo Shin, Hee Young Koo, Hong-Hoe Seo, Jong-Jin Choi, Ji-Eun Ahn, Yoon-Ok Kang, Daehee TI Paternal smoking, genetic polymorphisms in CYP1A1 and childhood leukemia risk SO LEUKEMIA RESEARCH LA English DT Article DE Childhood leukemia; Paternal smoking; CYP1A1; Interaction; Haplotype ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BULKY DNA-ADDUCTS; PARENTAL SMOKING; CIGARETTE-SMOKING; MATERNAL SMOKING; ENVIRONMENTAL-FACTORS; ALCOHOL-CONSUMPTION; TOBACCO-SMOKE; LUNG-CANCER; PREGNANCY AB We conducted a case-control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n = 164) and non-cancer controls (n = 164) were recruited front three teaching, hospitals in Seoul. Korea. Five single nucleotide polymorphisms in CYP1A1 (-17961T>C. -9893G>A. 1462V. 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR = 1.8. 95% CI = 1.1-2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2-3.4). Ail increasing trend in risk was observed for pack-years smoked after birth (P(trend) = 0.06 and 0.02, respectively) and the number of smokers in the home during, the child's life (P(trend) =0.05 and 0.03. respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8. 1.5-5.3) and the presence of at least one smoker in the home (2.3, 1.2-4.4). and the test for interaction was significant (P(interaction) = 0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13. 1.04-1.24) and smoking before the pregnancy of the child (1.12, 1.04-1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Lee, Kyoun -Mu; Han, Sohee; Ahn, Yoon-Ok; Kang, Daehee] Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Prevent Med, Seoul, South Korea. [Lee, Kyoun -Mu; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ahn, Hyo Seop; Kang, Hyoung Jin; Choi, Hyung Soo; Shin, Hee Young] Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Pediat, Seoul, South Korea. [Koo, Hong-Hoe] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pediat, Seoul, South Korea. [Seo, Jong-Jin] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pediat, Seoul, South Korea. [Choi, Ji-Eun] Borame Hosp, Dept Pediat, Seoul, South Korea. RP Kang, D (reprint author), Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Prevent Med, 28 Yongon Dong, Seoul, South Korea. EM dhkang@snu.ac.kr RI Kang, Hyoung Jin/J-2730-2012; Kang, Dae Hee/E-8631-2012; Ahn, Yoon-Ok/J-5530-2012; Shin, Hee Young/J-2766-2012; Choi, Ji Eun/J-5696-2012 FU Korea Electrotechnology Research Institute; Ministry of Knowledge Economy (MKE); Korea Health 21 RD Project; Ministry of Health, Welfare and Family Affairs, Republic of Korea [A030001: 03-PJ10-PG13-GD01-0002] FX We gratefully acknowledge the individuals who participated in the research and the clinicians who gave permission for us to approach their patients. This research was funded by Korea Electrotechnology Research Institute, Ministry of Knowledge Economy (MKE) and by a grant of the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea (A030001: 03-PJ10-PG13-GD01-0002). NR 45 TC 66 Z9 72 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD FEB PY 2009 VL 33 IS 2 BP 250 EP 258 DI 10.1016/j.leukres.2008.06.031 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 396FA UT WOS:000262576400010 PM 18691756 ER PT J AU Doria-Rose, VP Marcus, PM AF Doria-Rose, V. Paul Marcus, Pamela M. TI Death certificates provide an adequate source of cause of death information when evaluating lung cancer mortality: An example from the Mayo Lung Project SO LUNG CANCER LA English DT Article DE Lung cancer; Death certificate; Mortality; Sensitivity; Specificity ID PROSTATE-CANCER; MELANOMA AB To assess the accuracy of death certificates in assigning lung cancer as the underlying cause of death, death certificate data were compared to mortality review committee-determined causes of death among participants in the Mayo Lung Project. Further, the impact of death certificate misclassification on lung cancer mortality rates and Cox proportional hazards models was evaluated. The Mayo Lung Project (1971-1983) was a randomized controlled trial of lung cancer screening; participants were male smokers aged 45 years and older who were seen as outpatients at the Mayo Clinic in Rochester, Minnesota. Overall there were 237 lung cancer deaths according to mortality review, and 224 according to the death certificate (sensitivity 88.6 percent, 95 percent confidence interval (CI) 83.9, 92.4; specificity 99.1 percent, 95 percent CI 98.6, 99.5). As compared to the mortality review committee's determination, the use of death certificate data resulted only in slight decreases to the calculated lung cancer mortality rates for each screening arm, and did not result in appreciable changes to hazard ratios for lung cancer mortality in Cox regression models. In these data, death certificates were sufficiently sensitive and specific such that their use did not result in a meaningful change to mortality-based outcomes. Published by Elsevier Ireland Ltd. C1 [Doria-Rose, V. Paul] NCI, Dept Hlth & Human Serv, NIH, Canc Prevent Div,Biometry Res Grp, Bethesda, MD 20892 USA. [Doria-Rose, V. Paul] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, NIH, Bethesda, MD 20892 USA. RP Doria-Rose, VP (reprint author), NCI, Dept Hlth & Human Serv, NIH, Canc Prevent Div,Biometry Res Grp, 6130 Execut Blvd,Suite 3131, Bethesda, MD 20892 USA. EM doriaro@mail.nih.gov OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute Research Contract [N01-CN-53886]; Cancer Prevention Fellowship Program; Office of Preventive Oncology, National Cancer Institute FX The Mayo Lung Project was supported by National Cancer Institute Research Contract N01-CN-53886. This analysis had additional support from the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute. The authors would like to thank Robert Fontana and Eric Bergstralh for sharing their extensive knowledge of the Mayo Lung Project data. NR 23 TC 37 Z9 37 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD FEB PY 2009 VL 63 IS 2 BP 295 EP 300 DI 10.1016/j.lungcan.2008.05.019 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 402NP UT WOS:000263020700021 PM 18585822 ER PT J AU Kukekova, AV Goldstein, O Johnson, JL Richardson, MA Pearce-Kelling, SE Swaroop, A Friedman, JS Aguirre, GD Acland, GM AF Kukekova, Anna V. Goldstein, Orly Johnson, Jennifer L. Richardson, Malcolm A. Pearce-Kelling, Susan E. Swaroop, Anand Friedman, James S. Aguirre, Gustavo D. Acland, Gregory M. TI Canine RD3 mutation establishes rod-cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3 SO MAMMALIAN GENOME LA English DT Article ID CYCLIC-NUCLEOTIDE-METABOLISM; EARLY RETINAL DEGENERATION; RETINITIS-PIGMENTOSA; LINKAGE DISEQUILIBRIUM; INHERITED RETINOPATHY; DOMESTIC DOG; BREEDS; GENOME; COLLIE; LOCUS AB Rod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend the open reading frame. Thus, combined meiotic linkage and LD mapping within a single canine breed can yield critical reduction of the disease interval when appropriate advantage is taken of within-breed population structure. This should permit a similar approach to tackle other hereditary traits that segregate in single closed populations. C1 [Kukekova, Anna V.; Goldstein, Orly; Johnson, Jennifer L.; Richardson, Malcolm A.; Pearce-Kelling, Susan E.; Acland, Gregory M.] Cornell Univ, Coll Vet Med, James A Baker Inst Anim Hlth, Ithaca, NY 14853 USA. [Richardson, Malcolm A.] Dartmouth Hitchcock Med Ctr, Dartmouth Med Sch, Dept Microbiol & Immunol, Lebanon, NH 03766 USA. [Swaroop, Anand] Univ Michigan, WK Kellogg Eye Ctr, Ann Arbor, MI 48105 USA. [Swaroop, Anand; Friedman, James S.] NEI, NIH, Bethesda, MD 20892 USA. [Aguirre, Gustavo D.] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. RP Acland, GM (reprint author), Cornell Univ, Coll Vet Med, James A Baker Inst Anim Hlth, Hungerford Hill Rd, Ithaca, NY 14853 USA. EM gma2@cornell.edu OI Johnson, Jennifer/0000-0002-3339-4419; Swaroop, Anand/0000-0002-1975-1141 FU Foundation Fighting Blindness, [EY006855, MH077811]; Morris Animal Foundation,; Collie Health Foundation; Cornell VERGE Initiative FX We are grateful to Amanda Nickle, Gerri Antonini, and the staff of the RDS facility for research support. This study was supported by EY006855, MH077811, Foundation Fighting Blindness, Morris Animal Foundation, Collie Health Foundation, and Cornell VERGE Initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the supporting institutions or foundations. NR 34 TC 27 Z9 27 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 EI 1432-1777 J9 MAMM GENOME JI Mamm. Genome PD FEB PY 2009 VL 20 IS 2 BP 109 EP 123 DI 10.1007/s00335-008-9163-4 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 404JN UT WOS:000263147900005 PM 19130129 ER PT J AU Sumner, AE Luercio, MF Frempong, BA Ricks, M Sen, S Kushner, H Tulloch-Reid, MK AF Sumner, Anne E. Luercio, Marcella F. Frempong, Barbara A. Ricks, Madia Sen, Sabyasachi Kushner, Harvey Tulloch-Reid, Marshall K. TI Validity of the reduced-sample insulin modified frequently-sampled intravenous glucose tolerance test using the nonlinear regression approach SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID MINIMAL-MODEL; ASSESSING AGREEMENT; SENSITIVITY; POPULATION; RESISTANCE; PROTOCOLS AB The disposition index, the product of the insulin sensitivity index (S(l)) and the acute insulin response to glucose, is linked in African Americans to chromosome 11q. This link was determined with S(l) calculated with the nonlinear regression approach to the minimal model and data from the reduced-sample insulin-modified frequently-sampled intravenous glucose tolerance test (Reduced-Sample-IM-FSIGT). However, the application of the nonlinear regression approach to calculate S(l) using data from the Reduced-Sample-IM-FSIGT has been challenged as being not only inaccurate but also having a high failure rate in insulin-resistant subjects. Our goal was to determine the accuracy and failure rate of the Reduced-Sample-IM-FSIGT using the nonlinear regression approach to the minimal model. With S(l) from the Full-Sample-IM-FSIGT considered the standard and using the nonlinear regression approach to the minimal model, we compared the agreement between S(l) from the Full- and Reduced-Sample-IM-FSIGT protocols. One hundred African Americans (body mass index, 31.3 +/- 7.6 kg/m(2) [mean +/- SD]; range, 19.0-56.9 kg/m(2)) had FSIGTs. Glucose (0.3 g/kg) was given at baseline. Insulin was infused from 20 to 25 minutes (total insulin dose, 0.02 U/kg). For the Full-Sample-IM-FSIGT, S(l) was calculated based on the glucose and insulin samples taken at -1, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70 80, 90 100 120, 150, and 180 minutes. For the Reduced-Sample-FSIGT, S(l) was calculated based on the time points that appear in bold. Agreement was determined by Spearman correlation, concordance, and the Bland-Altman method. In addition, for both protocols, the population was divided into tertiles S(l). Insulin resistance was defined by the lowest tertile of S, from the Full-Sample-IM-FSIGT. The distribution of subjects across tertiles was compared by rank order and kappa statistic. We found that the rate of failure of resolution of S(l) by the Reduced-Sample-IM-FSIGT was 3% (3/100). For the remaining 97 subjects, S(l) for the Full- and Reduced-Sample-IM-FSIGTs were as follows: 3.76 +/- 2.41 L mU(-1) min(-1) (range, 0.58-14.50) and 4.29 +/- 2.89 L mU(-1) min(-1) (range, 0.52-14.42); relative error, 21% +/- 18%; Spearman r = 0.97; and concordance, 0.94 (both P < .001). After log transformation, the Bland-Altman limits of agreement were -0.29 and 0.53. The exact agreement for distribution of the population in the insulin-resistant tertile vs the insulin-sensitive tertiles was 92%, kappa of 0.82 +/- 0.06. Using the nonlinear regression approach and data from the Reduced-Sample-IM-FSIGT in subjects with a wide range of insulin sensitivity, failure to resolve S(l) occurred in only 3% of subjects. The agreement and maintenance of rank order of S(l) between protocols support the use of the nonlinear regression approach to the minimal model and the Reduced-Sainple-IM-FSIGT in clinical studies. Published by Elsevier Inc. C1 [Sumner, Anne E.; Luercio, Marcella F.; Frempong, Barbara A.; Ricks, Madia; Sen, Sabyasachi] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Kushner, Harvey] BioMed Comp Inst, Philadelphia, PA 19115 USA. [Tulloch-Reid, Marshall K.] Univ W Indies, Res Inst Trop Med, Epidemiol Res Unit, Kingston 7, Jamaica. RP Sumner, AE (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM annes@intra.niddk.nih.gov RI Tulloch-Reid, Marshall/E-4383-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the intramural research program at the National Institute of Diabetes and Digestive and Kidney Diseases. NR 19 TC 7 Z9 7 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD FEB PY 2009 VL 58 IS 2 BP 220 EP 225 DI 10.1016/j.metabol.2008.09.017 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402WS UT WOS:000263044400011 PM 19154955 ER PT J AU Robitaille, L Mamer, OA Miller, WH Levine, M Assouline, S Melnychuk, D Rousseau, C Hoffer, LJ AF Robitaille, Line Mamer, Orval A. Miller, Wilson H., Jr. Levine, Mark Assouline, Sarit Melnychuk, David Rousseau, Caroline Hoffer, L. John TI Oxalic acid excretion after intravenous ascorbic acid administration SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID TOTAL PARENTERAL-NUTRITION; ACUTE OXALATE NEPHROPATHY; VITAMIN-C INTAKE; HEMODIALYSIS-PATIENTS; URINARY OXALATE; LONG-TERM; STABILITY; OXALOGENESIS; SECONDARY; ANEMIA AB Ascorbic acid is frequently administered intravenously by alternative health practitioners and, occasionally, by mainstream physicians. Intravenous administration can greatly increase the amount of ascorbic acid that reaches the circulation, potentially increasing the risk of oxalate crystallization in the urinary space. To investigate this possibility, we developed gas chromatography mass spectrometry methodology and sampling and storage procedures for oxalic acid analysis without interference from ascorbic acid and measured urinary oxalic acid excretion in people administered intravenous ascorbic acid in doses ranging from 0.2 to 1.5 g/kg body weight. In vitro oxidation of ascorbic acid to oxalic acid did not occur when urine samples were brought immediately to pH less than 2 and stored at -30 degrees C within 6 hours. Even very high ascorbic acid concentrations did not interfere with the analysis when oxalic acid extraction was carried out at pH 1. As measured during and over the 6 hours after ascorbic acid infusions, urinary oxalic acid excretion increased with increasing doses, reaching approximately 80 mg at a dose of approximately 100 g. We conclude that, when Studied using correct procedures for sample handling, storage, and analysis, less than 0.5% of a very large intravenous dose of ascorbic acid is recovered as urinary oxalic acid in people with normal renal function. (C) 2009 Elsevier Inc. All rights reserved. C1 [Robitaille, Line; Miller, Wilson H., Jr.; Hoffer, L. John] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. [Mamer, Orval A.; Hoffer, L. John] McGill Univ, Mass Spectrometry Lab, Montreal, PQ H3A 1A4, Canada. [Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Assouline, Sarit; Melnychuk, David; Rousseau, Caroline] McGill Univ, Jewish Gen Hosp, Montreal Ctr Expt Therapeut Canc, Montreal, PQ H3T 1E2, Canada. RP Hoffer, LJ (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. EM l.hoffer@mcgill.ca FU Lotte and John Hecht Memorial Foundation; Canadian Institutes of Health Research [PRG-80160]; Intramural Research Program; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases FX This study was funded by a grant from the Lotte and John Hecht Memorial Foundation and from Research Resource Program Grant PRG-80160 from the Canadian Institutes of Health Research. WHM is a Chercheur National of the Fonds de la Recherche en Sante du Quebec. ML is supported by the Intramural Research Program, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. NR 38 TC 15 Z9 15 U1 2 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD FEB PY 2009 VL 58 IS 2 BP 263 EP 269 DI 10.1016/j.metabol.2008.09.023 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 402WS UT WOS:000263044400017 PM 19154961 ER PT J AU Polgar, O Deeken, JF Ediriwickrema, LS Tamaki, A Steinberg, SM Robey, RW Bates, SE AF Polgar, Orsolya Deeken, John F. Ediriwickrema, Lilangi S. Tamaki, Akina Steinberg, Seth M. Robey, Robert W. Bates, Susan E. TI The 315-316 deletion determines the BXP-21 antibody epitope but has no effect on the function of wild type ABCG2 or the Q141K variant SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE ABCG2; ABC transporter; Multidrug resistance; Single nucleotide polymorphism; Mitoxantrone; Pheophorbide a ID SINGLE NUCLEOTIDE POLYMORPHISMS; TYROSINE KINASE INHIBITORS; RESISTANCE PROTEIN ABCG2; BREAST-CANCER CELLS; MULTIDRUG TRANSPORTER; SUBSTRATE-SPECIFICITY; ACQUIRED MUTATIONS; HALF-TRANSPORTER; ATP HYDROLYSIS; BINDING AB ABCG2 is a half-transporter initially described in multidrug-resistant cancer cells and lately identified as an important factor in the pharmacokinetics of its substrates. Q141K is by far the most intensively studied single nucleotide polymorphism of ABCG2 with potential clinical relevance. Here we used stably transfected HEK cells to study the Q141K polymorphism together with the deletion of amino acids 315-316, which were recently reported to coexist in two cancer cell lines (A549 and SK-OV-3). Functional studies confirmed our previous report that when normalized to surface expression, Q141K has impaired transport of mitoxantrone. This result was extended to include the ABCG2-specific substrate pheophorbide a. While we found no functional consequence of deleting amino acids 315 and 316, we did find that the deletion mutant is no longer recognized by the BXP-21 antibody. We conclude that amino acids 315 and 316 form part of the epitope for the BXP-21 antibody. C1 [Polgar, Orsolya; Ediriwickrema, Lilangi S.; Tamaki, Akina; Robey, Robert W.; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Deeken, John F.] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov FU NIH; National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 34 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD FEB PY 2009 VL 322 IS 1-2 BP 63 EP 71 DI 10.1007/s11010-008-9940-0 PG 9 WC Cell Biology SC Cell Biology GA 403XT UT WOS:000263116000007 PM 19002564 ER PT J AU Matsuda, H Paul, BD Choi, CY Hasebe, T Shi, YB AF Matsuda, Hiroki Paul, Bindu D. Choi, Cheol Young Hasebe, Takashi Shi, Yun-Bo TI Novel Functions of Protein Arginine Methyltransferase 1 in Thyroid Hormone Receptor-Mediated Transcription and in the Regulation of Metamorphic Rate in Xenopus laevis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID IN-VIVO ANALYSIS; AMPHIBIAN METAMORPHOSIS; GENE-EXPRESSION; POSTEMBRYONIC DEVELOPMENT; CELL-PROLIFERATION; HISTONE H4; EPITHELIAL APOPTOSIS; COREPRESSOR COMPLEX; FROG METAMORPHOSIS; NEURAL FATE AB Protein arginine methyltransferase 1 (PRMT1) acts as a transcription coactivator for nuclear receptors through histone H4 R3 methylation. The in vivo function of PRMT1 is largely unknown. Here we investigated the role of PRMT1 in thyroid hormone (T3) receptor (TR)-mediated transcription in vivo during vertebrate development. By using intestinal remodeling during T3-dependent Xenopus laevis metamorphosis for in vivo molecular analysis, we first showed that PRMT1 expression was upregulated during metamorphosis when both TR and T3 were present. We then demonstrated a role for PRMT1 in TR-mediated transcription by showing that PRMT1 enhanced transcriptional activation by liganded TR in the frog oocyte transcription system and was recruited to the T3 response element (TRE) of the target promoter in the oocyte, as well as to endogenous TREs during frog metamorphosis. Surprisingly, we found that PRMT1 was only transiently recruited to the TREs in the target during metamorphosis and observed no PRMT1 recruitment to TREs at the climax of intestinal remodeling when both PRMT1 and T3 were at peak levels. Mechanistically, we showed that overexpression of PRMT1 enhanced TR binding to TREs both in the frog oocyte model system and during metamorphosis. More importantly, transgenic overexpression of PRMT1 enhanced gene activation in vivo and accelerated both natural and T3-induced metamorphosis. These results thus indicate that PRMT1 functions transiently as a coactivator in TR-mediated transcription by enhancing TR-TRE binding and further suggest that PRMT1 has tissue-specific roles in regulating the rate of metamorphosis. C1 [Shi, Yun-Bo] NICHHD, LGRD, NIH, PCRM,Sect Mol Morphogenesis, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHHD, LGRD, NIH, PCRM,Sect Mol Morphogenesis, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU Intramural Research Program of NICHD; NIH FX This research was supported by the Intramural Research Program of NICHD, NIH. NR 89 TC 26 Z9 27 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB 1 PY 2009 VL 29 IS 3 BP 745 EP 757 DI 10.1128/MCB.00827-08 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396RP UT WOS:000262609100012 PM 19047371 ER PT J AU Han, Q Robinson, H Cai, T Tagle, DA Li, JY AF Han, Qian Robinson, Howard Cai, Tao Tagle, Danilo A. Li, Jianyong TI Biochemical and Structural Properties of Mouse Kynurenine Aminotransferase III SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SPONTANEOUSLY HYPERTENSIVE-RATS; GLUTAMINE TRANSAMINASE-K; EXCITATORY AMINO-ACIDS; CRYSTAL-STRUCTURE; SUBSTRATE-SPECIFICITY; HUMAN BRAIN; ASPARTATE-AMINOTRANSFERASE; SYNAPTIC-TRANSMISSION; HUNTINGTONS-DISEASE; NICOTINIC RECEPTORS AB Kynurenine aminotransferase III (KAT III) has been considered to be involved in the production of mammalian brain kynurenic acid (KYNA), which plays an important role in protecting neurons from over-stimulation by excitatory neurotransmitters. The enzyme was identified based on its high sequence identity with mammalian KAT I, but its activity toward kynurenine and its structural characteristics have not been established. In this study, the biochemical and structural properties of mouse KAT III (mKAT III) were determined. Specifically, mKAT III cDNA was amplified from a mouse brain cDNA library, and its recombinant protein was expressed in an insect cell protein expression system. We established that mKAT III is able to efficiently catalyze the transamination of kynurenine to KYNA and has optimum activity at relatively basic conditions of around pH 9.0 and at relatively high temperatures of 50 to 60 C. In addition, mKAT III is active toward a number of other amino acids. Its activity toward kynurenine is significantly decreased in the presence of methionine, histidine, glutamine, leucine, cysteine, and 3-hydroxykynurenine. Through macromolecular crystallography, we determined the mKAT III crystal structure and its structures in complex with kynurenine and glutamine. Structural analysis revealed the overall architecture of mKAT III and its cofactor binding site and active center residues. This is the first report concerning the biochemical characteristics and crystal structures of KAT III enzymes and provides a basis toward understanding the overall physiological role of mammalian KAT III in vivo and insight into regulating the levels of endogenous KYNA through modulation of the enzyme in the mouse brain. C1 [Han, Qian; Li, Jianyong] Virginia Tech, Dept Biochem, Blacksburg, VA 24061 USA. [Robinson, Howard] Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. [Cai, Tao] NIDCR, OIIB, NIH, Bethesda, MD 20892 USA. [Tagle, Danilo A.] NINDS, NIH, Bethesda, MD 20892 USA. RP Li, JY (reprint author), Virginia Tech, Dept Biochem, Blacksburg, VA 24061 USA. EM lij@vt.edu RI Han, Qian/J-8696-2014 OI Han, Qian/0000-0001-6245-5252 FU NIH; Agriculture and Life Sciences, Virginia Tech FX We acknowledge the support of the Virginia Tech Department of Biological Sciences in the use of their X-ray facility and are grateful to Nancy Vogelaar, Chris Ceccarelli (Oxford Diffraction), and Florian Schubot for engaging us in helpful discussions. NR 60 TC 36 Z9 38 U1 2 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB 1 PY 2009 VL 29 IS 3 BP 784 EP 793 DI 10.1128/MCB.01272-08 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396RP UT WOS:000262609100015 PM 19029248 ER PT J AU Shin, BS Kim, JR Acker, MG Maher, KN Lorsch, JR Dever, TE AF Shin, Byung-Sik Kim, Joo-Ran Acker, Michael G. Maher, Kathryn N. Lorsch, Jon R. Dever, Thomas E. TI rRNA Suppressor of a Eukaryotic Translation Initiation Factor 5B/Initiation Factor 2 Mutant Reveals a Binding Site for Translational GTPases on the Small Ribosomal Subunit SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ELONGATION-FACTOR TU; AMINOACYL-TRANSFER-RNA; CONFORMATIONAL-CHANGES; PROTEIN-SYNTHESIS; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; 80S RIBOSOME; FACTOR EIF5B; IN-VIVO AB The translational GTPases promote initiation, elongation, and termination of protein synthesis by interacting with the ribosome. Mutations that impair GTP hydrolysis by eukaryotic translation initiation factor 5B/initiation factor 2 (eIF5B/IF2) impair yeast cell growth due to failure to dissociate from the ribosome following subunit joining. A mutation in helix h5 of the 18S rRNA in the 40S ribosomal subunit and intragenic mutations in domain II of eIF5B suppress the toxic effects associated with expression of the eIF5B-H480I GTPase-deficient mutant in yeast by lowering the ribosome binding affinity of eIF5B. Hydroxyl radical mapping experiments reveal that the domain II suppressors interface with the body of the 40S subunit in the vicinity of helix h5. As the helix h5 mutation also impairs elongation factor function, the rRNA and eIF5B suppressor mutations provide in vivo evidence supporting a functionally important docking of domain II of the translational GTPases on the body of the small ribosomal subunit. C1 [Shin, Byung-Sik; Kim, Joo-Ran; Maher, Kathryn N.; Dever, Thomas E.] NICHHD, Lab Gene Regulat & Dev Hlth, NIH, Bethesda, MD 20892 USA. [Acker, Michael G.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. RP Dever, TE (reprint author), NICHHD, Lab Gene Regulat & Dev Hlth, NIH, Bldg 6A,Rm B1A-03,6 Ctr Dr, Bethesda, MD 20892 USA. EM tdever@nih.gov OI Dever, Thomas/0000-0001-7120-9678 FU National Institute of Child Health and Development; National Institutes of Health; American Cancer Society [RSG-03-156-01-GMC] FX This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health (T.E.D.), and by American Cancer Society grant RSG-03-156-01-GMC (J.R.L.). NR 57 TC 13 Z9 14 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB 1 PY 2009 VL 29 IS 3 BP 808 EP 821 DI 10.1128/MCB.00896-08 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396RP UT WOS:000262609100017 PM 19029250 ER PT J AU Chae, JI Ju, SK Lee, MK Park, JH Yoon, JH Shim, JH Lee, DS AF Chae, J. I. Ju, S. K. Lee, M. K. Park, J. H. Yoon, J. H. Shim, J. H. Lee, D. S. TI cDNA cloning and analysis of tissue-specific gene expression of rat urocortin II SO MOLECULAR BIOLOGY LA English DT Article DE urocortin II; recombinant proteins; FACS ID CORTICOTROPIN-RELEASING-FACTOR; FACTOR CRF; BINDING-PROTEIN; NEUROPEPTIDE; RECEPTORS; PEPTIDE; HORMONE; FAMILY; GLUCOCORTICOIDS; SECRETION AB The corticotropin-releasing hormone (CRH) family of neuropeptides includes CRH (a 41-amino acid hypothalamic peptide) and urocortin. Corticotropin-releasing factor (CRF), a peptide first isolated from mammalian, plays an important role in the regulation of the pituitary-adrenal axis, and in endocrine, autonomic, immune and behavioral responses to stress. In this study, we cloned rat urocortin II (UCN II) cDNA from rat mid-brain by RT-PCR. The rat UCN II clone contained an open reading frame (ORF) 109 amino acids which shared 90% and 63% homology with mouse and human homologues, respectively. The expression of UCN II mRNA is mainly distributed in bone marrow, ovary, uterus, hypophysis, adrenal gland, and skin. In this study, rat recombinant UCN was expressed in E. coli and purified in active form. Furthermore, purified recombinant UCN II protein specifically binds to CRF receptor 2 in rat ROS 17 / 2.8 and GH3 cells by flow-cytometry analysis. UCN II cDNA clone obtained in this study will be useful for further investigation on behavioral responses to stress in rats. C1 [Chae, J. I.; Yoon, J. H.] Korea Res Inst Biosci & Biotechnol, Ctr Regenerat Med, Taejon 305333, South Korea. [Ju, S. K.; Lee, M. K.] Korea Res Inst Biosci & Biotechnol, Om & Integrat Res Ctr, Taejon 305333, South Korea. [Park, J. H.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Shim, J. H.] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lee, D. S.] Kyungpook Natl Univ, Coll Nat Sci, Taegu 702701, South Korea. RP Chae, JI (reprint author), Korea Res Inst Biosci & Biotechnol, Ctr Regenerat Med, Taejon 305333, South Korea. EM lee1@knu.ac.kr FU Kyungpook National University Research Fund, Republic of Korea FX This research was supported by Kyungpook National University Research Fund, 2007, Republic of Korea. NR 23 TC 1 Z9 1 U1 0 U2 0 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 J9 MOL BIOL+ JI Mol. Biol. PD FEB PY 2009 VL 43 IS 1 BP 82 EP 87 DI 10.1134/S0026893309010117 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411WS UT WOS:000263684800011 ER PT J AU Hur, JH Van Doninck, K Mandigo, ML Meselson, M AF Hur, Jae H. Van Doninck, Karine Mandigo, Morgan L. Meselson, Matthew TI Degenerate Tetraploidy Was Established Before Bdelloid Rotifer Families Diverged SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article ID PHYLUM ROTIFERA; CLUSTAL-W; ALIGNMENT; RATES; GENE; DNA; SUBSTITUTION; EVOLUTION; DATABASE AB Rotifers of Class Bdelloidea are abundant freshwater invertebrates known for their remarkable ability to survive desiccation and their lack of males and meiosis. Sequencing and annotation of approximately 50-kb regions containing the four hsp82 heat shock genes of the bdelloid Philodina roseola, each located on a separate chromosome, have suggested that its genome is that of a degenerate tetraploid. In order to determine whether a similar structure exists in a bdelloid distantly related to P. roseola and if degenerate tetraploidy was established before the two species separated, we sequenced regions containing the hsp82 genes of a bdelloid belonging to a different family, Adineta vaga, and the histone gene clusters of P. roseola and A. vaga. Our findings are entirely consistent with degenerate tetraploidy and show that it was established before the two bdelloid families diverged and therefore probably before the bdelloid radiation. C1 [Hur, Jae H.; Van Doninck, Karine; Mandigo, Morgan L.; Meselson, Matthew] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Mandigo, Morgan L.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Van Doninck, Karine] Univ Namur FUNDP, Dept Biol, URBO, Namur, Belgium. RP Hur, JH (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. EM msm@wjh.harvard.edu FU US National Science Foundation; Belgian - American Educational Foundation; Fulbright Program FX We thank David and Jessica Mark Welch for helpful discussions and technical assistance at every stage of the experiments. Other members of the Josephine Bay Paul Center for Comparative Molecular Biology and Evolution at the Marine Biological Laboratory, Woods Hole, MA provided assistance in fosmid sequencing and contig construction. At Harvard, Beth Weiner and others in the Kleckner laboratory provided access to their fluorescent microscope and instruction in its use, Christian Daly, George Kenty, and Peter Wang provided assistance in library construction, and members of the Maniatis laboratory and Kevin McMullen provided assistance in library screening. Financial support was provided by the US National Science Foundation (M. M.), the Belgian - American Educational Foundation (K. V. D.), and the Fulbright Program (K. V. D.). NR 38 TC 22 Z9 23 U1 3 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD FEB PY 2009 VL 26 IS 2 BP 375 EP 383 DI 10.1093/molbev/msn260 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 395LN UT WOS:000262525700013 PM 18996928 ER PT J AU Bryja, V Andersson, ER Schambony, A Esner, M Bryjova, L Biris, KK Hall, AC Kraft, B Cajanek, L Yamaguchi, TP Buckingham, M Arenas, E AF Bryja, Vitezslav Andersson, Emma R. Schambony, Alexandra Esner, Milan Bryjova, Lenka Biris, Kristin K. Hall, Anita C. Kraft, Bianca Cajanek, Lukas Yamaguchi, Terry P. Buckingham, Margaret Arenas, Ernest TI The Extracellular Domain of Lrp5/6 Inhibits Noncanonical Wnt Signaling In Vivo SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CONVERGENT EXTENSION MOVEMENTS; OUTFLOW TRACT DEVELOPMENT; PLANAR CELL POLARITY; WNT/BETA-CATENIN; BETA-CATENIN; DISHEVELLED PHOSPHORYLATION; GASTRULATION MOVEMENTS; XENOPUS GASTRULATION; DOPAMINERGIC CELLS; RECEPTOR AB Lrp5/6 are crucial coreceptors for Wnt/beta-catenin signaling, a pathway biochemically distinct from noncanonical Wnt signaling pathways. Here, we examined the possible participation of Lrp5/6 in noncanonical Wnt signaling. We found that Lrp6 physically interacts with Wnt5a, but that this does not lead to phosphorylation of Lrp6 or activation of the Wnt/beta-catenin pathway. Overexpression of Lrp6 blocks activation of the Wnt5a downstream target Rac1, and this effect is dependent on intact Lrp6 extracellular domains. These results suggested that the extracellular domain of Lrp6 inhibits noncanonical Wnt signaling in vitro. In vivo, Lrp6-/- mice exhibited exencephaly and a heart phenotype. Surprisingly, these defects were rescued by deletion of Wnt5a, indicating that the phenotypes resulted from noncanonical Wnt gain-of-function. Similarly, Lrp5 and Lrp6 antisense morpholino-treated Xenopus embryos exhibited convergent extension and heart phenotypes that were rescued by knockdown of noncanonical XWnt5a and XWnt11. Thus, we provide evidence that the extracellular domains of Lrp5/6 behave as physiologically relevant inhibitors of noncanonical Wnt signaling during Xenopus and mouse development in vivo. C1 [Bryja, Vitezslav; Andersson, Emma R.; Bryjova, Lenka; Hall, Anita C.; Cajanek, Lukas; Arenas, Ernest] Karolinska Inst, Ctr Dev Biol & Regenerat Med, Mol Neurobiol Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden. [Schambony, Alexandra; Kraft, Bianca] Univ Karlsruhe TH, Inst Zool 2, D-76131 Karlsruhe, Germany. [Esner, Milan; Buckingham, Margaret] Inst Pasteur, CNRS, Unite Rech Associee 2578, Dept Dev Biol, F-75724 Paris, France. [Biris, Kristin K.; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Bryja, Vitezslav; Bryjova, Lenka] Acad Sci Czech Republic, Inst Biophys, Dept Cytokinet, Brno 60177, Czech Republic. [Bryja, Vitezslav; Bryjova, Lenka] Masaryk Univ, Fac Sci, Inst Expt Biol, Brno 60200, Czech Republic. RP Bryja, V (reprint author), Karolinska Inst, Ctr Dev Biol & Regenerat Med, Mol Neurobiol Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden. EM bryja@sci.muni.cz; 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; Schambony, Alexandra/0000-0001-8771-5487; Arenas, Ernest/0000-0003-0197-6577 NR 57 TC 53 Z9 54 U1 0 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2009 VL 20 IS 3 BP 924 EP 936 DI 10.1091/mbc.E08-07-0711 PG 13 WC Cell Biology SC Cell Biology GA 402RX UT WOS:000263031900017 PM 19056682 ER PT J AU Madhavan, S Zenklusen, JC Kotliarov, Y Sahni, H Fine, HA Buetow, K AF Madhavan, Subha Zenklusen, Jean-Claude Kotliarov, Yuri Sahni, Himanso Fine, Howard A. Buetow, Kenneth TI Rembrandt: Helping Personalized Medicine Become a Reality through Integrative Translational Research SO MOLECULAR CANCER RESEARCH LA English DT Editorial Material ID MOLECULAR SUBTYPES; GLIOBLASTOMA; CLASSIFICATION; TUMORS; BRAIN; CELLS AB Finding better therapies for the treatment of brain tumors Is hampered by the lack of consistently obtained molecular data In a large sample set and the ability to Integrate biomedical data from disparate sources enabling translation of therapies from bench to bedside. Hence, a critical factor in the advancement of biomedical research and clinical translation is the ease with which data can be Integrated, redistributed, and analyzed both within and across functional domains. Novel biomedical informatics infrastructure and tools are essential for developing Individualized patient treatment based on the specific genomic signatures In each patient's tumor. Here, we present Repository of Molecular Brain Neoplasia Data (Rembrandt), a cancer clinical genomics database and a Web-based data mining and analysis platform aimed at facilitating discovery by connecting the dots between clinical Information and genomic characterization data. To date, Rembrandt contains data generated through the Glioma Molecular Diagnostic Initiative from 874 glioma specimens comprising similar to 566 gene expression arrays, 834 copy number arrays, and 13,472 clinical phenotype data points. Data can be queried and visualized for a selected gene across all data platforms or for multiple genes In a selected platform. Additionally, gene sets can be limited to clinically Important annotations including secreted, kinase, membrane, and known gene-anomaly pairs to facilitate the discovery of novel biomarkers and therapeutic targets. We believe that Rembrandt represents a prototype of how high-throughput genomic and clinical data can be integrated in a way that will allow expeditious and efficient translation of laboratory discoveries to the clinic. (Mol Cancer Res 2009;7(2):157-67) C1 [Zenklusen, Jean-Claude; Kotliarov, Yuri; Fine, Howard A.] NCI, Ctr Canc Res, Neurooncol Branch, Bethesda, MD 20892 USA. [Madhavan, Subha; Buetow, Kenneth] NCI, Ctr Biomed Informat & Informat Technol, Neurooncol Branch, Bethesda, MD 20892 USA. [Sahni, Himanso] Sci Applicat Int Corp, San Diego, CA 92121 USA. RP Zenklusen, JC (reprint author), NCI, Ctr Canc Res, Neurooncol Branch, 37 Convent Dr,Room 1142B,MSC 4254, Bethesda, MD 20892 USA. EM jz44m@nih.gov RI Kotliarov, Yuri/B-6938-2017 FU Intramural NIH HHS [Z99 CA999999] NR 17 TC 151 Z9 156 U1 3 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2009 VL 7 IS 2 BP 157 EP 167 DI 10.1158/1541-7786.MCR-08-0435 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 410MG UT WOS:000263580800001 PM 19208739 ER PT J AU Palmer, MB Majumder, P Cooper, JC Yoon, H Wade, PA Boss, JM AF Palmer, Matthew B. Majumder, Parimal Cooper, John C. Yoon, Hyesuk Wade, Paul A. Boss, Jeremy M. TI Yin Yang 1 Regulates the Expression of Snail through a Distal Enhancer SO MOLECULAR CANCER RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITIONS; E-CADHERIN EXPRESSION; TRANSCRIPTION FACTOR; MELANOMA-CELLS; UP-REGULATION; DEPENDENT TRANSCRIPTION; ESTROGEN-RECEPTOR; BREAST-CARCINOMA; YY1; GENE AB Expression of the Snail gene is required for the epithelial-mesenchymal transitions that accompany mammalian gastrulation, neural crest migration, and organ formation. Pathologic expression of Snail contributes to the migratory capacity of invasive tumors, Including melanomas. To investigate the mechanism of Snail up-regulation In human melanoma cells, a conserved enhancer located 3' of the Snail gene was analyzed. An overlapping Ets and yin yang 1 (YY1) consensus sequence, In addition to a SOX consensus sequence, was required for full enhancer activity. Proteins specifically binding these sequences were detected by electrophoretic mobility shift assay. The Ets/YY1 binding activity was purified by DNA-affinity chromatography and identified as YY1. Although ubiquitously expressed, YY1 was bound at the Snail 3' enhancer in vivo In Snail-expressing cells but not In cells that did not express Snail. Knockdown of YY1 in A375 cells led to decreased Snail expression. These results identify a role for YY1 in regulating transcription of Snail In melanoma cells through binding to the Snag 3' enhancer. (Mol Cancer Res 2009;7(2):221-9) C1 [Palmer, Matthew B.; Majumder, Parimal; Cooper, John C.; Yoon, Hyesuk; Boss, Jeremy M.] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Wade, Paul A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. RP Boss, JM (reprint author), Emory Univ, Sch Med, Dept Microbiol & Immunol, 1510 Clifton Rd, Atlanta, GA 30322 USA. EM boss@microbio.emory.edu FU National Institute of Environmental Health Sciences; NIH [Z01ES101965]; NIDDK [DK065961] FX Grant support: Intramural Research Program of the National Institute of Environmental Health Sciences, NIH grant Z01ES101965 (RA. Wade) and NIDDK grant DK065961 (J.M. Bass). NR 48 TC 16 Z9 20 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2009 VL 7 IS 2 BP 221 EP 229 DI 10.1158/1541-7786.MCR-08-0229 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 410MG UT WOS:000263580800007 PM 19208738 ER PT J AU Kyrkanides, S Yang, MX Tallents, R Miller, JN Brouxhon, S Harvey, B AF Kyrkanides, Stephanos Yang, Meixiang Tallents, Ross Miller, Jen-nie Brouxhon, Sabine Harvey, Brandon TI The trigeminal retrograde transfer pathway in LSD gene therapy SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Yang, Meixiang; Tallents, Ross; Miller, Jen-nie; Harvey, Brandon] Univ Rochester, Buffalo, NY USA. [Harvey, Brandon] Natl Inst Drug Abuse, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 79 BP S29 EP S29 DI 10.1016/j.ymgme.2008.11.080 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800087 ER PT J AU Medin, J Walia, J Neschadim, A Fan, X Madden, M Cheung, F Jaffray, D Levade, T Brady, R McCart, JA AF Medin, Jeffrey Walia, Jagdeep Neschadim, Anton Fan, Xin Madden, Melissa Cheung, Fred Jaffray, David Levade, Thierry Brady, Roscoe McCart, J. Andrea TI Outcomes of testing Lentivector-mediated Gene Therapy for Farber Disease in Non-Human Primates SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Medin, Jeffrey; Walia, Jagdeep; Fan, Xin; Jaffray, David] Ontario Canc Inst, Div Stem Cell & Dev Biol, Univ Hlth Network, Toronto, ON M4X 1K9, Canada. [Neschadim, Anton] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada. [Madden, Melissa] UHN, Anim Resources Ctr, Toronto, ON, Canada. [Cheung, Fred; Jaffray, David] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Jaffray, David; McCart, J. Andrea] Toronto Gen Res Inst, Toronto, ON, Canada. [Levade, Thierry] Univ Toulouse 3, INSERM, Inst Med Mol Rangueil, F-31062 Toulouse, France. [Brady, Roscoe] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RI Levade, Thierry/O-8948-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 87 BP S31 EP S31 DI 10.1016/j.ymgme.2008.11.088 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800095 ER PT J AU Namboodiri, A Madhavarao, C Arun, P Mog, S Grunberg, N Gahl, W Anikster, Y Moffett, J AF Namboodiri, Aryan Madhavarao, C. Arun, P. Mog, S. Grunberg, N. Gahl, W. Anikster, Y. Moffett, J. TI Canavan disease treatment using glyceryltriacetate SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Namboodiri, Aryan; Madhavarao, C.; Arun, P.; Mog, S.; Grunberg, N.; Moffett, J.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Gahl, W.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 96 BP S33 EP S33 DI 10.1016/j.ymgme.2008.11.097 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800104 ER PT J AU Patterson, M Porter, F Vaurio, R Brown, T AF Patterson, Marc Porter, Forbes Vaurio, Rebecca Brown, Tanya TI Longitudinal study of cognition in subjects with Niemann-Pick disease, type C SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 5th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 18-20, 2009 CL San Diego, NV SP Lysosomal Dis Network C1 [Patterson, Marc; Brown, Tanya] Mayo Clin, Rochester, MN 55905 USA. [Porter, Forbes] Natl Inst Hlth, Bethesda, MD USA. [Vaurio, Rebecca] Kennedy Krieger Inc, Hugo W Moser Res Inst, Kennett Sq, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 101 BP S34 EP S34 DI 10.1016/j.ymgme.2008.11.102 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800109 ER PT J AU Puertollano, R Vergarajauregui, S Martina, J AF Puertollano, Rosa Vergarajauregui, Silvia Martina, Jose TI Autophagic dysfunction in mucolipidosis type IV patients SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Puertollano, Rosa; Vergarajauregui, Silvia; Martina, Jose] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 111 BP S36 EP S36 DI 10.1016/j.ymgme.2008.11.112 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800119 ER PT J AU Schiffmann, R Caruso, R Goldin, E AF Schiffmann, Raphael Caruso, Rafael Goldin, Ehud TI Mucolipidosis type IV is both a developmental brain disease and a degenerative retinopathy SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Schiffmann, Raphael] Inst Metab Dis, Dallas, TX USA. [Caruso, Rafael] NEI, Bethesda, MD 20892 USA. [Goldin, Ehud] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 122 BP S39 EP S39 DI 10.1016/j.ymgme.2008.11.123 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800130 ER PT J AU Sidranskyu, E Goker-Alpan, O AF Sidranskyu, Ellen Goker-Alpan, Ozlem TI Gaucher disease and parkinsonism SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Sidranskyu, Ellen; Goker-Alpan, Ozlem] NHGRI, MGB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 131 BP S41 EP S41 DI 10.1016/j.ymgme.2008.11.132 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800139 ER PT J AU Slaugenhaupt, S Curcio-Morelli, C Charles, F Venugopal, B Cao, Y Browning, M Walkley, S Pickel, J Cotman, S Purpura, DP AF Slaugenhaupt, Susan Curcio-Morelli, Cyntia Charles, Florie Venugopal, Bhuvarahamurthy Cao, Yi Browning, Marsha Walkley, Steven Pickel, James Cotman, Susan Purpura, Dominck P. TI Characterization of neuronal storage in the mucolipidosis type IV murine model SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Slaugenhaupt, Susan; Curcio-Morelli, Cyntia; Charles, Florie; Venugopal, Bhuvarahamurthy; Cao, Yi; Browning, Marsha; Cotman, Susan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Slaugenhaupt, Susan; Curcio-Morelli, Cyntia; Charles, Florie; Venugopal, Bhuvarahamurthy; Cao, Yi; Browning, Marsha; Cotman, Susan] Harvard Univ, Sch Med, Boston, MA USA. [Walkley, Steven; Purpura, Dominck P.] Albert Einstein Coll Med, Rose F Kennedy Ctr, Dept Neurosci, Bronx, NY 10467 USA. [Pickel, James] Natl Inst Hlth, NIMH Transgen Core, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 134 BP S41 EP S42 DI 10.1016/j.ymgme.2008.11.135 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800142 ER PT J AU Zheng, W Motabar, O Liu, K Goldin, E Southall, N Marugan, J Austin, C Sidransky, E AF Zheng, Wei Motabar, Omid Liu, Ke Goldin, Ehud Southall, Noel Marugan, Juan Austin, Christopher Sidransky, Ellen TI High Throughput screen for identifying small molecule modulators of alpha-glucosidase for the potential treatment of Pompe disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 4th Annual World Symposium of the Lysosomal-Disease-Network CY FEB 13-15, 2009 CL Las Vegas, NV SP Lysosomal Dis Network C1 [Zheng, Wei; Liu, Ke; Southall, Noel; Marugan, Juan; Austin, Christopher] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Motabar, Omid; Goldin, Ehud; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2009 VL 96 IS 2 MA 155 BP S46 EP S46 DI 10.1016/j.ymgme.2008.11.156 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 399QG UT WOS:000262813800163 ER PT J AU Fattakhova, GV Masilamani, M Narayanan, S Borrego, F Gilfillan, AM Metcalfe, DD Coligan, JE AF Fattakhova, Gul'nar V. Masilamani, Madhan Narayanan, Sriram Borrego, Francisco Gilfillan, Alasdair M. Metcalfe, Dean D. Coligan, John E. TI Endosomal trafficking of the ligated Fc epsilon RI receptor SO MOLECULAR IMMUNOLOGY LA English DT Article DE Fc epsilon RI; Endosomes; Co-localization; Syk ID AFFINITY IGE RECEPTOR; MAST-CELL ACTIVATION; IMMUNOGLOBULIN-E; DEPENDENT ENDOCYTOSIS; MEMBRANE GLYCOPROTEIN; TYROSINE KINASE; PLASMA-MEMBRANE; GAMMA-SUBUNIT; LIPID RAFTS; SYK AB In addition to initiating signaling cascades leading to mast cell mediator release, aggregation of the high affinity IgE receptor (Fc epsilon RI) leads to rapid internalization of the cross-linked receptor. However, little is known about the trafficking of the internalized Fc epsilon RI. Here we demonstrate that in RBL-2H3 cells, aggregated Fc epsilon RI appears in the early endosomal antigen 1 (EEA1(+)) domains of the early endosomes within 15 min after ligation, Minimal co-localization of Fc epsilon RI with Rab5 was observed by 30 min, followed by its appearance in the Rab7(+) late endosomes and lysosomes at later time points. During endosomal sorting, Fc epsilon RI alpha and gamma Subunits remain associated. In Syk-deficient RBL-2H3 cells, the rate of transport to lysosomes is markedly increased. Taken together, our data demonstrate time-dependent sorting of aggregated Fc epsilon RI within the endosomal-lysosomal network, and that Syk may play an essential role in regulating the trafficking and retention of Fc epsilon RI in endosomes. Published by Elsevier Ltd. C1 [Fattakhova, Gul'nar V.; Masilamani, Madhan; Narayanan, Sriram; Borrego, Francisco; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Gilfillan, Alasdair M.; Metcalfe, Dean D.] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov FU Division of Intrainural Research; NIAID/NIH FX This work was supported by funds from the Division of Intrainural Research, NIAID/NIH. NR 49 TC 13 Z9 13 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD FEB PY 2009 VL 46 IS 5 BP 793 EP 802 DI 10.1016/j.molimm.2008.09.002 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 415OA UT WOS:000263942200005 PM 18945491 ER PT J AU Barchi, JJ Kaczmarek, P AF Barchi, Joseph J., Jr. Kaczmarek, Piotr TI Short and Sweet: Evolution of a Small Glycopeptide from a Bladder Disorder to an Anticancer Lead SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID INTERSTITIAL CYSTITIS PATIENTS; ANTIPROLIFERATIVE FACTOR; PROTEINS; CELLS C1 [Barchi, Joseph J., Jr.; Kaczmarek, Piotr] NCI, Frederick, MD 21702 USA. RP Barchi, JJ (reprint author), NCI, 376 Boyles St,POB B, Frederick, MD 21702 USA. EM barchi@helix.nih.gov RI Barchi Jr., Joseph/N-3784-2014 NR 16 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD FEB 1 PY 2009 VL 9 IS 1 BP 14 EP 17 DI 10.1124/mi.9.1.5 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 497TA UT WOS:000270084100002 PM 19299659 ER PT J AU Hatfield, DL Gladyshev, VN AF Hatfield, Dolph L. Gladyshev, Vadim N. TI The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) Reveals the Need for Better Understanding of Selenium Biology SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID PROSTATE-CANCER; NUTRITIONAL PREVENTION; BETA-CAROTENE; LUNG-CANCER; SUPPLEMENTATION; RISK; POLYMORPHISM; DEFICIENCY; MORTALITY; MICE C1 [Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov; vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013 FU Intramural NIH HHS [Z01 BC005317-24]; NCI NIH HHS [R01 CA080946, R01 CA080946-09] NR 24 TC 64 Z9 66 U1 3 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD FEB 1 PY 2009 VL 9 IS 1 BP 18 EP 21 DI 10.1124/mi.9.1.6 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 497TA UT WOS:000270084100003 PM 19299660 ER PT J AU Cadet, J Krasnova, I AF Cadet, Jean Lud Krasnova, Irina N. TI Cellular and Molecular Neurobiology of Brain Preconditioning SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Neuronal degeneration; Ischemia; Stroke; Tolerance; Brain preconditioning ID OXYGEN-GLUCOSE DEPRIVATION; DELAYED NEURONAL DEATH; NERVE GROWTH-FACTOR; FOCAL CEREBRAL-ISCHEMIA; ELEMENT-BINDING PROTEIN; TRANSIENT GLOBAL-ISCHEMIA; HIPPOCAMPAL CA1 REGION; RAT CORTICAL-NEURONS; INDUCIBLE FACTOR-I; MEDIATED AKT1 ACTIVATION AB The tolerant brain which is a consequence of adaptation to repeated nonlethal insults is accompanied by the upregulation of protective mechanisms and the downregulation of prodegenerative pathways. During the past 20 years, evidence has accumulated to suggest that protective mechanisms include increased production of chaperones, trophic factors, and other antiapoptotic proteins. In contrast, preconditioning can cause substantial dampening of the organism's metabolic state and decreased expression of proapoptotic proteins. Recent microarray analyses have also helped to document a role of several molecular pathways in the induction of the brain refractory state. The present review highlights some of these findings and suggests that a better understanding of these mechanisms will inform treatment of a number of neuropsychiatric disorders. C1 [Cadet, Jean Lud; Krasnova, Irina N.] NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Cadet, J (reprint author), NIDA, Mol Neuropsychiat Res Branch, Intramural Res Program, NIH,DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU National Institute on Drug Abuse; NIH; DHHS FX This paper is supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS. The authors also thank the reviewers whose suggestions helped to improve the paper. NR 155 TC 31 Z9 35 U1 1 U2 12 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD FEB PY 2009 VL 39 IS 1 BP 50 EP 61 DI 10.1007/s12035-009-8051-6 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 402OP UT WOS:000263023300005 PM 19153843 ER PT J AU Konno, Y Kodama, S Moore, R Kamiya, N Negishi, M AF Konno, Yoshihiro Kodama, Susumu Moore, Rick Kamiya, Nobuhiro Negishi, Masahiko TI Nuclear Xenobiotic Receptor Pregnane X Receptor Locks Corepressor Silencing Mediator for Retinoid and Thyroid Hormone Receptors (SMRT) onto the CYP24A1 Promoter to Attenuate Vitamin D(3) Activation SO MOLECULAR PHARMACOLOGY LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; DRUG-INDUCED OSTEOMALACIA; CROSS-TALK; METABOLISM; EXPRESSION; RIFAMPICIN; ENZYMES; GENES; CAR; SXR AB We have studied the molecular mechanism by which the nuclear xenobiotic receptors pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR) regulate transcription of the vitamin D(3) 24-hydroxylase (CYP24A1) gene. In the absence of vitamin D(3), PXR activates the CYP24A1 gene by directly binding to and transactivating vitamin D-response elements (VDREs) within its promoter. Vitamin D(3) activates the CYP24A1 promoter by dissociating the corepressor silencing mediator for retinoid and thyroid hormone receptors ( SMRT) from the vitamin D receptor (VDR) on those VDREs. PXR strongly represses vitamin D(3) activation of the CYP24A1 gene, in which PXR indirectly binds to and prevents vitamin D(3)-dependent dissociation of SMRT from the CYP24A1 promoter. The degree of the PXR-mediated locking of SMRT depends on the relative concentration of vitamin D 3 to the human PXR activator rifampicin; SMRT increased its dissociation as this ratio increased. CAR is also found to prevent dissociation of SMRT from the CYP24A1 promoter. Thus, our present study defines the novel molecular mechanism by which PXR and CAR mediate drug interactions with vitamin D 3 to regulate the CYP24A1 gene. Pxr(+/+) and Pxr(-/-) mice were continuously treated with mouse PXR activator PCN to evaluate the hypothesis that induction of the Cyp24a1 gene is responsible for the loss of bone mineral density often observed in patients treated continuously with PXR-activating drugs. PCN-dependent loss of mineral density is observed in the metaphyseal bones of only the Pxr(+/+) mice. This loss, however, does not correlate with the expression levels of the Cyp24a1 gene in these mice. C1 [Konno, Yoshihiro; Kodama, Susumu; Moore, Rick; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kamiya, Nobuhiro] NIEHS, Mol Dev Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural NIH HHS NR 19 TC 18 Z9 21 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2009 VL 75 IS 2 BP 265 EP 271 DI 10.1124/mol.108.051904 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 396WX UT WOS:000262623400002 PM 18981260 ER PT J AU Caldwell, HK Stephens, SI Young, WS AF Caldwell, H. K. Stephens, S. I. Young, W. S., III TI Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice SO MOLECULAR PSYCHIATRY LA English DT Article DE psychotomimetics; prepulse inhibition; sensorimotor gating; schizophrenia; phencyclidine ID OBSESSIVE-COMPULSIVE DISORDER; STARTLE GATING DEFICITS; PREPULSE INHIBITION DEFICITS; LOW-DOSE KETAMINE; SCHIZOPHRENIC-PATIENTS; ACOUSTIC STARTLE; CEREBROSPINAL-FLUID; TOURETTES-SYNDROME; NEUROLEPTIC MEDICATION; HABITUATION DEFICITS AB It has been previously suggested that oxytocin (Oxt) may act as a natural antipsychotic. To test this hypothesis, we investigated whether disruption of the oxytocin gene (Oxt-/-) made mice more susceptible to the psychosis-related effects of amphetamine (Amp), apomorphine (Apo) and phencyclidine (PCP). We examined drug-induced changes in the prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating deficits characteristic of several psychiatric and neurological disorders, including schizophrenia. We found that treatment with Amp, Apo and PCP all had effects on PPI. However, in Oxt-/- mice, but not Oxt-/- mice, PCP treatment resulted in large PPI deficits. As PCP is a noncompetitive N-methyl-D-aspartic acid receptor antagonist, these findings suggest that the absence of Oxt alters the glutamatergic component of the PPI. C1 [Caldwell, H. K.; Stephens, S. I.; Young, W. S., III] NIMH, Sect Neural Gene Express, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Caldwell, HK (reprint author), Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA. EM wsy@mail.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU NIMH Intramural Research Program [Z01-MH-002498-17] FX We thank the NIH Animal Facility in Building 49 for their exceptional care. We also thank Selen Tolu, James Heath and Emily Shepard for technical assistance as well as Dr Eric Mintz for his statistical expertise. This work was supported by the NIMH Intramural Research Program (Z01-MH-002498-17). NR 80 TC 60 Z9 61 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2009 VL 14 IS 2 BP 190 EP 196 DI 10.1038/sj.mp.4002150 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 395VD UT WOS:000262550700008 PM 18227836 ER PT J AU Wang, J Mansfield, SG Cote, CA Du Jiang, P Weng, K Amar, MJA Brewer, BH Remaley, AT McGarrity, GJ Garcia-Blanco, MA Puttaraju, M AF Wang, Jun Mansfield, S. Gary Cote, Colette A. Du Jiang, Ping Weng, Ke Amar, Marcelo J. A. Brewer, Bryan H., Jr. Remaley, Alan T. McGarrity, Gerard J. Garcia-Blanco, Mariano A. Puttaraju, M. TI Trans-splicing Into Highly Abundant Albumin Transcripts for Production of Therapeutic Proteins In Vivo SO MOLECULAR THERAPY LA English DT Article ID APOLIPOPROTEIN-A-I; RNA-POLYMERASE-II; MESSENGER-RNA; HEMOPHILIA-A; TRANSGENE EXPRESSION; NUCLEOTIDE-SEQUENCE; CYSTIC-FIBROSIS; SERUM-ALBUMIN; GENE DELIVERY; DNA AB Spliceosome-mediated RNA trans-splicing has emerged as an exciting mode of RNA therapy. Here we describe a novel trans-splicing strategy, which targets highly abundant pre-mRNAs, to produce therapeutic proteins in vivo. First, we used a pre-trans-splicing molecule (PTM) that mediated trans-splicing of human apolipoprotein A-I (hapoA-I) into the highly abundant mouse albumin exon 1. Hydrodynamic tail vein injection of the hapoA-I PTM plasmid in mice followed by analysis of the chimeric transcripts and protein, confirmed accurate and efficient trans-splicing into albumin pre-mRNA and production of hapoA-I protein. The versatility of this approach was demonstrated by producing functional human papillomavirus type-16 E7 (HPV16-E7) single-chain antibody in C57BL/6 mice and functional factor VIII (FVIII) and phenotypic correction in hemophilia A mice. Altogether, these studies demonstrate that trans-splicing to highly abundant albumin transcripts can be used as a general platform to produce therapeutic proteins in vivo. C1 [Wang, Jun; Mansfield, S. Gary; Cote, Colette A.; Du Jiang, Ping; Weng, Ke; McGarrity, Gerard J.; Puttaraju, M.] VIRxSYS Corp, Gaithersburg, MD 20877 USA. [Amar, Marcelo J. A.; Brewer, Bryan H., Jr.; Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20892 USA. [Garcia-Blanco, Mariano A.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC USA. RP Puttaraju, M (reprint author), VIRxSYS Corp, 200 Perry Pkwy,Suite 1A, Gaithersburg, MD 20877 USA. EM raju@virxsys.com FU National Heart, Lung, and Blood Institute [R44-HL072687] FX The hemophilia work was supported in part by a Phase II SBIR grant from the National Heart, Lung, and Blood Institute ( grant no. R44-HL072687). We thank Laurent Humeau and Peter Donnelly for critical reading of the manuscript; John Stonik, Catherine Knapper, Boris Vaisman for assistance in experimental design and technical help; Lili Portilla for assistance with the CRADA. The apoA-I research was performed under a CRADA between NHLBI's Vascular Medicine Branch/Lipoprotein Metabolism Section and Intronn, Inc. We thank Paul McCray ( University of Iowa) for his advice on performing the tail clip assay. J.W., S.G.M., P.D.J., G.J.M., and M.P. are employees of VIRxSYS Corporation (formerly with Intronn, Inc) and C.A.C. and K. W. were former Intronn, Inc employees. Spliceosome-mediated RNA trans-splicing technology was developed by Intronn, Inc., and majority of the work in this article was conducted at Intronn, Inc. In September 2007, VIRxSYS Corporation acquired all of Intronn, Inc., assets including intellectual property. M.A.G.-B is a co-corresponding author in this article and was a co-founder and consultant to Intronn, Inc., and is currently a consultant to VIRxSYS Corporation. NR 45 TC 11 Z9 11 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD FEB PY 2009 VL 17 IS 2 BP 343 EP 351 DI 10.1038/mt.2008.260 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 406IB UT WOS:000263287100022 PM 19066600 ER PT J AU Guimond, M Veenstra, RG Grindler, DJ Zhang, H Cui, YZ Murphy, RD Kim, SY Na, RS Hennighausen, L Kurtulus, S Erman, B Matzinger, P Merchant, MS Mackall, CL AF Guimond, Martin Veenstra, Rachelle G. Grindler, David J. Zhang, Hua Cui, Yongzhi Murphy, Ryan D. Kim, Su Young Na, Risu Hennighausen, Lothar Kurtulus, Sema Erman, Batu Matzinger, Polly Merchant, Melinda S. Mackall, Crystal L. TI Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4(+) T cells SO NATURE IMMUNOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; MHC CLASS-II; IN-VIVO; FUNCTIONAL INTERLEUKIN-7; INTENSIVE CHEMOTHERAPY; DISEASE PROGRESSION; HIV-1 INFECTION; IL-7 INCREASES; POTENTIAL ROLE; STROMAL CELLS AB Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-alpha-positive (IL-7R alpha(+)) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4(+) T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7R alpha(+) DCs. Our results indicate that IL-7R alpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo. C1 [Guimond, Martin; Veenstra, Rachelle G.; Grindler, David J.; Zhang, Hua; Cui, Yongzhi; Murphy, Ryan D.; Kim, Su Young; Merchant, Melinda S.; Mackall, Crystal L.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Na, Risu; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Erman, Batu] Sabanci Univ, Biol Sci & Bioengn Program, TR-34956 Istanbul, Turkey. [Kurtulus, Sema] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Matzinger, Polly] NIAID, Ghost Lab, NIH, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov FU Intramural Program of the National Cancer Institute FX We thank V. Kapoor and N. Voong for flow cytometry expertise; M. A. Caligiuri (Ohio State University) for Flt3 ligand; S. Durum (National Cancer Institute) for Rag1-/- Il7-/- mice; and S. Durum, A. Singer and R. Gress for review of the manuscript. Supported by the Intramural Program of the National Cancer Institute. NR 48 TC 117 Z9 118 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2009 VL 10 IS 2 BP 149 EP 157 DI 10.1038/ni.1695 PG 9 WC Immunology SC Immunology GA 404UM UT WOS:000263178500008 PM 19136960 ER PT J AU Subach, FV Patterson, GH Manley, S Gillette, JM Lippincott-Schwartz, J Verkhusha, VV AF Subach, Fedor V. Patterson, George H. Manley, Suliana Gillette, Jennifer M. Lippincott-Schwartz, Jennifer Verkhusha, Vladislav V. TI Photoactivatable mCherry for high-resolution two-color fluorescence microscopy SO NATURE METHODS LA English DT Article ID LOCALIZATION MICROSCOPY; TRANSFERRIN RECEPTOR; MONOMERIC RED; AMINO-ACID; PROTEIN; NANOSCOPY; CLATHRIN; CELLS; INTERNALIZATION; CONVERSION AB The reliance of modern microscopy techniques on photoactivatable fluorescent proteins prompted development of mCherry variants that are initially dark but become red fluorescent after violet-light irradiation. Using ensemble and single-molecule characteristics as selection criteria, we developed PAmCherry1 with excitation/emission maxima at 564/595 nm. Compared to other monomeric red photoactivatable proteins, it has faster maturation, better pH stability, faster photoactivation, higher photoactivation contrast and better photostability. Lack of green fluorescence and single-molecule behavior make monomeric PAmCherry1 a preferred tag for two-color diffraction-limited photoactivation imaging and for super-resolution techniques such as one-and two-color photoactivated localization microscopy (PALM). We performed PALM imaging using PAmCherry1-tagged transferrin receptor expressed alone or with photoactivatable GFP-tagged clathrin light chain. Pair correlation and cluster analyses of the resulting PALM images identified <= 200 nm clusters of transferrin receptor and clathrin light chain at <= 25 nm resolution and confirmed the utility of PAmCherry1 as an intracellular probe. C1 [Subach, Fedor V.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. [Subach, Fedor V.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, Bronx, NY 10461 USA. [Subach, Fedor V.; Patterson, George H.; Manley, Suliana; Gillette, Jennifer M.; Lippincott-Schwartz, Jennifer] NICHHD, Sect Organelle Biol, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Verkhusha, VV (reprint author), Albert Einstein Coll Med, Dept Anat & Struct Biol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM vverkhus@aecom.yu.edu RI Manley, Suliana/D-3818-2012; Subach, Fedor/K-7080-2014 OI Manley, Suliana/0000-0002-4755-4778; FU US National Institutes of Health [GM070358, GM073913] FX We thank R. Tsien (University of California at San Diego) for providing the pRSETBmCherry plasmid, J. Wiedenmann (University of Ulm) for providing plasmids encoding EosFP variants, J. Zhang for assistance with flow cytometry, O. Subach for assistance with cell culture and imaging, and E. Betzig and H. Hess for assistance with PALM experiments, analysis and discussion. This work was supported by grants GM070358 and GM073913 from the US National Institutes of Health to V. V. V. NR 30 TC 285 Z9 296 U1 12 U2 92 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD FEB PY 2009 VL 6 IS 2 BP 153 EP 159 DI 10.1038/NMETH.1298 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 405CA UT WOS:000263198500016 PM 19169259 ER PT J AU Yang, JM Siao, CJ Nagappan, G Marinic, T Jing, DQ McGrath, K Chen, ZY Mark, W Tessarollo, L Lee, FS Lu, B Hempstead, BL AF Yang, Jianmin Siao, Chia-Jen Nagappan, Guhan Marinic, Tina Jing, Deqiang McGrath, Kelly Chen, Zhe-Yu Mark, Willie Tessarollo, Lino Lee, Francis S. Lu, Bai Hempstead, Barbara L. TI Neuronal release of proBDNF SO NATURE NEUROSCIENCE LA English DT Article ID NEUROTROPHIC FACTOR; CORTICAL-NEURONS; RAT; BIOSYNTHESIS; ACTIVATION; EXPRESSION; P75(NTR); SORTILIN; PATHWAY; BDNF AB Pro-brain-derived neurotrophic factor (proBDNF) and mature BDNF utilize distinct receptors to mediate divergent neuronal actions. Using new tools to quantitate endogenous BDNF isoforms, we found that mouse neurons secrete both proBDNF and mature BDNF. The highest levels of proBDNF and p75 were observed perinatally and declined, but were still detectable, in adulthood. Thus, BDNF actions are developmentally regulated by secretion of proBDNF or mature BDNF and by local expression of p75 and TrkB. C1 [Yang, Jianmin; Siao, Chia-Jen; Marinic, Tina; McGrath, Kelly; Hempstead, Barbara L.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Jing, Deqiang; Chen, Zhe-Yu; Lee, Francis S.] Weill Cornell Med Coll, Dept Psychiat, New York, NY 10065 USA. [Mark, Willie] Mem Sloan Kettering Canc Ctr, Dept Dev Biol, New York, NY 10065 USA. [Tessarollo, Lino] NCI, Frederick, MD 21702 USA. [Nagappan, Guhan; Lu, Bai] NICHHD, Bethesda, MD 20892 USA. RP Hempstead, BL (reprint author), Weill Cornell Med Coll, Dept Med, 1300 York Ave, New York, NY 10065 USA. EM blhempst@med.cornell.edu RI Lu, Bai/A-4018-2012 FU National Institute of Neurological Disorders and Stroke [NS30687, NS52819]; National 973 Basic Research Program of China [2006CB503803, 2009CB941403]; National Institute of Child Health and Human Development; National Institute of Mental Health FX We thank K. Teng and members of the Hempstead laboratory for their input. These studies were supported by grants from the National Institute of Neurological Disorders and Stroke (NS30687 to B. L.H. and NS52819 to F. S. L.), National 973 Basic Research Program of China (No. 2006CB503803 and 2009CB941403 to Z.-Y.C.) and the Intramural Program of the National Institute of Child Health and Human Development and the National Institute of Mental Health (to B.L.). NR 13 TC 177 Z9 185 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2009 VL 12 IS 2 BP 113 EP 115 DI 10.1038/nn.2244 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 404VV UT WOS:000263182000008 PM 19136973 ER PT J AU Joksimovic, M Yun, BA Kittappa, R Anderegg, AM WChang, W Taketo, MM McKay, RDG Awatramani, RB AF Joksimovic, Milan Yun, Beth A. Kittappa, Raja Anderegg, Angela M. WChang, Wendy Taketo, Makoto M. McKay, Ronald D. G. Awatramani, Rajeshwar B. TI Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis SO NATURE NEUROSCIENCE LA English DT Article ID BETA-CATENIN GENE; SONIC-HEDGEHOG; DOPAMINERGIC-NEURONS; EXPRESSION; CELLS; FATE; PROGENITORS; BRAIN; IDENTIFICATION; FOREBRAIN AB The floor plate, an essential ventral midline organizing center that produces the morphogen Shh, has distinct properties along the neuraxis. The neurogenic potential of the floor plate and its underlying mechanisms remain unknown. Using Shh as a driver for lineage analysis, we found that the mouse midbrain, but not the hindbrain, floor plate is neurogenic, giving rise to dopamine (DA) neurons. Distinct spatiotemporal Shh and Wnt expression may distinguish the neurogenetic potential of these structures. We discovered an inhibitory role for Shh: removal of Shh resulted in neurogenesis from the hindbrain midline and, conversely, high doses of Shh inhibited proliferation and DA neuron production in midbrain cultures. We found that Wnt/beta-catenin signaling is necessary and sufficient for antagonizing Shh, DA progenitor marker induction and promotion of dopaminergic neurogenesis. These findings demonstrate how the dynamic interplay of canonical Wnt/beta-catenin signaling and Shh may orchestrate floor plate neurogenesis or a lack thereof. C1 [Joksimovic, Milan; Yun, Beth A.; Anderegg, Angela M.; Awatramani, Rajeshwar B.] Northwestern Univ, Feinberg Med Sch, Dept Neurol, Chicago, IL 60611 USA. [Joksimovic, Milan; Yun, Beth A.; Anderegg, Angela M.; Awatramani, Rajeshwar B.] Northwestern Univ, Feinberg Med Sch, Ctr Genet Med, Chicago, IL 60611 USA. [Kittappa, Raja; WChang, Wendy; McKay, Ronald D. G.] NINDS, Mol Biol Lab, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Taketo, Makoto M.] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. RP Awatramani, RB (reprint author), Northwestern Univ, Feinberg Med Sch, Dept Neurol, 7-113 Lurie Bldg,303 Super St, Chicago, IL 60611 USA. EM r-awatramani@northwestern.edu RI Joksimovic, Milan/A-4952-2016 OI Joksimovic, Milan/0000-0002-3936-4632 FU Dana Foundation; American Parkinson's Disease Association; Parkinson's Disease Foundation FX We thank C. Tabin for Shh::cre mice and Shh cDNA; M. German for antibody to Lmx1a; T. Muller and C. Birchmeier for antibody to Lmx1b; D. Anderson for antibody to Ngn2; T. Edlund for antibodies to Gbx2; and A. Klar for the Spon1l cDNA. We thank A. Chenn for supplying Ctnnb1 mouse strains. We thank J. Kessler for suggestions. R. B. A was supported by the Dana Foundation and the American Parkinson's Disease Association. M. J. was supported by the Parkinson's Disease Foundation. NR 37 TC 105 Z9 107 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2009 VL 12 IS 2 BP 125 EP 131 DI 10.1038/nn.2243 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 404VV UT WOS:000263182000012 PM 19122665 ER PT J AU Finkel, T AF Finkel, Toren TI WHERE'S WALDO FOR AUTOPHAGOSOMES SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Editorial Material ID MATURATION; NIX C1 NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Translat Med Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD FEB PY 2009 VL 10 IS 2 BP 89 EP 89 DI 10.1038/nrm2603 PG 1 WC Cell Biology SC Cell Biology GA 404US UT WOS:000263179100008 ER PT J AU Li, L Dutra, A Pak, E Labrie, JE Gerstein, RM Pandolfi, PP Recht, LD Ross, AH AF Li, Li Dutra, Amalia Pak, Evgenia Labrie, Joseph E., III Gerstein, Rachel M. Pandolfi, Pier Paolo Recht, Larry D. Ross, Alonzo H. TI EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors SO NEURO-ONCOLOGY LA English DT Article DE aneuploidy; EGFRvIII; glioblastoma; neural precursor cells; PTEN ID GROWTH-FACTOR RECEPTOR; NEURAL STEM-CELL; HUMAN BRAIN-TUMORS; GLIOBLASTOMA-MULTIFORME; SELF-RENEWAL; DNA-DAMAGE; PHOSPHATIDYLINOSITOL 3-KINASE; CONSTITUTIVE ACTIVATION; GENETIC INSTABILITY; SIGNAL-TRANSDUCTION AB Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/-neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/-cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas, and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker CD133, and resistance to oxidative stress and ionizing radiation. The RAS/mitogen-activated protein kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways were activated, and checkpoint kinase 1 (Chk1), the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/-cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, glial fibrillary acidic protein-positive, nestin-positive tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability. Neuro-Oncology 11, 9-21, 2009 (Posted to Neuro-Oncology [serial online], Doc. D07-00253, September 23, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-081) C1 [Li, Li; Ross, Alonzo H.] Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, Worcester, MA 01605 USA. [Labrie, Joseph E., III; Gerstein, Rachel M.] Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01605 USA. [Dutra, Amalia; Pak, Evgenia] NHGRI, NIH, Bethesda, MD 20892 USA. [Pandolfi, Pier Paolo] Beth Israel Deaconess Med Ctr, Dept Pathol, Program Canc Genet, Boston, MA 02215 USA. [Recht, Larry D.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Palo Alto, CA USA. RP Ross, AH (reprint author), Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, 364 Plantat St, Worcester, MA 01605 USA. EM Alonzo.Ross@umassmed.edu FU NIH [NS21716]; Human Genome Research Institute; Goldhirsh Foundation; Worcester Foundation FX This work was supported in part by NIH NS21716, the Intramural Program of the Human Genome Research Institute, the Goldhirsh Foundation, and the Worcester Foundation. NR 71 TC 50 Z9 52 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2009 VL 11 IS 1 BP 9 EP 21 DI 10.1215/15228517-2008-081 PG 13 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 406LK UT WOS:000263296800003 PM 18812521 ER PT J AU McCallion, AS Pavan, WJ Chakravarti, A Johnson, S Antonellis, A Huynh, JL Stine, ZE McGaughey, D Gorkin, D Prasad, MK Emison, ES Loftus, SK AF McCallion, A. S. Pavan, W. J. Chakravarti, A. Johnson, S. Antonellis, A. Huynh, J. L. Stine, Z. E. McGaughey, D. M. Gorkin, D. Prasad, M. K. Emison, E. S. Loftus, S. K. TI Identification of mammalian neural crest enhancers through transgenesis in Zebrafish SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [McCallion, A. S.; Chakravarti, A.; Huynh, J. L.; Stine, Z. E.; McGaughey, D. M.; Gorkin, D.; Prasad, M. K.; Emison, E. S.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Pavan, W. J.; Antonellis, A.; Loftus, S. K.] NHGRI, NIH, Bethesda, MD 20892 USA. [Johnson, S.] Washington Univ, St Louis, MO USA. NR 0 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 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD FEB PY 2009 VL 21 IS 2 BP IX EP IX PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 397UT UT WOS:000262688300043 ER PT J AU Pavan, WJ Watkins-Chow, DE Matera, I Buac, K Larson, D Loftus, SK Hou, L Incao, A Silver, DL Rivas, C Elliott, EC Baxter, LL AF Pavan, W. J. Watkins-Chow, D. E. Matera, I. Buac, K. Larson, D. Loftus, S. K. Hou, L. Incao, A. Silver, D. L. Rivas, C. Elliott, E. C. Baxter, L. L. TI A sensitized mouse mutagenesis screen for modifiers of Sox10 neurocristopathies SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Pavan, W. J.; Watkins-Chow, D. E.; Matera, I.; Buac, K.; Larson, D.; Loftus, S. K.; Hou, L.; Incao, A.; Silver, D. L.; Rivas, C.; Elliott, E. C.; Baxter, L. L.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD FEB PY 2009 VL 21 IS 2 BP XXV EP XXV PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 397UT UT WOS:000262688300103 ER PT J AU Sumner, JP Shapiro, EM Maric, D Conroy, R Koretsky, AP AF Sumner, James P. Shapiro, Erik M. Maric, Dragan Conroy, Richard Koretsky, Alan P. TI In vivo labeling of adult neural progenitors for MRI with micron sized particles of iron oxide: Quantification of labeled cell phenotype SO NEUROIMAGE LA English DT Article ID POSTNATAL RAT FOREBRAIN; SUBVENTRICULAR ZONE; OLFACTORY-BULB; NEURONAL MIGRATION; MAMMALIAN BRAIN; GENERATED NEURONS; RODENT BRAIN; STEM; OLIGODENDROCYTES; ASTROCYTES AB The subventricular zone (SVZ) is a continual source of neural progenitors throughout adulthood. Many of the animal models designed to study the migration of these cells from the ventricle to places of interest like the olfactory bulb or an injury site require histology to localize precursor cells. Here, it is demonstrated that up to 30% of the neural progenitors that migrate along the rostral migratory stream (RMS) in an adult rodent can be labeled for MRI via intraventricular injection of micron sized particles of iron oxide (MPIOs). The precursors migrating from the SVZ along the RMS were found to populate the olfactory bulb with all three types of neural cells; neurons, oligodendrocytes, and astrocytes. In all cases 10-30% of these cells were labeled in the RMS en route to the olfactory bulb. Ara- C, an anti- mitotic agent, eliminated precursor cells at the SVZ, RMS, and olfactory bulb and also eliminated the MRI detection of the precursors. This indicates that the MRI signal detected is due to progenitor cells that leave the SVZ and is not due to nonspeci. c diffusion of MPIOs. Using MRI to visualize neural progenitor cell behavior in individual animals during plasticity or disease models should be a useful tool, especially in combination with other information that MRI can supply. Published by Elsevier Inc. C1 [Sumner, James P.; Conroy, Richard; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Shapiro, Erik M.] Yale Univ, Sch Med, Dept Radiol, New Haven, CT 06510 USA. [Maric, Dragan] NINDS, FACS Facil, Bethesda, MD 20892 USA. [Conroy, Richard] Natl Inst Stand & Technol, Boulder, CO USA. RP Koretsky, AP (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, Bldg 10,Room B1D728,10 Ctr Dr,MSC 1065, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Conroy, Richard/D-1979-2009; Koretsky, Alan/C-7940-2015 OI Conroy, Richard/0000-0002-8896-6090; Koretsky, Alan/0000-0002-8085-4756 FU NINDS Intramural Research Program; NIH FX This research was supported by the NINDS Intramural Research Program of NIH. We thank N. Bouraoud and S. Dodd, for their technical assistance with animal surgeries and MRI, respectively. We also thank Carolyn Smith for use of the NINDS Light Imaging Facility. NR 34 TC 49 Z9 54 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2009 VL 44 IS 3 BP 671 EP 678 DI 10.1016/j.neuroimage.2008.07.050 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 392KL UT WOS:000262301500008 PM 18722534 ER PT J AU Saad, ZS Glen, DR Chen, G Beauchamp, MS Desai, R Cox, RW AF Saad, Ziad S. Glen, Daniel R. Chen, Gang Beauchamp, Michael S. Desai, Rutvik Cox, Robert W. TI A new method for improving functional-to-structural MRI alignment using local Pearson correlation SO NEUROIMAGE LA English DT Article ID SURFACE-BASED ANALYSIS; IMAGE REGISTRATION; CEREBRAL-CORTEX; BRAIN IMAGES; ROBUST; OPTIMIZATION; SOFTWARE; LANGUAGE; GRADIENT AB Accurate registration of Functional Magnetic Resonance Imaging (FMRI) T2*-weighted volumes to sames-subject high-resolution T1-weighted structural volumes is important for Blood Oxygenation Level Dependent (BOLD) FMRI and crucial for applications such as cortical surface-based analyses and pre-surgical planning. Such registration is generally implemented by minimizing a cost functional, which measures the mismatch between two image volumes over the group of proper affine transformations. Widely used cost functionals, such as mutual information (MI) and correlation ratio (CR), appear to yield decent alignments when visually judged by matching outer brain contours. However, close inspection reveals that internal brain structures are often significantly misaligned. Poor registration is most evident in the ventricles and sulcal folds, where CSF is concentrated. This observation motivated our development of an improved modality-specific cost functional which uses a weighted local Pearson coefficient (LPC) to align T2*-and T1-weighted images. In the absence of an alignment gold standard, we used three human observers blinded to registration method to provide an independent assessment of the quality of the registration for each cost functional. We found that LPC performed significantly better (p<0.001) than generic cost functionals including MI and CR. Generic cost functionals were very often not minimal near the best alignment, thereby suggesting that optimization is not the cause of their failure. Lastly, we emphasize the importance of precise visual inspection of alignment quality and present an automated method for generating composite images that help capture errors of misalignment. Published by Elsevier Inc. C1 [Saad, Ziad S.; Glen, Daniel R.; Chen, Gang; Cox, Robert W.] NIMH, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Beauchamp, Michael S.] Univ Texas Hlth Sci Ctr Houston, Dept Neurobiol & Anat, Houston, TX USA. [Desai, Rutvik] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. RP Cox, RW (reprint author), NIMH, NIH, US Dept HHS, 10 Ctr Dr,Room 1D80, Bethesda, MD 20892 USA. EM rwcox@nih.gov OI Beauchamp, Michael/0000-0002-7599-9934 FU NIMH; NINDS Intramural Programs; NIH; MSB; NSF [0642532]; NIH/NIDCD [5R03DC008416-02, 2R01NS33576-11] FX This research was supported by the NIMH and NINDS Intramural Programs of the NIH. MSB was supported by NSF grant 0642532 (PI Michael Beauchamp); RD was supported by NIH/NIDCD grant 5R03DC008416-02 (PI Rutvik Desai) and NIH/ NINDS grant 2R01NS33576- 11 (PI Jeffery Binder). NR 29 TC 165 Z9 166 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2009 VL 44 IS 3 BP 839 EP 848 DI 10.1016/j.neuroimage.2008.09.037 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 392KL UT WOS:000262301500024 PM 18976717 ER PT J AU Murphy, K Birn, RM Handwerker, DA Jones, TB Bandettini, PA AF Murphy, Kevin Birn, Rasmus M. Handwerker, Daniel A. Jones, Tyler B. Bandettini, Peter A. TI The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced? SO NEUROIMAGE LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; BOLD HEMODYNAMIC-RESPONSES; DEFAULT-MODE NETWORK; CEREBRAL-BLOOD-FLOW; FUNCTIONAL MRI; HUMAN BRAIN; FMRI DATA; EMPIRICAL ANALYSES; NULL-HYPOTHESIS; LOCAL CHANGES AB Low-frequency fluctuations in fMRI signal have been used to map several consistent resting state networks in the brain. Using the posterior cingulate cortex as a seed region, functional connectivity analyses have found not only positive correlations in the default mode network but negative correlations in another resting state network related to attentional processes. The interpretation is that the human brain is intrinsically organized into dynamic, anti-correlated functional networks. Global variations of the BOLD signal are often considered nuisance effects and are commonly removed using a general linear model (GLM) technique. This global signal regression method has been shown to introduce negative activation measures in standard fMRI analyses. The topic of this paper is whether such a correction technique could be the cause of anti-correlated resting state networks in functional connectivity analyses. Here we show that, after global signal regression, correlation values to a seed voxel must sum to a negative value. Simulations also show that small phase differences between regions can lead to spurious negative correlation values. A combination breath holding and visual task demonstrates that the relative phase of global and local signals can affect connectivity measures and that, experimentally, global signal regression leads to bell-shaped correlation value distributions, centred on zero. Finally, analyses of negatively correlated networks in resting state data show that global signal regression is most likely the cause of anti-correlations. These results call into question the interpretation of negatively correlated regions in the brain when using global signal regression as an initial processing step. (C) 2008 Published by Elsevier Inc. C1 [Bandettini, Peter A.] NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. [Bandettini, Peter A.] NIMH, Funct MRI Facil, Bethesda, MD 20892 USA. RP Bandettini, PA (reprint author), NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, Bldg 10,Room 1D80B,10 Ctr Dr MSC 1148, Bethesda, MD 20892 USA. EM bandettini@nih.gov RI Murphy, Kevin/A-1581-2010 OI Murphy, Kevin/0000-0002-6516-313X FU Intramural Research Program; National Institute of Mental Health; NIH FX This study was supported by the Intramural Research Program, National Institute of Mental Health, NIH. Thanks go to Phil Reiss and Clare Kelly for helpful discussions. NR 63 TC 851 Z9 858 U1 4 U2 43 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2009 VL 44 IS 3 BP 893 EP 905 DI 10.1016/j.neuroimage.2008.09.036 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 392KL UT WOS:000262301500029 PM 18976716 ER PT J AU Tucciarone, J Chuang, KH Dodd, SJ Silva, A Pelled, G Koretsky, AP AF Tucciarone, Jason Chuang, Kai-Hsiang Dodd, Steven J. Silva, Afonso Pelled, Galit Koretsky, Alan P. TI Layer specific tracing of corticocortical and thalamocortical connectivity in the rodent using manganese enhanced MRI SO NEUROIMAGE LA English DT Article ID RESONANCE-IMAGING MEMRI; SOMATIC SENSORY CORTEX; IN-VIVO; SOMATOSENSORY CORTEX; BRAIN ACTIVITY; MOUSE-BRAIN; RAT; ORGANIZATION; CONTRAST; MODEL AB Information about layer specific connections in the brain comes mainly from classical neuronal tracers that rely on histology. Manganese Enhanced MRI (MEMRI) has mapped connectivity along a number of brain pathways in several animal models. It is not clear at what level of specificity neuronal connectivity measured using MEMRI tracing can resolve. The goal of this work was to determine if neural tracing using MEMRI could distinguish layer inputs of major pathways of the cortex. To accomplish this, tracing was performed between hemispheres of the somatosensory (S1) cortex and between the thalamus and S1 cortex. T(1) mapping and T(1) weighted pulse sequences detected layer specific tracing after local injection of MnCl(2). Approximately 12 h following injections into S1 cortex, maximal T(1) reductions were observed at 0.6 +/- 0.07 and 1.1 +/- 0.12 mm from the brain surface in the contralateral S1. These distances correspond to the positions of layer 3 and 5 consistent with the known callosal inputs along this pathway. Four to six hours following injection of MnCl2 into the thalamus there were maximal T(1) reductions between 0.7 +/- 0.08 and 0.8 +/- 0.08 mm from the surface of the brain, which corresponds to layer 4. This is consistent with terminations of the known thalamocortical projections. In order to observe the first synapse projection, it was critical to perform MRI at the right time after injections to detect layer specificity with MEMRI. At later time points, tracing through the cortical network led to more uniform contrast throughout the cortex due to its complex neuronal connections. These results are consistent with well established neuronal pathways within the somatosensory cortex and demonstrate that layer specific somatosensory connections can be detected in vivo using MEMRI. Published by Elsevier Inc. C1 [Tucciarone, Jason; Chuang, Kai-Hsiang; Dodd, Steven J.; Silva, Afonso; Pelled, Galit; Koretsky, Alan P.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,B1D728, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Chuang, Kai-Hsiang/0000-0002-8356-0657 FU NINDS; NIH FX The authors would like to acknowledge the surgical assistance and expertise of Ms. Nadia Bouraoud and Ms. Kathy Sharer. This research was supported by the Intramural Research Program of the NINDS, NIH. NR 49 TC 29 Z9 32 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2009 VL 44 IS 3 BP 923 EP 931 DI 10.1016/j.neuroimage.2008.07.036 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 392KL UT WOS:000262301500032 PM 18755280 ER PT J AU Mooshagian, E Iacoboni, M Zaidel, E AF Mooshagian, Eric Iacoboni, Marco Zaidel, Eran TI Spatial attention and interhemispheric visuomotor integration in the absence of the corpus callosum SO NEUROPSYCHOLOGIA LA English DT Article DE Reaction time; Poffenberger paradigm; Interhemispheric transfer; Task context; Split brain; CUD; Laterality ID SIMPLE REACTION-TIMES; LATERALIZED LEXICAL DECISION; CROSSED-UNCROSSED DIFFERENCE; S-R COMPATIBILITY; SPLIT-BRAIN; ANATOMICAL FACTORS; LIGHT STIMULI; LONG-TERM; FLASHES; CALLOSOTOMY AB In the lateralized simple reaction time (SRT) task with unimanual responses (Poffenberger paradigm), reaction times (RTs) are faster with ipsilateral (uncrossed) than with contralateral (crossed) response hand-target hemifield combinations. The difference between crossed and uncrossed responses (CUD) has typically been interpreted to reflect callosal transfer time. Indeed, acallosal subjects and split-brain subjects have longer CUDs than control subjects. However, a few recent studies have demonstrated that, contrary to classical findings, the CUD is also affected by non-anatomical factors. Here we show that the CUD is also affected by non-anatomical factors in patients with agenesis of the corpus callosum and complete commissurotomy where interhemispheric transfer must be subcallosal. We tested acallosal subject M.M. and split brain patient A.A. on a lateralized SRT task with their arms alternately uncrossed (natural arms position) or crossed (unnatural arms position) across blocks of trials. The results revealed a significant effect of arms crossing on the size and direction of the CUD as previously found in normal subjects [Mooshagian, E., lacoboni, M., & Zaidel, E. (2008). The role of task history in simple reaction time to lateralized light flashes. Neuropsychologia, 46(2), 659-664]. This suggests that non-anatomical factors that modulate interhemispheric visuomotor integration may occur in absence of the corpus callosum. Anterior commissure and interhemispheric cortico-subcortical pathways are likely implicated in these effects. (C) Published by Elsevier Ltd. C1 [Mooshagian, Eric; Zaidel, Eran] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Iacoboni, Marco; Zaidel, Eran] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. [Iacoboni, Marco] Univ Calif Los Angeles, David Geffen Sch Med, Neuropsychiat Inst,Ahmanson Lovelace Brain Mappin, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Mooshagian, E (reprint author), Natl Inst Neurol Disorders & Stroke, Brain Stimulat Unit, NIH, MSC 1440,10 Ctr Dr, Bethesda, MD 20892 USA. EM mooshage@ninds.nih.gov FU National Institutes of Health [NIH NS-20187] FX We thank A.A. and M.M. for their participation in the experiments, Aakash Kishore for assistance with data analysis, and three anonymous reviewers for comments on a previous draft of the manuscript. This work was supported by a grant from the National Institutes of Health (NIH NS-20187). NR 30 TC 10 Z9 10 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD FEB PY 2009 VL 47 IS 3 BP 933 EP 937 DI 10.1016/j.neuropsychologia.2008.12.005 PG 5 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 419RP UT WOS:000264237300036 PM 19124029 ER PT J AU Schmidt, PJ Steinberg, EM Negro, PP Haq, N Gibson, C Rubinow, DR AF Schmidt, Peter J. Steinberg, Emma M. Negro, Paula Palladino Haq, Nazli Gibson, Carolyn Rubinow, David R. TI Pharmacologically Induced Hypogonadism and Sexual Function in Healthy Young Women and Men SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE sexual function; hypogonadism; estradiol; progesterone; testosterone; GnRH agonist ID PLACEBO-CONTROLLED TRIAL; QUALITY-OF-LIFE; ESTROGEN REPLACEMENT THERAPY; SURGICALLY MENOPAUSAL WOMEN; POSTMENOPAUSAL WOMEN; MENSTRUAL-CYCLE; DOUBLE-BLIND; AGING MEN; PREMENOPAUSAL WOMEN; TESTOSTERONE LEVELS AB Studies fail to find uniform effects of age-related or induced hypogonadism on human sexual function. We examined the effects of induced hypogonadism on sexual function in healthy men and women and attempted to identify predictors of the sexual response to induced hypogonadism or hormone addback. The study design used was a double-blind, controlled, crossover (self-as-own control). The study setting was an ambulatory care clinic in a research hospital, and the participants were 20 men (average +/- SD age 28.5 +/- 6.2 years) and 20 women (average +/- SD age 33.5 +/- 8.7 years), all healthy and with no history of psychiatric illness. A multidimensional scale assessing several domains of sexual function was the main outcome measure. Participants of the study received depot leuprolide acetate (Lupron) every 4 weeks for 3 months (men) or 5 months (women). After the first month of Lupron alone, men received (in addition to Lupron) testosterone enanthate (200 mg intramuscularly) or placebo every 2 weeks for 1 month each. Women received Lupron alone for 2 months, and then, in addition to Lupron, they received estradiol and progesterone for 5 weeks each. The results of the study: in women, hypogonadism resulted in a significant decrease in global measures of sexual functioning, principally reflecting a significant decrease in the reported quality of orgasm. In men, hypogonadism resulted in significant reductions in all measured domains of sexual function. Testosterone restored sexual functioning scores in men to those seen at baseline, whereas neither estradiol nor progesterone significantly improved the reduced sexual functioning associated with hypogonadism in women. Induced hypogonadism decreased sexual function in a similar number of men and women. No predictors of response were identified except for levels of sexual function at baseline. In conclusion, our data do not support a simple deficiency model for the role of gonadal steroids in human sexual function; moreover, while variable, the role of testosterone in sexual function in men is more apparent than that of estradiol or progesterone in women. C1 [Schmidt, Peter J.; Steinberg, Emma M.; Negro, Paula Palladino; Haq, Nazli; Gibson, Carolyn] Natl Inst Mental Hlth, Behav Endocrinol Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Schmidt, PJ (reprint author), Natl Inst Mental Hlth, Behav Endocrinol Branch, NIH, DHHS, Bldg 10 CRC,Room 6-5340,10 Ctr Dr,MSC 1276, Bethesda, MD 20892 USA. EM peterschmidt@mail.nih.gov FU National Institute of Mental Health's Intramural Research Program FX This work was supported by the National Institute of Mental Health's Intramural Research Program. Dr Schmidt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Other authors have nothing to disclose. NR 103 TC 20 Z9 20 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2009 VL 34 IS 3 BP 565 EP 576 DI 10.1038/npp.2008.24 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 393MA UT WOS:000262376200005 PM 18354393 ER PT J AU Cheeran, B Cohen, L Dobkin, B Ford, G Greenwood, R Howard, D Husain, M Macleod, M Nudo, R Rothwell, J Rudd, A Teo, J Ward, N Wolf, S AF Cheeran, Binith Cohen, Leonardo Dobkin, Bruce Ford, Gary Greenwood, Richard Howard, David Husain, Masud Macleod, Malcolm Nudo, Randolph Rothwell, John Rudd, Anthony Teo, James Ward, Nicholas Wolf, Steven CA Cumberland Consensus Working Grp TI The Future of Restorative Neurosciences in Stroke: Driving the Translational Research Pipeline From Basic Science to Rehabilitation of People After Stroke SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE Rehabilitation; Research pipeline; Translation ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; RECOVERY FOLLOWING STROKE; EARLY SUPPORTED DISCHARGE; MOTOR CORTEX STIMULATION; EAST MELBOURNE STROKE; CORTICAL STIMULATION; BRAIN-INJURY; PROMOTES RECOVERY; OCCUPATIONAL-THERAPY AB Background. Major advances during the past 50 years highlight the immense potential for restoration of function after neural injury, even in the damaged adult human brain. Yet, the translation of these advances into clinically useful treatments is painstakingly slow. Objective. Here, we consider why the traditional model of a "translational research pipeline" that transforms basic science into novel clinical practice has failed to improve rehabilitation practice for people after stroke. Results. We find that (1) most treatments trialed in vitro and in animal models have not yet resulted in obviously useful functional gains in patients; (2) most clinical trials of restorative treatments after stroke have been limited to small-scale studies; (3) patient recruitment for larger clinical trials is difficult; (4) the determinants of patient outcomes and what patients want remain complex and ill-defined, so that basic scientists have no clear view of the clinical importance of the problems that they are addressing; (5) research in academic neuroscience centers is poorly integrated with practice in front-line hospitals and the community, where the majority of patients are treated; and (6) partnership with both industry stakeholders and patient pressure groups is poorly developed, at least in the United Kingdom where research in the translational restorative neurosciences in stroke depends on public sector research funds and private charities. Conclusions. We argue that interaction between patients, front-line clinicians, and clinical and basic scientists is essential so that they can explore their different priorities, skills, and concerns. These interactions can be facilitated by funding research consortia that include basic and clinical scientists, clinicians and patient/carer representatives with funds targeted at those impairments that are major determinants of patient and carer outcomes. Consortia would be instrumental in developing a lexicon of common methods, standardized outcome measures, data sharing and long-term goals. Interactions of this sort would create a research-friendly, rather than only target-led, culture in front-line stroke rehabilitation services. C1 [Greenwood, Richard; Husain, Masud] Natl Hosp Neurol & Neurosurg, Inst Neurol, London WC1N 3BG, England. [Cheeran, Binith; Greenwood, Richard; Rothwell, John; Teo, James; Ward, Nicholas] Inst Neurol, Sobell Dept Motor Neurosci, London WC1N 3BG, England. [Ward, Nicholas] Inst Neurol, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Dobkin, Bruce] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Cohen, Leonardo] NINDS, NIH, Bethesda, MD 20892 USA. [Nudo, Randolph] Univ Kansas, Med Ctr, Lawrence, KS 66045 USA. [Wolf, Steven] Emory Univ, Atlanta, GA 30322 USA. [Macleod, Malcolm] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Rudd, Anthony] Kings Coll London, London, England. [Ford, Gary; Howard, David] Univ Newcastle, Callaghan, NSW 2308, Australia. [Husain, Masud] UCL, Inst Cognit Neurosci, London WC1E 6BT, England. RP Greenwood, R (reprint author), Natl Hosp Neurol & Neurosurg, Inst Neurol, Queen Sq, London WC1N 3BG, England. EM richard.greenwood@uclh.nhs.uk RI Nudo, Randolph/B-1623-2009; Macleod, Malcolm/B-2052-2010; Ford, Gary/A-6353-2012; Husain, Masud/C-2074-2008; van Vliet, Paulette/F-4616-2010; Teo, James/D-9696-2011; OI Macleod, Malcolm Robert/0000-0001-9187-9839; Husain, Masud/0000-0002-6850-9255; Teo, James/0000-0002-6899-8319; Howard, David/0000-0001-9141-5751; Burridge, Jane/0000-0003-3497-6725; Teo, Jeanette/0000-0002-9321-3341; Rothwell, John/0000-0003-1367-6467; Cheeran, Binith/0000-0002-3442-1044 NR 99 TC 67 Z9 67 U1 3 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD FEB PY 2009 VL 23 IS 2 BP 97 EP 107 DI 10.1177/1545968308326636 PG 11 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 401OG UT WOS:000262949900001 ER PT J AU Cai, Q Sheng, ZH AF Cai, Qian Sheng, Zu-Hang TI Molecular Motors and Synaptic Assembly SO NEUROSCIENTIST LA English DT Article DE synaptogenesis; synaptic plasticity; kinesin; myosin; motor adaptor; axonal transport ID KINESIN SUPERFAMILY MOTOR; AMPA RECEPTOR TRAFFICKING; AXONAL-TRANSPORT; HIPPOCAMPAL-NEURONS; VESICLE TRANSPORT; HEAVY-CHAIN; MYOSIN-V; INTRACELLULAR-TRANSPORT; NEUROMUSCULAR-JUNCTION; CYTOPLASMIC DYNEIN AB Proper synaptic function requires the seamless integration of the transport, assembly, and regulation of synaptic components and structures. Inasmuch as the synapse is often distant from the neuronal cell body, newly synthesized synaptic proteins, the precursors of synaptic vesicles, active zone compartments, channels and receptors, and mitochondria, must be transported along lengthy neuronal processes to participate in synaptogenesis. Neuronal transport is mediated by motor proteins that associate with their cargoes via adaptors ( or receptors) and that travel along the cytoskeleton network within the neuronal processes. Thus, the identity of membranous protein cargoes and the specificity of motor-cargo interactions are critical for correctly targeting cargoes and properly assembling synapses in developing neurons and in remodeling synapses of mature neurons in response to neuronal activity. In this article, the authors review recent progress in characterizing microtubule- and actin-based motor proteins that are involved in delivering synaptic components and discuss potential mechanisms underlying the formation of motor-receptor-cargo complexes that contribute to synaptogenesis and activity-induced synaptic plasticity. C1 [Cai, Qian; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. 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 Research Program of NINDS; NIH FX The authors thank the members of the Sheng lab for helpful discussions, and D. Glazer-Schoenberg and A. Simone for editing. This work was supported by the Intramural Research Program of NINDS, NIH (Z-HS). NR 69 TC 15 Z9 16 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD FEB PY 2009 VL 15 IS 1 BP 78 EP 89 DI 10.1177/1073858408329511 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 407LG UT WOS:000263364000014 PM 19218232 ER PT J AU Hazin, R Cadet, J Kahook, M Saed, D AF Hazin, Ribhi Cadet, Jean Lud Kahook, Malik Y. Saed, Dunia TI Ocular Manifestations of Crystal Methamphetamine Use SO NEUROTOXICITY RESEARCH LA English DT Article DE Crystal methamphetamine; Meth abuse; Neurotoxicity; Ocular injury; Ocular development ID RAT RETINA; DRUG-ABUSE; INFANT DEVELOPMENT; PRENATAL EXPOSURE; PHOSPHINE GAS; LIFE-STYLE; COCAINE; AMPHETAMINE; ENVIRONMENT; INHALATION AB Numerous medical sequelae associated with illicit drug use have been reported. Nevertheless, there has been scarce documentation of the effects of these drugs on the eyes. Drug-induced ocular symptoms include decreased visual acuity, disturbances in perception, and even flashbacks. Methamphetamine (METH) is a highly addictive drug whose abuse has spread worldwide during the past two decades. METH abuse is associated with many adverse psychiatric and medical consequences including strokes and psychosis. METH-induced ophthalmic complications are rarely discussed but include retinal vasculitis, episcleritis, panophthalmitis, endophthalmitis, scleritis, retinopathy, corneal ulceration, and transient visual losses. Because the drug has shown a marked increase in the prevalence of its use amongst pregnant women, there has also been an increase of drug-induced complications in fetuses and newborn babies. These complications need to be further detailed and studied. Herein, the authors report on the ocular complications associated with METH abuse. They also discuss some potential mechanisms for the toxic effects of the drug on that system. C1 [Hazin, Ribhi] Harvard Univ, Fac Arts & Sci, Cambridge, MA 02138 USA. [Hazin, Ribhi; Saed, Dunia] Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Ophthalmol & Visual Sci, Omaha, NE 68198 USA. [Cadet, Jean Lud] NIDA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Kahook, Malik Y.] Univ Colorado, Sch Med, Rocky Mt Lions Eye Inst, Aurora, CO 80045 USA. RP Hazin, R (reprint author), Harvard Univ, Fac Arts & Sci, 219 Garden St,Suite 214, Cambridge, MA 02138 USA. EM Hazin@fas.harvard.edu NR 36 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD FEB PY 2009 VL 15 IS 2 BP 187 EP 191 DI 10.1007/s12640-009-9019-z PG 5 WC Neurosciences SC Neurosciences & Neurology GA 418XZ UT WOS:000264184700010 PM 19384581 ER PT J AU Fagan, P Rigotti, NA AF Fagan, Pebbles Rigotti, Nancy A. TI Light and intermittent smoking: The road less traveled SO NICOTINE & TOBACCO RESEARCH LA English DT Editorial Material C1 [Fagan, Pebbles] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rigotti, Nancy A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tobacco Res & Treatment Ctr, Boston, MA USA. RP Fagan, P (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4042,6130 Execut Blvd,MSC 733, Bethesda, MD 20892 USA. EM faganp@mail.nih.gov NR 14 TC 32 Z9 32 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2009 VL 11 IS 2 BP 107 EP 110 DI 10.1093/ntr/ntn015 PG 4 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 421ZA UT WOS:000264395600001 PM 19264864 ER PT J AU Fagan, P Brook, JS Rubenstone, E Zhang, CS Brook, DW AF Fagan, Pebbles Brook, Judith S. Rubenstone, Elizabeth Zhang, Chenshu Brook, David W. TI Longitudinal precursors of young adult light smoking among African Americans and Puerto Ricans SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID CIGARETTE-SMOKING; SUBSTANCE USE; RACIAL-DISCRIMINATION; DEPRESSIVE SYMPTOMS; ADOLESCENT SMOKING; SCHOOL-STUDENTS; PEER INFLUENCES; RISK BEHAVIORS; SMOKERS; HEALTH AB Studies have consistently documented the importance of examining light smoking among African American and Latino adolescent and adult smokers. Little is known, however, about the psychosocial antecedents of adolescent and young adult light smoking in these racial/ethnic minority groups. This study examined the longitudinal interrelationships and pathways leading to light smoking among African Americans (n = 288) and Puerto Ricans (n = 262). Specifically, we assessed parental factors, perceived discrimination, peer smoking, personality factors, and light smoking in late adolescence as precursors to light smoking among African American and Puerto Rican young adults. The results of structural equation modeling showed that a history of greater parental smoking, less parental educational attainment, and more perceived discrimination were each mediated by peer smoking and the youth's maladaptive personality and behavior in late adolescence. The youth's maladaptive personality and behavioral characteristics and light smoking in late adolescence, in turn, predicted light smoking in young adulthood. There were no significant racial/ethnic or gender differences in the pathways to light smoking. Findings highlight the longitudinal pathways to light smoking among African Americans and Puerto Ricans. The results suggest that effective prevention and cessation programs must address peer and parental social influences, perceived discrimination, and especially, emotional and behavioral problems in late adolescence to reduce light smoking among late adolescents and young adults in these racial/ethnic groups. C1 [Brook, Judith S.; Rubenstone, Elizabeth; Zhang, Chenshu; Brook, David W.] NYU, Dept Psychiat, Sch Med, New York, NY 10016 USA. [Fagan, Pebbles] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Brook, JS (reprint author), NYU, Dept Psychiat, Sch Med, 215 Lexington Ave,15th Floor, New York, NY 10016 USA. EM judith.brook@nyumc.org OI Zhang, Chenshu/0000-0002-3233-3905 FU National Cancer Institute [CA 084063]; National Institute on Drug Abuse of the National Institutes of Health [DA 00244, DA 05702] FX National Cancer Institute (CA 084063); National Institute on Drug Abuse of the National Institutes of Health (DA 00244 and Research Scientist Award DA 05702) to JSB. NR 59 TC 14 Z9 14 U1 3 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2009 VL 11 IS 2 BP 139 EP 147 DI 10.1093/ntr/ntp009 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 421ZA UT WOS:000264395600006 PM 19251769 ER PT J AU Reitzel, LR Costello, TJ Mazas, CA Vidrine, JI Businelle, MS Kendzor, DE Li, YS Cofta-Woerpel, L Wetter, DW AF Reitzel, Lorraine R. Costello, Tracy J. Mazas, Carlos A. Vidrine, Jennifer I. Businelle, Michael S. Kendzor, Darla E. Li, Yisheng Cofta-Woerpel, Ludmila Wetter, David W. TI Low-level smoking among Spanish-speaking Latino smokers: Relationships with demographics, tobacco dependence, withdrawal, and cessation SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID CHIPPERS AB Although recent research indicates that many Latino smokers are nondaily smokers or daily smokers who smoke at a low level (<= 5 cigarettes/day), almost no research has investigated the characteristics of low-level smokers because such individuals are typically excluded from clinical trial research. The present study examined the associations of daily smoking level and demographics, tobacco dependence, withdrawal, and abstinence during a specific quit attempt among 280 Spanish-speaking Latino smokers (54% male) who participated in a clinical trial of a telephone counseling intervention. Daily smokers were classified as low-level (1-5 cigarettes/day; n = 81), light (6-10 cigarettes/day; n = 99), or moderate/heavy smokers (>= 11 cigarettes/day; n = 100). Data were collected prior to the quit attempt and at 5 and 12 weeks postquit. Results yielded three key findings. First, smoking level was positively associated with the total score and 12 of 13 subscale scores on a comprehensive, multidimensional measure of tobacco dependence. Low-level smokers consistently reported the least dependence, and moderate/heavy smokers reported the most dependence on tobacco. Second, low-level smokers reported the least craving in pre- to postcessation longitudinal analyses. Third, despite significant differences on dependence and craving, low-level smoking was not associated with abstinence. Smoking level was not associated with demographic variables. This is a preliminary step in understanding factors influencing tobacco dependence and smoking cessation among low-level Spanish-speaking Latino smokers, a subgroup with high prevalence in the Latino population. C1 [Reitzel, Lorraine R.; Costello, Tracy J.; Mazas, Carlos A.; Vidrine, Jennifer I.; Businelle, Michael S.; Kendzor, Darla E.; Wetter, David W.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Houston, TX 77230 USA. [Li, Yisheng] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77230 USA. [Cofta-Woerpel, Ludmila] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77230 USA. [Cofta-Woerpel, Ludmila] NCI, Canc Informat Serv, Houston, TX USA. RP Reitzel, LR (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Unit 1440,POB 301402, Houston, TX 77230 USA. EM lrreitzel@mdanderson.org RI Reitzel, Lorraine/A-4843-2014; OI Reitzel, Lorraine/0000-0002-7165-5720; Costello, Tracy/0000-0001-6138-2450; Kendzor, Darla/0000-0002-7947-7981; Wetter, David/0000-0002-6366-0108; Kendzor, Darla/0000-0002-7273-1916; Businelle, Michael/0000-0002-9038-2238; LI, Yisheng/0000-0001-9847-8544 FU National Cancer Institute [R01 CA94826, R01 CA89350, R25 CA57730]; Centers for Disease Control and Prevention [K01DP001120, K01DP000086] FX Minority Health Research and Education Program of the Texas Higher Education Coordinating Board; National Cancer Institute (R01 CA94826, R01 CA89350, R25 CA57730); and Centers for Disease Control and Prevention (K01DP001120, K01DP000086). NR 23 TC 39 Z9 39 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2009 VL 11 IS 2 BP 178 EP 184 DI 10.1093/ntr/ntn021 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 421ZA UT WOS:000264395600011 PM 19246627 ER PT J AU Rutten, LJF Augustson, EM Doran, KA Moser, RP Hesse, BW AF Rutten, Lila J. Finney Augustson, Erik M. Doran, Kelly A. Moser, Richard P. Hesse, Bradford W. TI Health information seeking and media exposure among smokers: A comparison of light and intermittent tobacco users with heavy users SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SMOKING-CESSATION; CONTROLLED-TRIAL; INTERVENTION; INTERNET; PROGRAM AB Introduction: We examined population-based data to assess potential differences between light and intermittent smokers as compared with moderate to heavy tobacco users in health information-seeking behavior and attitudes and media exposure. Methods: Data from the 2003 and 2005 Health Information National Trends Surveys were combined to examine the information-seeking characteristics of light daily smokers (n = 594), intermittent smokers (n = 532), and moderate to heavy daily smokers (n = 1,131). Results: Compared with moderate to heavy daily smokers, intermittent smokers reported less exposure to television, greater trust in doctors as a source of health information, and greater intention to quit smoking. No differences in information-seeking experiences and preferences were observed between light daily smokers and moderate to heavy daily smokers. Intermittent smokers were distinct from moderate to heavy smokers in their information-seeking experiences and preferences. Discussion: The insight into the media use and information preferences of different smoking populations lays the groundwork for conducting further research to examine the information needs and preferences of smoking groups and to more effectively develop and deliver smoking cessation interventions. C1 [Rutten, Lila J. Finney] HealthPartners Res Fdn, Bloomington, MN 55425 USA. [Augustson, Erik M.; Moser, Richard P.; Hesse, Bradford W.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Hlth Commun & Informat Res Branch,NIH, Bethesda, MD 20892 USA. [Doran, Kelly A.] Div Canc Control & Populat Sci, Silver Spring, MD USA. [Doran, Kelly A.] DB Consulting Grp Inc, Silver Spring, MD USA. RP Rutten, LJF (reprint author), HealthPartners Res Fdn, 8170 33rd Ave S, Bloomington, MN 55425 USA. EM lila.j.rutten@healthpartners.com OI Hesse, Bradford/0000-0003-1142-1161 NR 30 TC 25 Z9 25 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2009 VL 11 IS 2 BP 190 EP 196 DI 10.1093/ntr/ntn019 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 421ZA UT WOS:000264395600013 PM 19264865 ER PT J AU Apinunmahakul, A Barham, V Devlin, RA AF Apinunmahakul, Amornrat Barham, Vicky Devlin, Rose Anne TI Charitable Giving, Volunteering, and the Paid Labor Market SO NONPROFIT AND VOLUNTARY SECTOR QUARTERLY LA English DT Article DE charitable giving; volunteering; labor market; altruism; philanthropy ID PUBLIC-GOODS; CROWD; MONEY; TIME; TAX AB Among the few articles that jointly determine an individual's gifts of time and money, there exists disagreement as to whether these gifts are complements or substitutes. The authors try to shed some light on this debate by expanding the analysis of private contributions to take account of whether or not the individual is working in the paid labor market. The analysis indicates that gifts of time and money are largely complementary to each other, especially for employed individuals. The donations of employed males also appear to be crowded out by government expenditures. The fact that employment status as well as gender affect how individuals respond to fiscal stimulus may have important policy implications. C1 [Apinunmahakul, Amornrat] NIDA, Sch Dev Econ, Bangkok, Thailand. [Barham, Vicky; Devlin, Rose Anne] Univ Ottawa, Ottawa, ON K1N 6N5, Canada. RP Apinunmahakul, A (reprint author), NIDA, Sch Dev Econ, Bangkok, Thailand. NR 22 TC 10 Z9 10 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0899-7640 J9 NONPROF VOLUNT SEC Q JI Nonprofit Volunt. Sect. Q. PD FEB PY 2009 VL 38 IS 1 BP 77 EP 94 DI 10.1177/0899764008315845 PG 18 WC Social Issues SC Social Issues GA 389NP UT WOS:000262100400004 ER PT J AU Altschul, SF Gertz, EM Agarwala, R Schaffer, AA Yu, YK AF Altschul, Stephen F. Gertz, E. Michael Agarwala, Richa Schaffer, Alejandro A. Yu, Yi-Kuo TI PSI-BLAST pseudocounts and the minimum description length principle SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ACID SUBSTITUTION MATRICES; SEQUENCE WEIGHTS; PROTEIN-SEQUENCE; DATABASE; ALIGNMENT; INFORMATION; HOMOLOGY; SEARCHES; BLOCKS AB Position specific score matrices (PSSMs) are derived from multiple sequence alignments to aid in the recognition of distant protein sequence relationships. The PSI-BLAST protein database search program derives the column scores of its PSSMs with the aid of pseudocounts, added to the observed amino acid counts in a multiple alignment column. In the absence of theory, the number of pseudocounts used has been a completely empirical parameter. This article argues that the minimum description length principle can motivate the choice of this parameter. Specifically, for realistic alignments, the principle supports the practice of using a number of pseudocounts essentially independent of alignment size. However, it also implies that more highly conserved columns should use fewer pseudocounts, increasing the inter-column contrast of the implied PSSMs. A new method for calculating pseudocounts that significantly improves PSI-BLAST's retrieval accuracy is now employed by default. C1 [Altschul, Stephen F.; Gertz, E. Michael; Agarwala, Richa; Schaffer, Alejandro A.; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Altschul, SF (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM altschul@ncbi.nlm.nih.gov RI Schaffer, Alejandro/F-2902-2012; OI Gertz, E. Michael/0000-0001-8390-4387 FU Intramural NIH HHS NR 35 TC 48 Z9 49 U1 0 U2 5 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 FEB PY 2009 VL 37 IS 3 BP 815 EP 824 DI 10.1093/nar/gkn981 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413YP UT WOS:000263831400025 PM 19088134 ER PT J AU Keating, CP Hill, MK Hawkes, DJ Smyth, RP Isel, C Le, SY Palmenberg, AC Marshall, JA Marquet, R Nabel, GJ Mak, J AF Keating, Cameron P. Hill, Melissa K. Hawkes, David J. Smyth, Redmond P. Isel, Catherine Le, Shu-Yun Palmenberg, Ann C. Marshall, John A. Marquet, Roland Nabel, Gary J. Mak, Johnson TI The A-rich RNA sequences of HIV-1 pol are important for the synthesis of viral cDNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REV-INDEPENDENT EXPRESSION; MURINE LEUKEMIA-VIRUS; REVERSE-TRANSCRIPTASE; GENOMIC RNA; CODON USAGE; IN-VIVO; DIMER STABILITY; NONCODING RNA; DNA FLAP AB The bias of A-rich codons in HIV-1 pol is thought to be a record of hypermutations in viral genomes that lack biological functions. Bioinformatic analysis predicted that A-rich sequences are generally associated with minimal local RNA structures. Using codon modifications to reduce the amount of A-rich sequences within HIV-1 genomes, we have reduced the flexibility of RNA sequences in pol to analyze the functional significance of these A-rich 'structurally poor' RNA elements in HIV-1 pol. Our data showed that codon modification of HIV-1 sequences led to a suppression of virus infectivity by 5-100-fold, and this defect does not correlate with, viral entry, viral protein expression levels, viral protein profiles or virion packaging of genomic RNA. Codon modification of HIV-1 pol correlated with an enhanced dimer stability of the viral RNA genome, which was associated with a reduction of viral cDNA synthesis both during HIV-1 infection and in a cell free reverse transcription assay. Our data provided direct evidence that the HIV-1 A-rich pol sequence is not merely an evolutionary artifact of enzyme-induced hypermutations, and that HIV-1 has adapted to rely on A-rich RNA sequences to support the synthesis of viral cDNA during reverse transcription, highlighting the utility of using structurally poor' RNA domains in regulating biological process. C1 [Keating, Cameron P.; Hill, Melissa K.; Hawkes, David J.; Smyth, Redmond P.; Mak, Johnson] Macfarlane Burnet Inst Med Res & Publ Hlth, Ctr Virol, Melbourne, Vic, Australia. [Hawkes, David J.; Smyth, Redmond P.; Mak, Johnson] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia. [Hill, Melissa K.; Mak, Johnson] Monash Univ, Dept Microbiol, Melbourne, Vic 3004, Australia. [Isel, Catherine; Marquet, Roland] Univ Strasbourg, CNRS, IBMC, Architecture & Reactivite ARN, Strasbourg, France. [Le, Shu-Yun] NCI, Ctr Canc Res Nanobiol Program, CCR, Frederick, MD 21701 USA. [Palmenberg, Ann C.] Univ Wisconsin, Inst Mol Virol, Madison, WI 53706 USA. [Marshall, John A.] VIDRL, Melbourne, Vic, Australia. [Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mak, J (reprint author), Macfarlane Burnet Inst Med Res & Publ Hlth, Ctr Virol, Melbourne, Vic, Australia. EM mak@burnet.edu.au RI mak, johnson/H-4605-2014; Isel, Catherine/B-9406-2015; OI mak, johnson/0000-0002-5229-5707; Isel, Catherine/0000-0001-7258-869X; Hawkes, David/0000-0002-3882-801X; Smyth, Redmond/0000-0002-1580-0671; Marquet, Roland/0000-0002-4209-3976 FU Intramural NIH HHS NR 72 TC 15 Z9 15 U1 0 U2 3 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 FEB PY 2009 VL 37 IS 3 BP 945 EP 956 DI 10.1093/nar/gkn1015 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 413YP UT WOS:000263831400037 PM 19106143 ER PT J AU Bogardus, C AF Bogardus, Clifton TI Missing Heritability and GWAS Utility SO OBESITY LA English DT Editorial Material ID BODY-MASS INDEX; HUMAN OBESITY; COMMON; POPULATION; CHILDHOOD; VARIANTS; MC4R; RISK C1 NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Bogardus, C (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM clifton_bogardus@nih.gov FU Intramural NIH HHS [Z01 DK069015-25] NR 14 TC 44 Z9 48 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD FEB PY 2009 VL 17 IS 2 BP 209 EP 210 DI 10.1038/oby.2008.613 PG 2 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 400VJ UT WOS:000262897200001 PM 19169219 ER PT J AU Caritis, SN Rouse, DJ Peaceman, AM Sciscione, A Momirova, V Spong, CY Iams, JD Wapner, RJ Varner, M Carpenter, M Lo, J Thorp, J Mercer, BM Sorokin, Y Harper, M Ramin, S Anderson, G AF Caritis, Steve N. Rouse, Dwight J. Peaceman, Alan M. Sciscione, Anthony Momirova, Valerija Spong, Catherine Y. Iams, Jay D. Wapner, Ronald J. Varner, Michael Carpenter, Marshall Lo, Julie Thorp, John Mercer, Brian M. Sorokin, Yoram Harper, Margaret Ramin, Susan Anderson, Garland CA Kennedy Shriver Natl Inst Child Hu Maternal-Fetal Med Units Network M TI Prevention of Preterm Birth in Triplets Using 17 Alpha-Hydroxyprogesterone Caproate A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; CLINICAL-TRIALS; RAT MYOMETRIUM; DELIVERY; PROGESTERONE; EXPRESSION; PREGNANCY; LABOR AB OBJECTIVE: To assess whether 17 alpha-hydroxyprogesterone caproate reduces the rate of preterm birth in women carrying triplets. METHODS: We performed this randomized, double-blinded, placebo-controlled trial in 14 centers. Healthy women with triplets were randomly assigned to weekly intramuscular injections of either 250 mg of 17 alpha-hydroxyprogesterone caproate or matching placebo, starting at 16-20 weeks and ending at delivery or 35 weeks of gestation. The primary study outcome was delivery or fetal loss before 35 weeks. RESULTS: One hundred thirty-four women were assigned, 71 to 17 alpha-hydroxyprogesterone caproate and 63 to placebo; none were lost to follow-up. Baseline demographic data were similar in the two groups. The proportion of women experiencing the primary outcome (a composite of delivery or fetal loss before 35 0/7 weeks) was similar in the two treatment groups: 83% of pregnancies in the 17 alpha-hydroxyprogesterone caproate group and 84% in the placebo group, relative risk 1.0, 95% confidence interval 0.9-1.1. The lack of benefit of 17 alpha-hydroxyprogesterone caproate was evident regardless of the conception method or whether a gestational age cutoff for delivery was set at 32 or 28 weeks. CONCLUSION: Treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with triplet gestations. C1 Univ Pittsburgh, Dept Obstet, Pittsburgh, PA USA. Univ Pittsburgh, Dept Gynecol, Pittsburgh, PA USA. Univ Alabama, Ctr Women Reprod Hlth, Birmingham, AL USA. Northwestern Univ, Chicago, IL 60611 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. Ohio State Univ, Columbus, OH 43210 USA. Columbia Univ, New York, NY USA. Univ Utah, Salt Lake City, UT USA. Brown Univ, Providence, RI USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ N Carolina, Chapel Hill, NC USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Wayne State Univ, Detroit, MI USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Texas Houston, Houston, TX USA. Univ Texas Med Branch, Galveston, TX USA. RP Caritis, SN (reprint author), 300 Halket St,Room 2229, Pittsburgh, PA 15213 USA. EM scaritis@mail.magee.edu RI Varner, Michael/K-9890-2013; OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU Etinice Kennedy Shriver National Institute of Child, Health and Human Development [HD21410, HD2 7869, HD40512, HD2 7975, HD40485, HD34208, HD40500, HD34776, HD40560, HD40544, HD27917, HD27860, HD40545, HD53097, HD36801, HD34136] FX Sopported by grants from the Etinice Kennedy Shriver National Institute of Child, Health and Human Development, (HD21410; HD2 7869; HD40512; HD2 7975; HD40485; HD34208, HD40500; HD34776; HD40560, HD40544; HD27917; HD27860; HD40545; HD53097; HD36801; HD34136). NR 23 TC 63 Z9 64 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2009 VL 113 IS 2 BP 285 EP 292 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 399YK UT WOS:000262835000006 PM 19155896 ER PT J AU Kuklina, EV Meikle, SF Jamieson, DJ Whiteman, MK Barfield, WD Hillis, SD Posner, SF AF Kuklina, Elena V. Meikle, Susan F. Jamieson, Denise J. Whiteman, Maura K. Barfield, Wanda D. Hillis, Susan D. Posner, Samuel F. TI Severe Obstetric Morbidity in the United States: 1998-2005 SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MATERNAL MORBIDITY; PREGNANCY; MORTALITY; DELIVERY; TRANSFUSION; HEMORRHAGE; OUTCOMES; RISK AB OBJECTIVE: To examine trends in the rates of severe obstetric complications and the potential contribution of changes in delivery mode and maternal characteristics to these trends. METHODS: We performed a cross-sectional study of severe obstetric complications identified from the 1998-2005 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project. Logistic regression was used to examine the effect of changes in delivery mode and maternal characteristics on rates of severe obstetric complications. RESULTS: The prevalence of delivery hospitalizations (per 1,000) complicated by at least one severe obstetric complication increased from 0.64% (n=48,645) in 1998-1999 to 0.81% (n=68,433) in 2004-2005. Rates of complications that increased significantly during the study period included renal failure by 21% (from 0.23 to 0.28), pulmonary embolism by 52% (0.12 to 0.18), adult respiratory distress syndrome by 26% (0.36 to 0.45), shock by 24% (0.15 to 0.19), blood transfusion by 92% (2.38 to 4.58), and ventilation by 21% (0.47 to 0.57). In logistic regression models, adjustment for maternal age had no effect on the increased risk for these complications in 2004-2005 relative to 1998-1999. However, after adjustment for mode of delivery, the increased risks for these complications in 2004-2005 relative to 1998-1999 were no longer significant, with the exception of pulmonary embolism (odds ratio 1.30) and blood transfusion (odds ratio 1.72). Further adjustment for payer, multiple births, and select comorbidities had little effect. CONCLUSION: Rates of severe obstetric complications increased from 1998-1999 to 2004-2005. For many of these complications, these increases were associated with the increasing rate of cesarean delivery. C1 Quantell Inc, Taneytown, MD USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Reprod Hlth, Atlanta, GA USA. RP Meikle, SF (reprint author), NICHD, CRHB, NIH, 6100 Execut Blvd,Suite 8B13C, Bethesda, MD 20892 USA. EM meikles@mail.nih.gov OI Posner, Samuel/0000-0003-1574-585X FU Intramural NIH HHS [Z99 HD999999] NR 20 TC 102 Z9 105 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2009 VL 113 IS 2 BP 293 EP 299 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 399YK UT WOS:000262835000007 PM 19155897 ER PT J AU Huff, J Infante, P AF Huff, J. Infante, P. TI Identifying cancer sites for human carcinogens in the IARC monographs SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Letter ID FORMALDEHYDE C1 [Huff, J.] NIEHS, Res Triangle Pk, NC 27709 USA. [Infante, P.] George Washington Univ, Washington, DC USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov RI Richardson, Sylvia/G-4691-2015 OI Richardson, Sylvia/0000-0003-1998-492X NR 7 TC 2 Z9 2 U1 1 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD FEB PY 2009 VL 66 IS 2 BP 140 EP 140 DI 10.1136/oem.2008.042036 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 396HG UT WOS:000262582200013 PM 19151229 ER PT J AU Ren, L Hong, SH Cassavaugh, J Osborne, T Chou, AJ Kim, SY Gorlick, R Hewitt, SM Khanna, C AF Ren, L. Hong, S. H. Cassavaugh, J. Osborne, T. Chou, A. J. Kim, S. Y. Gorlick, R. Hewitt, S. M. Khanna, C. TI The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC SO ONCOGENE LA English DT Article DE ezrin; ERM; PKC; tumor metastasis ID EZRIN/RADIXIN/MOESIN ERM PROTEINS; KINASE-C; PLASMA-MEMBRANE; EPITHELIAL-CELLS; CARCINOMA-CELLS; T-LYMPHOCYTES; CRUCIAL ROLE; PHOSPHORYLATION; EXPRESSION; MOESIN AB Ezrin is a member of the ERM (ezrin, radixin, moesin) protein family and links F-actin to the cell membrane following phosphorylation. Ezrin has been associated with tumor progression and metastasis in several cancers including the pediatric solid tumors, osteosarcoma and rhabdomyosarcoma. In this study, we were surprised to find that ezrin was not constitutively phosphorylated but rather was dynamically regulated during metastatic progression in osteosarcoma. Metastatic osteosarcoma cells expressed phosphorylated ERM early after their arrival in the lung, and then late in progression, only at the invasive front of larger metastatic lesions. To pursue mechanisms for this regulation, we found that inhibitors of PKC (protein kinase C) blocked phosphorylation of ezrin, and that ezrin coimmunoprecipitated in cells with PKC alpha, PKC iota and PKC gamma. Furthermore, phosphorylated forms of ezrin and PKC had identical expression patterns at the invasive front of pulmonary metastatic lesions in murine and human patient samples. Finally, we showed that the promigratory effects of PKC were linked to ezrin phosphorylation. These data are the first to suggest a dynamic regulation of ezrin phosphorylation during metastasis and to connect the PKC family members with this regulation. C1 [Khanna, C.] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Chou, A. J.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [Gorlick, R.] Childrens Hosp Montefiore, Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA. [Hewitt, S. M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Khanna, C (reprint author), NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res, 37 Convent Dr,Rm 2144, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov OI Chou, Alexander/0000-0002-7926-3326; Hewitt, Stephen/0000-0001-8283-1788 NR 51 TC 66 Z9 75 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB PY 2009 VL 28 IS 6 BP 792 EP 802 DI 10.1038/onc.2008.437 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 406UI UT WOS:000263320000002 PM 19060919 ER PT J AU Guo, C Gasparian, AV Zhuang, Z Bosykh, DA Komar, AA Gudkov, AV Gurova, KV AF Guo, C. Gasparian, A. V. Zhuang, Z. Bosykh, D. A. Komar, A. A. Gudkov, A. V. Gurova, K. V. TI 9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-kappa B and p53 pathways SO ONCOGENE LA English DT Article DE proteomics; quinacrine; cell death; PI3 kinase-gamma; PTEN ID RHEUMATOID-ARTHRITIS; MESSENGER-RNAS; CELLS; INFLAMMATION; PI3K-GAMMA; KINASE; TRANSLATION; INHIBITION; ACTIVATION; MECHANISM AB Acquisition of a transformed phenotype involves deregulation of several signal transduction pathways contributing to unconstrained cell growth. Understanding the interplay of different cancer-related signaling pathways is important for development of efficacious multitargeted anticancer drugs. The small molecule 9-aminoacridine (9AA) and its derivative, the antimalaria drug quinacrine, have selective toxicity for tumor cells and can simultaneously suppress nuclear factor-kappa B (NF-kappa B) and activate p53 signaling. To investigate the mechanism underlying these drug activities, we used a combination of two-dimensional protein separation by gel electrophoresis and mass spectrometry to identify proteins whose expression is altered in tumor cells by 9AA treatment. We found that 9AA treatment results in selective downregulation of a specific catalytic subunit of the phosphoinositide 3-kinase (PI3K) family, p110 gamma. Further exploration of this observation demonstrated that the mechanism of action of 9AA involves inhibition of the prosurvival AKT/ mammalian target of rapamycin (mTOR) pathway that lies downstream of PI3K. p110 gamma translation appears to be regulated by mTOR and feeds back to further modulate mTOR and AKT, there by impacting the p53 and NF-kappa B pathways as well. These results reveal functional interplay among the PI3K/AKT/mTOR, p53 and NF-kappa B pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by a single small molecule such as 9AA could result in efficacious and selective killing of transformed cells. C1 [Gudkov, A. V.; Gurova, K. V.] Roswell Pk Canc Inst, Dept Cell Stress Biol, Buffalo, NY 14263 USA. [Guo, C.] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. [Guo, C.] Lerner Res Inst, Dept Mol Genet, Cleveland, OH USA. [Gasparian, A. V.; Bosykh, D. A.; Gudkov, A. V.; Gurova, K. V.] Cleveland Biolabs Inc, Buffalo, NY USA. [Zhuang, Z.] Natl Inst Hlth, Bethesda, MD USA. [Komar, A. A.] Cleveland State Univ, Dept Biol, Ctr Gene Regulat Hlth & Dis, Cleveland, OH 44115 USA. RP Gudkov, AV (reprint author), Roswell Pk Canc Inst, Dept Cell Stress Biol, BLSC L3-301,Elm & Carlton St, Buffalo, NY 14263 USA. EM andrei.gudkov@roswellpark.org; katerina.gurova@roswellpark.org NR 29 TC 64 Z9 68 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB PY 2009 VL 28 IS 8 BP 1151 EP 1161 DI 10.1038/onc.2008.460 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 412KE UT WOS:000263722900010 PM 19137016 ER PT J AU Shi, Z Parmar, S Peng, XX Shen, T Robey, RW Bates, SE Fu, LW Shao, YN Chen, YM Zang, FY Chen, ZS AF Shi, Zhi Parmar, Smitaben Peng, Xing-Xiang Shen, Tong Robey, Robert W. Bates, Susan E. Fu, Li-Wu Shao, Yining Chen, Yang-Min Zang, Feiyang Chen, Zhe-Sheng TI The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance SO ONCOLOGY REPORTS LA English DT Article DE multidrug resistance; ABCG2; AG1478; erlotinib ID MULTIDRUG-RESISTANCE; FACTOR RECEPTOR; CANCER-CELLS; P-GLYCOPROTEIN; IMATINIB MESYLATE; IN-VITRO; HALF-TRANSPORTER; FUMITREMORGIN-C; ABCG2 BCRP; PROTEIN AB ABCG2 is an important member of ATP-binding cassette (ABC) transporter shown to confer drug resistance in cancer cells. Recent studies show that an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, is able to modulate the function of ABCG2 and reverse ABCG2-mediated multidrug resistance (MDR) in cancer cells. Additionally, ABCG2 expression has been shown to impact treatment efficacy and development of side-effects in patients receiving gefitinib. However, it is unclear whether other EGFR TKIs interact with ABCG2 in a similar manner. In the present study, we investigated the interaction of two other EGFR TKIs, AG1478 and erlotinib, with ABCG2. Our data show that AG1478 and erlotinib potently sensitized drug-resistant cells overexpressing either wild-type or mutated ABCG2 to the ABCG2 substrate anti-cancer drugs flavopiridol and mitoxantrone. Neither AG1478 nor erlotinib sensitized ABCG2-overexpressing cells to drugs that are not substrates of ABCG2 nor did they impact drug sensitivity of parental cells. Furthermore, AG1478 and erlotinib were able to significantly enhance the intracellular accumulation of mitoxantrone in cells expressing either wildtype or mutated ABCG2. Additionally, they did not alter the protein expression of ABCG2 in the ABCG2-overexpressing cells. Taken together, we conclude that AG1478 and erlotinib potently reverse ABCG2-mediated MDR through directly inhibiting the drug efflux function of ABCG2 in the ABCG2-overexpressing cells. These results will be useful in the development of novel and more effective EGFR TKIs as well as the development of combinational chemotherapeutic strategies. C1 [Shi, Zhi; Parmar, Smitaben; Peng, Xing-Xiang; Shen, Tong; Shao, Yining; Chen, Yang-Min; Zang, Feiyang; Chen, Zhe-Sheng] St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Allied Hlth Profess, Jamaica, NY 11439 USA. [Shi, Zhi; Fu, Li-Wu] Sun Yat Sen Univ, State Key Lab Oncol S China, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. [Robey, Robert W.; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chen, ZS (reprint author), St Johns Univ, Dept Pharmaceut Sci, Coll Pharm & Allied Hlth Profess, Jamaica, NY 11439 USA. EM chenz@stjohns.edu RI Shen, Tong/C-8853-2012 FU St. John's University Tenure Track Faculty Start-Up [C0531]; St. John's University [579-1110] FX We thank OSI Pharmaceuticals (Melville, NY) for providing erlotinib. This work was supported by funds from St. John's University Tenure Track Faculty Start-Up Funding (No. C0531, Z.S. Chen) and Seed Grant of St. John's University (No. 579-1110, Z.S. Chen). Z. Shi is a recipient of Kaisi fellowship for overseas study at St. John's University from Sun Yat-Sen University. Yining Shao, Yang-Min Chen and Feiyang Zang are the summer research students from high schools. NR 37 TC 34 Z9 37 U1 0 U2 10 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD FEB PY 2009 VL 21 IS 2 BP 483 EP 489 DI 10.3892/or_00000248 PG 7 WC Oncology SC Oncology GA 397RH UT WOS:000262679300031 PM 19148526 ER PT J AU Chew, EY Sperduto, RD Milton, RC Clemons, TE Gensler, GR Bressler, SB Klein, R Klein, BEK Ferris, FL AF Chew, Emily Y. Sperduto, Robert. D. Milton, Roy C. Clemons, Traci E. Gensler, Gary R. Bressler, Susan B. Klein, Ronald Klein, Barbara E. K. Ferris, Frederick L., III TI Risk of Advanced Age-Related Macular Degeneration after Cataract Surgery in the Age-Related Eye Disease Study AREDS Report 25 SO OPHTHALMOLOGY LA English DT Article ID BLUE MOUNTAINS EYE; VISUAL IMPAIRMENT; INTRAOCULAR-LENS; SEVERITY SCALE; BEAVER DAM; MACULOPATHY; ASSOCIATION; EXTRACTION; IMPLANTATION; PREVALENCE AB Purpose: To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. Design: Cohort study. Participants: Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). Methods: Development of advanced AMD, either neovascular (NV) AMD or geographic atrophy (GA), was evaluated with annual fundus photographs, and history of cataract surgery was assessed every 6 months. Cox proportional hazard models with time-dependent covariates were conducted for NV AMD and GA separately. Main Outcome Measures: Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). Results: The Cox proportional hazards model of right eyes showed nonsignificant hazard ratios of 1.20 (95% confidence interval [CI], 0.82-1.75) for NV AMD, 0.80 (95% CI, 0.61-1.06) for GA, and 0.87 (95% CI, 0.64-1.18) for CGA. Similar results were obtained for left eyes: 1.07 (95% CI, 0.72-1.58) for NV AMD, 0.94 (95% CI, 0.71-1.25) for GA, and 0.86 (95% CI, 0.63-1.19) for CGA. For participants with advanced AMD in 1 eye (AREDS category 4), the hazard ratios for fellow eyes were 1.08 (95% CI, 0.65-1.72) for NV AMD and 0.98 (95% CI, 0.64-1.49) for CGA. Conclusions. The AREDS results show-ad no clear effect of cataract surgery on the risk of progression to advanced AMD. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2009;116:297-303 (C) 2009 by the American Academy of Ophthalmology. C1 [Chew, Emily Y.; Ferris, Frederick L., III] NEI, Bethesda, MD 20892 USA. [Bressler, Susan B.] Johns Hopkins Wilmer Eye Inst, Baltimore, MD USA. [Sperduto, Robert. D.; Milton, Roy C.; Clemons, Traci E.; Gensler, Gary R.] EMMES Corp, Rockville, MD USA. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Chew, EY (reprint author), NEI, Bethesda, MD 20892 USA. OI Klein, Ronald/0000-0002-4428-6237 FU National Eye Institute; National Institutes of Health; Department of Health and Human Services, Bethesda, Maryland FX Supported by contracts from the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland. NR 22 TC 66 Z9 69 U1 1 U2 7 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 FEB PY 2009 VL 116 IS 2 BP 297 EP 303 DI 10.1016/j.ophtha.2008.09.019 PG 7 WC Ophthalmology SC Ophthalmology GA 403QW UT WOS:000263098100020 PM 19091420 ER PT J AU Imrich, R Eldadah, BA Bentho, O Pechnik, S Sharabi, Y Holmes, C Grossman, E Goldstein, DS AF Imrich, Richard Eldadah, Basil A. Bentho, Oladi Pechnik, Sandra Sharabi, Yehonatan Holmes, Courtney Grossman, Ehud Goldstein, David S. TI Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson disease; Pure autonomic failure; Sympathetic denervation; Pre-ejection period ID SYSTOLIC-TIME INTERVALS; PARKINSONS-DISEASE; DOPAMINE CONTAMINATION; TYRAMINE; VASODILATION; SENSITIVITY; ACTIVATION; PRESSURE; INDEXES AB Background: Diseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. We Studied the impact of such denervation on cardiac chronotropic and inotropic function. Methods: Cardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD+NOH or PAF (PD + NOH/PAF group, N = 13). We compared the results to those in patients with multiple system atrophy, which Usually entails NOH with normal cardiac sympathetic innervation (MSA, N = 15), and in normal control subjects (N = 5). Results: The innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD + NOR/PAF group. For similar heart rate responses, the PD + NOH/PAF group required less isoproterenol (p < 0.01) and had lower plasma isoproterenol levels (p < 0.01) than did the MSA group. Conclusions: Among patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors, Published by Elsevier Ltd. C1 [Imrich, Richard; Eldadah, Basil A.; Bentho, Oladi; Pechnik, Sandra; Holmes, Courtney; Goldstein, David S.] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. [Sharabi, Yehonatan; Grossman, Ehud] Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. [Sharabi, Yehonatan; Grossman, Ehud] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. RP Imrich, R (reprint author), Slovak Acad Sci, Inst Expt Endocrinol, Vlarska 3, SK-83306 Bratislava, Slovakia. EM richard.imrich@savba.sk OI Grossman, Ehud/0000-0001-8353-0661 FU NIH FX The research reported here was supported by the intramural research program of the NIH. NR 26 TC 18 Z9 19 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD FEB PY 2009 VL 15 IS 2 BP 122 EP 127 DI 10.1016/j.parkreldis.2008.04.002 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 407ZA UT WOS:000263401600008 PM 18514012 ER PT J AU King, JR Acosta, EP Yogev, R Wiznia, A Kraimer, J Graham, B Carey, V Britto, P Jean-Philippe, P Moye, J Watson, D AF King, Jennifer R. Acosta, Edward P. Yogev, Ram Wiznia, Andrew Kraimer, Joyce Graham, Bobbie Carey, Vincent Britto, Paula Jean-Philippe, Patrick Moye, John Watson, Douglas TI STEADY-STATE PHARMACOKINETICS OF LOPINAVIR/RITONAVIR IN COMBINATION WITH EFAVIRENZ IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PEDIATRIC PATIENTS SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV; pharmacokinetics; lopinavir/ritonavir; efavirenz ID REVERSE-TRANSCRIPTASE INHIBITORS; HIV-1-INFECTED CHILDREN; GUIDELINES AB The pharmacokinetics of lopinavir/ritonavir (LPV/RTV) 300 mg/m(2) twice daily and efavirenz (EFV) 350 mg/m(2) once daily were evaluated in HIV-infected children. The minimum concentrations for LPV contained values above the target range, and the estimated minimum concentrations for EFV contained values below the range. Our data support the current LPV/RTV dose, but EFV 350 mg/m(2) may not be sufficient. C1 [King, Jennifer R.] Univ Alabama, Div Clin Pharmacol, Birmingham, AL 35294 USA. [Yogev, Ram] Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, Chicago, IL 60614 USA. [Wiznia, Andrew] Jacobi Med Ctr, Brooklyn, NY USA. [Kraimer, Joyce] Social & Sci Syst Inc, Silver Spring, MD USA. [Graham, Bobbie] Frontier Sci & Technol Res Fdn Inc, Buffalo, NY USA. [Carey, Vincent; Britto, Paula] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn, Therapeut Res Program, DAIDS,NIH, Bethesda, MD 20892 USA. [Moye, John] NICHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Watson, Douglas] Univ Maryland, Baltimore, MD 21201 USA. RP King, JR (reprint author), Univ Alabama, Div Clin Pharmacol, 1530 3rd Ave S,VH 101A, Birmingham, AL 35294 USA. EM jennifer.king@ccc.uab.edu OI moye, john/0000-0001-9976-8586 FU National Institute of Allergy and Infectious Diseases [U01AI068632] FX Supported by grant number U01AI068632 from the National Institute of Allergy and Infectious Diseases. NR 11 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2009 VL 28 IS 2 BP 159 EP 161 DI 10.1097/INF.0b013e3181861d8b PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 401OX UT WOS:000262952100021 PM 19106779 ER PT J AU Turkbey, B Ocak, I Daryanani, K Font-Montgomery, E Lukose, L Bryant, J Tuchman, M Mohan, P Heller, T Gahl, WA Choyke, PL Gunay-Aygun, M AF Turkbey, Baris Ocak, Iclal Daryanani, Kailash Font-Montgomery, Esperanza Lukose, Linda Bryant, Joy Tuchman, Maya Mohan, Parvathi Heller, Theo Gahl, William A. Choyke, Peter L. Gunay-Aygun, Meral TI Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF) SO PEDIATRIC RADIOLOGY LA English DT Review DE Autosomal recessive polycystic kidney disease; Congenital hepatic fibrosis; US; MR cholangiography; Children ID GENE AB ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents. C1 [Font-Montgomery, Esperanza; Lukose, Linda; Bryant, Joy; Tuchman, Maya; Gahl, William A.; Gunay-Aygun, Meral] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Ocak, Iclal; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Daryanani, Kailash] NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. [Mohan, Parvathi] George Washington Univ, Dept Pediat Gastroenterol, Washington, DC USA. [Heller, Theo] NIDDK, NIH, Bethesda, MD USA. [Gunay-Aygun, Meral] NIH, Intramural Program, Off Rare Dis, Off Directors, Bethesda, MD 20892 USA. RP Gunay-Aygun, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM mgaygun@mail.nih.gov FU National Human Genome Research Institute; National Cancer Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health Clinical Center FX We thank the ARPKD/CHF Alliance and all patients and their families who generously participated in this investigation. Supported by the intramural research programs of the National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institutes of Health Clinical Center. NR 12 TC 36 Z9 43 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD FEB PY 2009 VL 39 IS 2 BP 100 EP 111 DI 10.1007/s00247-008-1064-x PG 12 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 387NK UT WOS:000261958700002 PM 19089418 ER PT J AU Kleinerman, RA AF Kleinerman, Ruth A. TI Radiation-sensitive genetically susceptible pediatric sub-populations SO PEDIATRIC RADIOLOGY LA English DT Article DE Second cancers; Radiotherapy; Retinoblastoma; Neurofibromatosis type 1; Li-Fraumeni syndrome; Nevoid basal cell carcinoma syndrome ID NERVE SHEATH TUMORS; SOFT-TISSUE SARCOMAS; LI-FRAUMENI-SYNDROME; 2ND PRIMARY TUMORS; HEREDITARY RETINOBLASTOMA; THERAPEUTIC RADIATION; SUBSTANTIAL RISKS; CHILDHOOD-CANCER; UNITED-STATES; FOLLOW-UP AB Major advances in pediatric cancer treatment have resulted in Substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to Ionizing radiation. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. RP Kleinerman, RA (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 7044, Rockville, MD 20852 USA. EM kleinerr@mail.nih.gov OI Kleinerman, Ruth/0000-0001-7415-2478 FU Intramural NIH HHS [Z01 CP010131-12] NR 38 TC 40 Z9 42 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD FEB PY 2009 VL 39 BP S27 EP S31 DI 10.1007/s00247-008-1015-6 PG 5 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 452TF UT WOS:000266563400003 PM 19083227 ER PT J AU Linet, MS Kim, KP Rajaraman, P AF Linet, Martha S. Kim, Kwang pyo Rajaraman, Preetha TI Children's exposure to diagnostic medical radiation and cancer risk: epidemiologic and dosimetric considerations SO PEDIATRIC RADIOLOGY LA English DT Review DE Ionizing radiation; Pediatric neoplasms; Cancer risks; Diagnostic radiography; CT ID ATOMIC-BOMB SURVIVORS; X-RAY-EXPOSURE; ACUTE NONLYMPHOCYTIC LEUKEMIA; CENTRAL-NERVOUS-SYSTEM; CHILDHOOD-CANCER; THYROID-CANCER; BREAST-CANCER; BRAIN-TUMORS; CARDIAC-CATHETERIZATION; INTRAUTERINE EXPOSURE AB While the etiology of most childhood cancers is largely unknown, epiderniologic studies have consistently found an association between exposure to medical radiation during pregnancy and risk of childhood cancer in offspring. The relation between early life diagnostic radiation exposure and occurrence of pediatric cancer risks is less clear. This review summarizes current and historical estimated doses for common diagnostic radiologic procedures as well as the epiderniologic literature on the role of maternal prenatal, children's postnatal and parental preconception diagnostic radiologic procedures on subsequent risk of childhood malignancies. Risk estimates are presented according to factors such as the year of birth of the child, trimester and medical indication for the procedure, and the number of films taken. The paper also discusses limitations of the methods employed in epidemiologic studies to assess pediatric cancer risks, the effects on clinical practice of the results reported from the epiderniologic studies, and clinical and public health policy implications of the findings. Gaps in understanding and additional research needs are identified. Important research priorities include nationwide surveys to estimate fetal and childhood radiation doses from common diagnostic procedures, and epiderniologic studies to quantify pediatric and lifetime cancer risks from prenatal and early childhood exposures to diagnostic radiography, CT, and fluoroscopically guided procedures. C1 [Linet, Martha S.; Kim, Kwang pyo; Rajaraman, Preetha] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Linet, MS (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Room 7048, Bethesda, MD 20892 USA. EM linetm@mail.nih.gov FU National Cancer Institute; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The authors thank Annelie Landgren for technical support. NR 126 TC 108 Z9 111 U1 5 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 EI 1432-1998 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD FEB PY 2009 VL 39 SU 1 BP S4 EP S26 DI 10.1007/s00247-008-1026-3 PG 23 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 452TF UT WOS:000266563400002 PM 19083224 ER PT J AU Havens, PL Mofenson, LM AF Havens, Peter L. Mofenson, Lynne M. TI Routine Newborn HIV Testing: An Idea Whose Time Has Come In Reply SO PEDIATRICS LA English DT Letter C1 [Havens, Peter L.] Med Coll Wisconsin, Dept Pediat, Div Infect Dis, Milwaukee, WI 53226 USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Mat AIDS Branch, Rockville, MD USA. RP Havens, PL (reprint author), Med Coll Wisconsin, Dept Pediat, Div Infect Dis, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2009 VL 123 IS 2 BP E363 EP E364 DI 10.1542/peds.2008-3681 PG 5 WC Pediatrics SC Pediatrics GA 397RB UT WOS:000262678700091 ER PT J AU Wadhawan, R Oh, W Perritt, RL McDonald, SA Das, A Poole, WK Vohr, BR Higgins, RD AF Wadhawan, Rajan Oh, William Perritt, Rebecca L. McDonald, Scott A. Das, Abhik Poole, W. Kenneth Vohr, Betty R. Higgins, Rosemary D. TI Twin Gestation and Neurodevelopmental Outcome in Extremely Low Birth Weight Infants SO PEDIATRICS LA English DT Article DE twins; neurodevelopmental impairment; extremely low birth weight infants ID ASSISTED REPRODUCTION; NEONATAL OUTCOMES; PREGNANCIES; SINGLETONS AB OBJECTIVE. The purpose of this work was to compare the risk-adjusted incidence of death or neurodevelopmental impairment at 18 to 22 months' corrected age between twin and singleton extremely low birth weight infants. We hypothesized that twin gestation is independently associated with increased risk of death or adverse neurodevelopmental outcomes at 18 to 22 months' corrected age in these infants. METHODS. We conducted a retrospective study of inborn extremely low birth weight infants admitted to Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network units between 1997 and 2005, who either died or had follow-up data available at 18 to 22 months' corrected age. Neurodevelopmental impairment, the primary outcome variable, was defined as the presence of any 1 of the following: moderate or severe cerebral palsy, severe bilateral hearing loss, bilateral blindness, Bayley Mental Developmental Index or Psychomotor Developmental Index of < 70. Death was included with neurodevelopmental impairment as a composite outcome. Results were compared for both twins, twin A, twin B, same-gender twins, unlike-gender twins, and singleton infants. Logistic regression analysis was performed to control for demographic and clinical factors that were different among the groups. RESULTS. The cohort of infants who either died or were assessed for neurodevelopmental impairment consisted of 7630 singleton infants and 1376 twins. Logistic regression adjusting for clinical and sociodemographic risk factors showed an increased risk of death or neurodevelopmental impairment for twins as a group when compared with the singletons. On analyzing twin A and B separately as well, risk of death or neurodevelopmental impairment was increased in both twin A and twin B. CONCLUSIONS. Twin gestation in extremely low birth weight infants is associated with an independent increased risk of death or neurodevelopmental impairment at 18 to 22 months' corrected age compared with singleton-gestation infants. Both first- and second-born twins are at increased risk. Pediatrics 2009; 123: e220-e227 C1 [Wadhawan, Rajan] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Oh, William; Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Div Neonatol, Providence, RI USA. [Wadhawan, Rajan; Oh, William; Perritt, Rebecca L.; McDonald, Scott A.; Das, Abhik; Poole, W. Kenneth; Vohr, Betty R.; Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Wadhawan, R (reprint author), Univ S Florida, All Childrens Hosp, 880 6th St S,Suite 470, St Petersburg, FL 33701 USA. EM wadhawar@allkids.org FU NICHD [U10 HD53124, U10 HD53119, U10 HD53109, U10 HD53089, U10 HD40689, U10 HD40521, U10 HD40498, U10 HD40492, U10 HD40461, U10 HD34216, U10 HD34167, U10 HD27904, U10 HD27881, U10 HD27880, U10 HD27871, U10 HD27856, U10 HD27853, U10 HD27851, U10 HD21415, U10 HD21397]; National Institutes of Health [CCTS UL1 RR24128, CCTS UL1 RR24148, GCRC M01 RR30, GCRC M01 RR32, GCRC M01 RR39, GCRC M01 RR44, GCRC M01 RR54, GCRC M01 RR59, GCRC M01 RR64, GCRC M01 RR70, GCRC M01 RR80, GCRC M01 RR633, GCRC M01 RR750, GCRC M01 RR997, GCRC M01 RR1032, GCRC M01 RR2172, GCRC M01 RR2588] FX This work was supported by grants from the NICHD (U10 HD53124, U10 HD53119, U10 HD53109, U10 HD53089, U10 HD40689, U10 HD40521, U10 HD40498, U10 HD40492, U10 HD40461, U10 HD34216, U10 HD34167, U10 HD27904, U10 HD27881, U10 HD27880, U10 HD27871, U10 HD27856, U10 HD27853, U10 HD27851, U10 HD21415, U10 HD21397, U10 HD21385, U10 HD21373, U10 HD21364, and U01 HD36790) and the National Institutes of Health (CCTS UL1 RR24128, CCTS UL1 RR24148, GCRC M01 RR30, GCRC M01 RR32, GCRC M01 RR39, GCRC M01 RR44, GCRC M01 RR54, GCRC M01 RR59, GCRC M01 RR64, GCRC M01 RR70, GCRC M01 RR80, GCRC M01 RR633, GCRC M01 RR750, GCRC M01 RR997, GCRC M01 RR1032, GCRC M01 RR2172, GCRC M01 RR2588, GCRC M01 RR2635, GCRC M01 RR6022, GCRC M01 RR7122, GCRC M01 RR8084, and GCRC M01 RR16587). NR 27 TC 18 Z9 19 U1 0 U2 3 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 FEB PY 2009 VL 123 IS 2 BP E220 EP E227 DI 10.1542/peds.2008-1126 PG 8 WC Pediatrics SC Pediatrics GA 397RB UT WOS:000262678700053 PM 19139085 ER PT J AU Trebak, M Lemonnier, L DeHaven, W Wedel, B Bird, G Putney, JW AF Trebak, Mohamed Lemonnier, Loic DeHaven, Wayne I. Wedel, Barbara J. Bird, Gary S. Putney, James W., Jr. TI Complex functions of phosphatidylinositol 4,5-bisphosphate in regulation of TRPC5 cation channels SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Ion channels; Non-selective cation channels; TRPC5 channels; Phosphatidylinositol 4; 5-bisphosphate; Phospholipase C ID CAPACITATIVE CALCIUM-ENTRY; RECEPTOR POTENTIAL PROTEIN; FOCAL ADHESION KINASE; TRANSIENT RECEPTOR; SIGNAL-TRANSDUCTION; PLASMA-MEMBRANE; SENSITIVE POOLS; ION CHANNELS; WORTMANNIN; CELLS AB The canonical transient receptor potential (TRPC) proteins have been recognized as key players in calcium entry pathways activated through phospholipase-C-coupled receptors. While it is clearly demonstrated that members of the TRPC3/6/7 subfamily are activated by diacylglycerol, the mechanism by which phospholipase C activates members of the TRPC1/4/5 subfamily remains a mystery. In this paper, we provide evidence for both negative and positive modulatory roles for membrane polyphosphoinositides in the regulation of TRPC5 channels. Depletion of polyphosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate (PIP(2)) through inhibition of phosphatidylinositol 4-kinase activates calcium entry and membrane currents in TRPC5-expressing but not in TRPC3- or TRPC7-expressing cells. Inclusion of polyphosphatidylinositol 4-phosphate or PIP(2), but not phosphatidylinositol 3,4,5-trisphosphate, in the patch pipette inhibited TRPC5 currents. Paradoxically, depletion of PIP(2) with a directed 5-phosphatase strategy inhibited TRPC5. Furthermore, when the activity of single TRPC5 channels was examined in excised patches, the channels were robustly activated by PIP(2). These findings indicate complex functions for regulation of TRPC5 by PIP(2), and we propose that membrane polyphosphoinositides may have at least two distinct functions in regulating TRPC5 channel activity. C1 [Trebak, Mohamed; Lemonnier, Loic; DeHaven, Wayne I.; Wedel, Barbara J.; Bird, Gary S.; Putney, James W., Jr.] NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM trebakm@mail.amc.edu; putney@niehs.nih.gov RI Trebak, Mohamed/E-7405-2014 FU National Institute of Environmental Health Sciences; National Institutes of Health [Z01 ES090087] FX We are grateful to Dr. Lutz Birnbaumer who provided the plasmid containing the cDNA for murine TRPC5 and Dr. Tamas Balla who provided the constructs for plasma membrane targeting of PIP2 phosphatase. Drs. David Armstrong, Jerrel Yakel, Guillermo Vazquez, Jason Mercer, and Jeremy Smyth read the manuscript and provided useful criticism. This work was supported by the Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health, project number Z01 ES090087. NR 68 TC 49 Z9 53 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD FEB PY 2009 VL 457 IS 4 BP 757 EP 769 DI 10.1007/s00424-008-0550-1 PG 13 WC Physiology SC Physiology GA 397RO UT WOS:000262680000005 PM 18665391 ER PT J AU Garbuzenko, OB Saad, M Betigeri, S Zhang, M Vetcher, AA Soldatenkov, VA Reimer, DC Pozharov, VP Minko, T AF Garbuzenko, Olga B. Saad, Maha Betigeri, Seema Zhang, Min Vetcher, Alexandre A. Soldatenkov, Viatcheslav A. Reimer, David C. Pozharov, Vitaly P. Minko, Tamara TI Intratracheal Versus Intravenous Liposomal Delivery of siRNA, Antisense Oligonucleotides and Anticancer Drug SO PHARMACEUTICAL RESEARCH LA English DT Article DE antisense oligonucleotides; imaging; liposomes; local lung delivery of siRNA; lung cancer; pulmonary delivery ID IN-VITRO CYTOTOXICITY; ANTITUMOR-ACTIVITY; CIRCULATION TIME; DNA COMPLEXES; SOLID TUMOR; VIVO; PHARMACOKINETICS; DOXORUBICIN; EFFICACY; SYSTEM AB Purpose. To compare systemic intravenous and local intratracheal delivery of doxorubicin (DOX), antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Methods. "Neutral" and cationic liposomes were used to deliver DOX, ASO, and siRNA. Liposomes were characterized by dynamic light scattering, zeta-potential, and atomic force microscopy. Cellular internalization of DOX, ASO and siRNA was studied by confocal microscopy on human lung carcinoma cells. In vivo experiments were carried out on nude mice with an orthotopic model of human lung cancer. Results. Liposomes provided for an efficient intracellular delivery of DOX, ASO, and siRNA in vitro. Intratracheal delivery of both types of liposomes in vivo led to higher peak concentrations and much longer retention of liposomes, DOX, ASO and siRNA in the lungs when compared with systemic administration. It was found that local intratracheal treatment of lung cancer with liposomal DOX was more efficient when compared with free and liposomal DOX delivered intravenously. Conclusions. The present study outlined the clear advantages of local intratracheal delivery of liposomal drugs for the treatment of lung cancer when compared with systemic administration of the same drug. C1 [Garbuzenko, Olga B.; Saad, Maha; Betigeri, Seema; Zhang, Min; Pozharov, Vitaly P.; Minko, Tamara] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Pharmaceut, Piscataway, NJ 08854 USA. [Vetcher, Alexandre A.] George Mason Univ, Natl Ctr Biodef & Infect Dis, Manassas, VA USA. [Soldatenkov, Viatcheslav A.] Georgetown Univ, Med Ctr, Dept Radiat Med, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Reimer, David C.] Rutgers State Univ, Lab Anim Serv, Piscataway, NJ 08854 USA. [Vetcher, Alexandre A.] Alcyon Bio Inc, Germantown, MD 20874 USA. [Soldatenkov, Viatcheslav A.] NCI, DEA, SRLB, NIH, Bethesda, MD 20892 USA. RP Minko, T (reprint author), Rutgers State Univ, Ernest Mario Sch Pharm, Dept Pharmaceut, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM minko@rci.rutgers.edu FU NIH [CA100098, CA111766, CA074145]; National Cancer Institute [LCD-23812-N]; American Lung Association of New Jersey FX The research was supported in part by NIH grants CA100098, CA111766, and CA074145 from the National Cancer Institute and by a LCD-23812-N grant from the American Lung Association of New Jersey. NR 44 TC 74 Z9 77 U1 3 U2 17 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES-DORD JI Pharm. Res. PD FEB PY 2009 VL 26 IS 2 BP 382 EP 394 DI 10.1007/s11095-008-9755-4 PG 13 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 396CS UT WOS:000262570400013 PM 18958402 ER PT J AU Kim, I Kong, H Lee, Y Hong, SC Han, JO Jung, SH Jung, YJ Kim, YM AF Kim, Inho Kong, Hyesik Lee, Younghyun Hong, Sungchae Han, Jungoh Jung, Sunhwa Jung, Yunjin Kim, Young Mi TI Dexamethasone 21-Sulfate Improves the Therapeutic Properties of Dexamethasone Against Experimental Rat Colitis by Specifically Delivering the Steroid to the Large Intestine SO PHARMACEUTICAL RESEARCH LA English DT Article DE colon specific prodrug; dexamethasone; dexamethasone 21-sulfate; inflammatory bowel disease; systemic adverse effect ID INFLAMMATORY-BOWEL-DISEASE; APPENDED ALPHA-CYCLODEXTRIN; COLON-SPECIFIC DELIVERY; DRUG-DELIVERY; POTENTIAL PRODRUGS; PREDNISOLONE; TRANSPORT; SODIUM AB Purpose. We investigated in vivo-colon targetability and therapeutic properties of DS against experimental rat colitis. Methods. The systemic absorption and colonic delivery of D after oral administration of DS was analyzed by examining the concentration of drugs in the GI tract, plasma, urine and feces. Therapeutic activity of DS was determined using a TNBS-induced rat colitis model. Adrenal suppression by DS administration was evaluated by monitoring the concentration of ACTH and corticosterone in the plasma. Results. DS administered orally was delivered efficiently to the large intestine resulting in D accumulation at the target site. In addition, DS was not detectable in the plasma and was detected very low in the urine after DS administration. The fecal and urinary recovery of D ( after DS administration) was much greater and less than that after D administration, suggesting that DS should exhibit enhanced therapeutic activity and reduced systemic side effects. Consistent with this notion, DS was more effective than D in healing rat colitis. Moreover, oral administration of either D or DS reduced the plasma corticosterone and ACTH levels from the normal levels, which is significantly greater for D. Conclusion. DS is a promising colon specific prodrug that improves therapeutic properties of D C1 [Kim, Inho; Lee, Younghyun; Hong, Sungchae; Han, Jungoh; Jung, Sunhwa; Jung, Yunjin; Kim, Young Mi] Pusan Natl Univ, Coll Pharm, Lab Biomed Med Chem, Pusan 609735, South Korea. [Kong, Hyesik] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Jung, YJ (reprint author), Pusan Natl Univ, Coll Pharm, Lab Biomed Med Chem, Pusan 609735, South Korea. EM jungy@pusan.ac.kr; ymikim@pusan.ac.kr NR 20 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES-DORD JI Pharm. Res. PD FEB PY 2009 VL 26 IS 2 BP 415 EP 421 DI 10.1007/s11095-008-9758-1 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 396CS UT WOS:000262570400016 PM 18958401 ER PT J AU Shukla, S Zaher, H Hartz, A Bauer, B Ware, JA Ambudkar, SV AF Shukla, Suneet Zaher, Hani Hartz, Anika Bauer, Bjorn Ware, Joseph A. Ambudkar, Suresh V. TI Curcumin Inhibits the Activity of ABCG2/BCRP1, a Multidrug Resistance-Linked ABC Drug Transporter in Mice SO PHARMACEUTICAL RESEARCH LA English DT Article DE ABC transporter; ABCG2; curcumin; multidrug resistance; sulfasalazine ID BLOOD-BRAIN-BARRIER; GLYCOPROTEIN UP-REGULATION; NECROSIS-FACTOR-ALPHA; BREAST-CANCER CELLS; P-GLYCOPROTEIN; PROTEIN ABCG2; MODULATION; EXPRESSION; BIOAVAILABILITY; SULFASALAZINE AB Purpose. To evaluate the in vivo efficacy of curcumin as an inhibitor of the multidrug-resistance-linked ATP Binding Cassette (ABC) drug transporter, ABCG2. Methods. Photoaffinity labeling with [I-125]-iodoarylazidoprazosin was used to characterize the interaction of sulfasalazine, a substrate of the mouse ABCG2, with human ABCG2. In addition, the inhibitory effect of curcumin on ABCG2 was evaluated in brain capillaries from rats. Furthermore, the effect of curcumin on absorption of orally administered sulfasalazine in wild-type and abcg2(-/-)mice was also determined. Results. Sulfasalazine interacted at the drug-substrate site(s) of human ABCG2. Curcumin inhibited ABCG2 activity at nanomolar concentrations at the rat blood-brain barrier in the ex vivo assay. Based on studies in wild type and abcg2(-/-) mice, we observed that oral curcumin increased C-max and relative bioavailability of sulfasalazine by selectively inhibiting ABCG2 function. Conclusions. This study validates our previous in vitro results with human ABCG2 (Chearwae et al., Mol. Cancer Ther. 5:1995-2006, 2006) and provides the first in vivo evidence for the inhibition by curcumin of ABCG2-mediated efflux of sulfasalazine in mice. Based on these studies, we propose that non-toxic concentrations of curcumin may be used to enhance drug exposure when the rate-limiting step of drug absorption and/or tissue distribution is impacted by ABCG2. C1 [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Zaher, Hani; Ware, Joseph A.] Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Ann Arbor, MI 48105 USA. [Hartz, Anika] Univ Minnesota, Sch Med, Dept Biochem & Mol Biochem, Duluth, MN 55812 USA. [Bauer, Bjorn] Univ Minnesota, Coll Pharm, Dept Pharmaceut Sci, Duluth, MN 55812 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI shukla, suneet/B-4626-2012 FU 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, National Cancer Institute, Center for Cancer Research. We thank Dr. Krishnamachary Nandigama for providing ABCG2-expressing Hi-five insect cell crude membranes and George Leiman for editorial assistance. The authors wish to acknowledge the contribution of Joe Palandra of Pfizer Global Research and Development for his assistance in determination of SASP bioanalysis and for the input of Lisa Bernstein, Nonclinical Biostatistics, Genentech, Inc. NR 43 TC 70 Z9 75 U1 1 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD FEB PY 2009 VL 26 IS 2 BP 480 EP 487 DI 10.1007/s11095-008-9735-8 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 396CS UT WOS:000262570400024 PM 18841445 ER PT J AU Radinger, M Lotvall, J AF Radinger, Madeleine Loetvall, Jan TI Eosinophil progenitors in allergy and asthma - Do they matter? SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Allergic inflammation; Eosinophil progenitor cells; Hematopoiesis; Therapy; CCR3 ID IL-5 RECEPTOR-ALPHA; BONE-MARROW EOSINOPHILOPOIESIS; COLONY-STIMULATING FACTOR; MONOCYTE CHEMOATTRACTANT PROTEIN-3; NONATOPIC INTRINSIC ASTHMATICS; MAJOR BASIC-PROTEIN; GUINEA-PIG MODEL; CD8(+) T-CELLS; MURINE MODEL; CD34(+) CELLS AB Allergic inflammation is associated with marked infiltration of eosinophils in affected tissues. The eosinophil is believed to be a key effector cells in allergen induced asthma pathogenesis. However, the role of eosinophils in the clinical manifestation of asthma has recently been questioned, since therapies directed against eosinophil infiltration (i.e. anti-interieukin-5) failed to improve clinical symptoms such as airways hyper-responsiveness (AHR) in patients with asthma. Although eosinophils in peripheral blood and the airways were largely depleted after anti-IL-5 treatment, residual eosinophilia in lung tissue persisted, which permits speculation that the remaining eosinophils may be sufficient to drive the asthma symptomatology. Furthermore, recent findings suggest that primitive eosinophil progenitor cells traffic from the bone marrow to sites of inflammation in response to allergen exposure. These progenitors may then differentiate in situ and thus provide an ongoing supply of mature pro-inflammatory cells and secretory mediators that augment the inflammatory response. In the present article, we will review the evidence for these findings, and discuss the rationale for targeting hematopoiesis and their migration pathways in the treatment of allergic diseases. Furthermore, this review will highlight the hypothesis that both IL-5- and CCR3-mediated signaling pathways may need to be targeted in order to control the inflammation and AHR associated with asthma. Published by Elsevier Inc. C1 [Radinger, Madeleine] NIAID, Lab Allerg Dis, NIH, Mast Cell Biol Sect, Bethesda, MD 20892 USA. [Loetvall, Jan] Univ Gothenburg, Lung Pharmacol Grp, Dept Internal Med Resp Med & Allergol, Sahlgrenska Acad, Gothenburg, Sweden. RP Radinger, M (reprint author), NIAID, Lab Allerg Dis, NIH, Mast Cell Biol Sect, Bldg 10,Room 11C209,10 Ctr Dr,MSC1881, Bethesda, MD 20892 USA. EM radingerm@niaid.nih.gov OI Lotvall, Jan/0000-0001-9195-9249 FU Division of Intramural Research, National Institute of Allergy and Infection Diseases FX The authors are supported by the Swedish Heart and Lung Foundation. Dr Madeleine RAdinger is in part supported by the Division of Intramural Research, National Institute of Allergy and Infection Diseases. NR 150 TC 33 Z9 33 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2009 VL 121 IS 2 BP 174 EP 184 DI 10.1016/j.pharmthera.2008.10.008 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 419RD UT WOS:000264236100005 PM 19059433 ER PT J AU Minh, DDL Adib, AB AF Minh, David D. L. Adib, Artur B. TI Path integral analysis of Jarzynski's equality: Analytical results SO PHYSICAL REVIEW E LA English DT Article DE Brownian motion; harmonic oscillators; nonequilibrium thermodynamics ID FREE-ENERGY DIFFERENCES AB We apply path integrals to study nonequilibrium work theorems in the context of Brownian dynamics, deriving in particular the equations of motion governing the most typical and most dominant trajectories. For the analytically soluble cases of a moving harmonic potential and a harmonic oscillator with a time-dependent natural frequency, we find such trajectories, evaluate the work-weighted propagators, and validate Jarzynski's equality. C1 [Minh, David D. L.; Adib, Artur B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Minh, DDL (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM daveminh@gmail.com; adiba@mail.nih.gov RI Minh, David/A-4655-2009 OI Minh, David/0000-0002-4802-2618 FU NIH; NIDDK FX The authors are indebted to Attila Szabo for numerous discussions. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 16 TC 12 Z9 12 U1 1 U2 5 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD FEB PY 2009 VL 79 IS 2 AR 021122 DI 10.1103/PhysRevE.79.021122 PG 5 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 413QJ UT WOS:000263807300029 PM 19391721 ER PT J AU Loftus, SK Antonellis, A Matera, I Renaud, G Baxter, LL Reid, D Wolfsberg, TG Chen, YD Wang, CW Prasad, MK Bessling, SL McCallion, AS Green, ED Bennett, DC Pavan, WJ AF Loftus, Stacie K. Antonellis, Anthony Matera, Ivana Renaud, Gabriel Baxter, Laura L. Reid, Duncan Wolfsberg, Tyra G. Chen, Yidong Wang, ChenWei Prasad, Megana K. Bessling, Seneca L. McCallion, Andrew S. Green, Eric D. Bennett, Dorothy C. Pavan, William J. CA NISC Comparative Sequencing TI Gpnmb is a melanoblast-expressed, MITF-dependent gene SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE Gpnmb; Mitf; Sox10; melanoblast; melanocyte; melanoma ID MELANOCYTE-SPECIFIC EXPRESSION; TRANSCRIPTION FACTOR; DOPACHROME-TAUTOMERASE; EMBRYONIC-DEVELOPMENT; WAARDENBURG-SYNDROME; MALIGNANT-MELANOMA; MOUSE MELANOCYTES; SOX10 MUTATION; DBA/2J MICE; MICROPHTHALMIA AB Expression profile analysis clusters Gpnmb with known pigment genes, Tyrp1, Dct, and Si. During development, Gpnmb is expressed in a pattern similar to Mitf, Dct and Si with expression vastly reduced in Mitf mutant animals. Unlike Dct and Si, Gpnmb remains expressed in a discrete population of caudal melanoblasts in Sox10-deficient embryos. To understand the transcriptional regulation of Gpnmb we performed a whole genome annotation of 2,460,048 consensus MITF binding sites, and cross-referenced this with evolutionarily conserved genomic sequences at the GPNMB locus. One conserved element, GPNMB-MCS3, contained two MITF consensus sites, significantly increased luciferase activity in melanocytes and was sufficient to drive expression in melanoblasts in vivo. Deletion of the 5'-most MITF consensus site dramatically reduced enhancer activity indicating a significant role for this site in Gpnmb transcriptional regulation. Future analysis of the Gpnmb locus will provide insight into the transcriptional regulation of melanocytes, and Gpnmb expression can be used as a marker for analyzing melanocyte development and disease progression. C1 [Loftus, Stacie K.; Antonellis, Anthony; Matera, Ivana; Renaud, Gabriel; Baxter, Laura L.; Reid, Duncan; Wolfsberg, Tyra G.; Wang, ChenWei; Green, Eric D.; Pavan, William J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Matera, Ivana] Inst G Gaslini, Genet Mol Lab, Genoa, Italy. [Chen, Yidong] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Green, Eric D.; NISC Comparative Sequencing] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Prasad, Megana K.; Bessling, Seneca L.; McCallion, Andrew S.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Bennett, Dorothy C.] St Georges Univ London, Div Basic Med Sci, London, England. RP Loftus, SK (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM sloftus@mail.nih.gov RI Bennett, Dorothy/C-2418-2008 OI Bennett, Dorothy/0000-0002-3639-7527 FU National Human Genome Research Institute's (NHGRI) Intramural Research Program FX We would like to acknowledge Shih-Queen Lee-Lin for expert technical assistance, Abdel Elkahloun for technical assistance with microarray hybridizations, Julia Feckes for graphics assistance and NIH Intramural Sequencing Center (NISC) for generating sequence data. Handling of mice was performed in accordance with NIH guidelines under animal care and use mouse protocol G94-7. All zebrafish work was performed under protocols approved by the Johns Hopkins University Animal Care and Use Committee. This work was supported in part by the National Human Genome Research Institute's (NHGRI) Intramural Research Program. NR 49 TC 25 Z9 28 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD FEB PY 2009 VL 22 IS 1 BP 99 EP 110 DI 10.1111/j.1755-148X.2008.00518.x PG 12 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 395GV UT WOS:000262513500014 PM 18983539 ER PT J AU Arnheiter, H AF Arnheiter, Heinz TI 'A response to 'Mammalian paramutation: a tail's tale?'- a commentary by H. Arnheiter on our paramutation paper'- a reply SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Letter ID INHERITANCE; MOUSE C1 Natl Inst Neurol Disorders & Stroke, Mammalian Dev Sect, NIH, Bethesda, MD USA. RP Arnheiter, H (reprint author), Natl Inst Neurol Disorders & Stroke, Mammalian Dev Sect, NIH, Bethesda, MD USA. EM ha3p@nih.gov NR 3 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD FEB PY 2009 VL 22 IS 1 BP 142 EP 143 DI 10.1111/j.1755-148X.2008.00522.x PG 2 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 395GV UT WOS:000262513500022 ER PT J AU Kovalchuk, I Lyudvikova, Y Volgina, M Reed, BM AF Kovalchuk, Irina Lyudvikova, Yelena Volgina, Mariam Reed, Barbara M. TI Medium, container and genotype all influence in vitro cold storage of apple germplasm SO PLANT CELL TISSUE AND ORGAN CULTURE LA English DT Article DE In vitro storage; Malus domestica; Malus sieversii; Micropropagation; Germplasm storage ID SLOW-GROWTH; INVITRO; SURVIVAL; SHOOTS AB The goal of this study was to evaluate the in vitro storage of apple germplasm by screening a range of genotypes followed by more comprehensive testing of multiple parameters on two genotypes of differing species, Malus domestica cultivar Grushovka Vernenskaya and wild Malus sieversii selection TM-6. Stored plants were rated on a 6 point scale (0 low to 5 high) for plant appearance at 3 month intervals after storage at 4A degrees C. Combinations of carbon source (sucrose and/or mannitol), nitrate nitrogen content (25, 50 or 100%) and plant growth regulators (ABA, BAP, IBA) were studied in three types of containers (tissue culture bags, test tubes or jars). An initial screen of 16 genotypes stored in tissue culture bags indicated that plantlets could be stored at 4A degrees C for 9-14 months without subculture on standard 3% sucrose Murashige and Skoog (1962) (MS) medium with no plant growth regulators (PGRs). In subsequent in-depth studies on the two genotypes, ANOVA indicated highly significant interactions of medium, container and genotype. 'Grushovka Vernenskaya' shoots with no PGRs and 3% sucrose remained viable (ratings of a parts per thousand yen1) for 21 months of storage in bags. Storage on reduced nitrogen (MS with 25% nitrogen), PGRs, and 3% sucrose kept 'Grushovka Vernenskaya' shoot condition rated > 2 at 21 months. Addition of 0.5 or 1 mg(-1) abscisic acid (ABA) also improved plant ratings at 21 months. The longest storage for 'Grushovka Vernenskaya' was 33-39 months with PGRs and 3% sucrose in either tubes or jars. Addition of abscisic acid (ABA) to the medium did not improve storage of plantlets in jars and tubes at 15 months. TM-6 stored best in tubes on 3% sucrose with PGRs or in jars on 2% mannitol and 2% sucrose. Overall it appears that cold storage of apple shoot cultures can be successful for 21 months in tissue culture bags with 25% MS nitrate nitrogen, 3% sucrose, and no PGRs or for 33 months in jars or tubes on MS with 3% sucrose and PGRs. Preliminary RAPD analysis found no significant differences between plants stored for 39 months and non-stored controls. C1 [Reed, Barbara M.] USDA ARS, Natl Clonal Germplasm Repository, Corvallis, OR 97333 USA. [Kovalchuk, Irina; Lyudvikova, Yelena; Volgina, Mariam] Natl Biotechnol Ctr, Inst Plant Biol & Biotechnol, Alma Ata 050040, Kazakhstan. RP Reed, BM (reprint author), USDA ARS, Natl Clonal Germplasm Repository, 33447 Peoria Rd, Corvallis, OR 97333 USA. EM kovalchuk_i_u@mail.ru; Barbara.Reed@ars.usda.gov OI Reed, Barbara/0000-0003-0079-8473 FU International Science and Technology Center [K428]; USDA-ARS CRIS [5358-21000-033D] FX This research was supported by funds from the International Science and Technology Center Grant K428 and USDA-ARS CRIS project 5358-21000-033D. NR 20 TC 24 Z9 26 U1 1 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6857 J9 PLANT CELL TISS ORG JI Plant Cell Tissue Organ Cult. PD FEB PY 2009 VL 96 IS 2 BP 127 EP 136 DI 10.1007/s11240-008-9468-8 PG 10 WC Biotechnology & Applied Microbiology; Plant Sciences SC Biotechnology & Applied Microbiology; Plant Sciences GA 389JM UT WOS:000262088700002 ER PT J AU Sethi, AJ Angerer, RC Angerer, LM AF Sethi, Aditya J. Angerer, Robert C. Angerer, Lynne M. TI Gene Regulatory Network Interactions in Sea Urchin Endomesoderm Induction SO PLOS BIOLOGY LA English DT Article ID NUCLEAR BETA-CATENIN; ENDODERM DIFFERENTIATION; CELL FATE; MICROMERE-DESCENDANTS; EMBRYO; SPECIFICATION; EXPRESSION; BLASTOMERES; XENOPUS; AXIS AB A major goal of contemporary studies of embryonic development is to understand large sets of regulatory changes that accompany the phenomenon of embryonic induction. The highly resolved sea urchin pregastrular endomesoderm-gene regulatory network (EM-GRN) provides a unique framework to study the global regulatory interactions underlying endomesoderm induction. Vegetal micromeres of the sea urchin embryo constitute a classic endomesoderm signaling center, whose potential to induce archenteron formation from presumptive ectoderm was demonstrated almost a century ago. In this work, we ectopically activate the primary mesenchyme cell-GRN (PMC-GRN) that operates in micromere progeny by misexpressing the micromere determinant Pmar1 and identify the responding EM-GRN that is induced in animal blastomeres. Using localized loss-of-function analyses in conjunction with expression of endo16, the molecular definition of micromere-dependent endomesoderm specification, we show that the TGF beta cytokine, ActivinB, is an essential component of this induction in blastomeres that emit this signal, as well as in cells that respond to it. We report that normal pregastrular endomesoderm specification requires activation of the Pmar1-inducible subset of the EM-GRN by the same cytokine, strongly suggesting that early micromere-mediated endomesoderm specification, which regulates timely gastrulation in the sea urchin embryo, is also ActivinB dependent. This study unexpectedly uncovers the existence of an additional uncharacterized micromere signal to endomesoderm progenitors, significantly revising existing models. In one of the first network-level characterizations of an intercellular inductive phenomenon, we describe an important in vivo model of the requirement of ActivinB signaling in the earliest steps of embryonic endomesoderm progenitor specification. C1 [Sethi, Aditya J.; Angerer, Robert C.; Angerer, Lynne M.] Natl Inst Dental & Craniofacial Res, NIH, Bethesda, MD USA. RP Angerer, LM (reprint author), Natl Inst Dental & Craniofacial Res, NIH, Bethesda, MD USA. EM langerer@mail.nih.gov FU National Institute of Dental and Craniofacial Research, National Institutes of Health [NIH-GM25553] FX This work was supported initially by a grant to RCA (NIH-GM25553) and recently by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 22 Z9 22 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD FEB PY 2009 VL 7 IS 2 BP 248 EP 264 AR e1000029 DI 10.1371/journal.pbio.1000029 PG 17 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 410SZ UT WOS:000263599900007 PM 19192949 ER PT J AU Bruzzone, R Dubois-Dalcq, M Grau, GE Griffin, DE Kristensson, K AF Bruzzone, Roberto Dubois-Dalcq, Monique Grau, Georges E. Griffin, Diane E. Kristensson, Krister TI Infectious Diseases of the Nervous System and Their Impact in Developing Countries SO PLOS PATHOGENS LA English DT Editorial Material ID HUMAN AFRICAN TRYPANOSOMIASIS; CEREBRAL MALARIA; HIV; PATHOGENESIS; VIRUSES; TROPISM; BRAIN C1 [Bruzzone, Roberto] Univ Hong Kong, Pasteur Res Ctr, Hong Kong, Hong Kong, Peoples R China. [Dubois-Dalcq, Monique] NINDS, NIH, Bethesda, MD 20892 USA. [Grau, Georges E.] Univ Sidney, Dept Pathol, Sydney, NSW, Australia. [Grau, Georges E.] Bosch Inst, Sydney, NSW, Australia. [Griffin, Diane E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Kristensson, Krister] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. RP Bruzzone, R (reprint author), Univ Hong Kong, Pasteur Res Ctr, Hong Kong, Hong Kong, Peoples R China. EM bruzzone@hku.hk RI Bruzzone, Roberto/C-4719-2009; Grau, Georges/D-7690-2014 OI Bruzzone, Roberto/0000-0003-4373-1447; Grau, Georges/0000-0002-0442-0462 FU Arthritis Research UK; NINDS NIH HHS [R01 NS038932]; Wellcome Trust NR 22 TC 7 Z9 7 U1 0 U2 4 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 FEB PY 2009 VL 5 IS 2 AR e1000199 DI 10.1371/journal.ppat.1000199 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 415IR UT WOS:000263928000001 PM 19247436 ER PT J AU Lim, JK Lisco, A McDermott, DH Huynh, L Ward, JM Johnson, B Johnson, H Pape, J Foster, GA Krysztof, D Follmann, D Stramer, SL Margolis, LB Murphy, PM AF Lim, Jean K. Lisco, Andrea McDermott, David H. Huynh, Linda Ward, Jerrold M. Johnson, Bernard Johnson, Hope Pape, John Foster, Gregory A. Krysztof, David Follmann, Dean Stramer, Susan L. Margolis, Leonid B. Murphy, Philip M. TI Genetic Variation in OAS1 Is a Risk Factor for Initial Infection with West Nile Virus in Man SO PLOS PATHOGENS LA English DT Article ID UNITED-STATES; HEPATITIS-C; RNASE-L; 2'-5'-OLIGOADENYLATE SYNTHETASE; FLAVIVIRUS RESISTANCE; ENZYME-ACTIVITY; BLOOD-DONORS; NEW-YORK; INTERFERON; SUSCEPTIBILITY AB West Nile virus (WNV) is a re-emerging pathogen that can cause fatal encephalitis. In mice, susceptibility to WNV has been reported to result from a single point mutation in oas1b, which encodes 2'-5' oligoadenylate synthetase 1b, a member of the type I interferon-regulated OAS gene family involved in viral RNA degradation. In man, the human ortholog of oas1b appears to be OAS1. The 'A' allele at SNP rs10774671 of OAS1 has previously been shown to alter splicing of OAS1 and to be associated with reduced OAS activity in PBMCs. Here we show that the frequency of this hypofunctional allele is increased in both symptomatic and asymptomatic WNV seroconverters (Caucasians from five US centers; total n = 501; OR = 1.6 [95% CI 1.2-2.0], P = 0.0002 in a recessive genetic model). We then directly tested the effect of this SNP on viral replication in a novel ex vivo model of WNV infection in primary human lymphoid tissue. Virus accumulation varied markedly among donors, and was highest for individuals homozygous for the 'A' allele (P, 0.0001). Together, these data identify OAS1 SNP rs10774671 as a host genetic risk factor for initial infection with WNV in humans. C1 [Lim, Jean K.; McDermott, David H.; Huynh, Linda; Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Lisco, Andrea; Margolis, Leonid B.] NICHHD, Sect Intercellular Interact, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Ward, Jerrold M.] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Johnson, Bernard; Johnson, Hope] Illinois Dept Publ Hlth, Div Labs, Chicago, IL USA. [Pape, John] Colorado Dept Publ Hlth & Environm, Denver, CO USA. [Foster, Gregory A.; Krysztof, David; Stramer, Susan L.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Follmann, Dean] Amer Red Cross, Gaithersburg, MD USA. RP Lim, JK (reprint author), NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov OI McDermott, David/0000-0001-6978-0867 FU Intramural Research Program of the NIH/NIAID/DIR FX This research was supported by the Intramural Research Program of the NIH/NIAID/DIR. NR 44 TC 98 Z9 101 U1 1 U2 9 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 FEB PY 2009 VL 5 IS 2 AR e1000321 DI 10.1371/journal.ppat.1000321 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 415IR UT WOS:000263928000012 PM 19247438 ER PT J AU Buice, MA Cowan, JD AF Buice, Michael A. Cowan, Jack D. TI Statistical mechanics of the neocortex SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Statistical mechanics; Field theory; Neocortex; Criticality; Scaling laws; Directed percolation; Critical branching; Spike model; Epilepsy; Random and rhythmic activity ID FOREST-FIRE MODEL; SELF-ORGANIZED CRITICALITY; REGGEON FIELD-THEORY; RANGE TEMPORAL CORRELATIONS; NEURAL SPIKE TRAIN; PHASE-TRANSITIONS; RENORMALIZATION-GROUP; STOCHASTIC RESONANCE; SYNAPTIC DEPRESSION; CRITICAL-BEHAVIOR AB We analyze neocortical dynamics using field theoretic methods for non-equilibrium statistical processes. Assuming the dynamics is Markovian, we introduce a model that describes both neural fluctuations and responses to stimuli. We show that at low spiking rates, neocortical activity exhibits a dynamical phase transition which is in the universality class of directed percolation (DP). Because of the high density and large spatial extent of neural interactions, there is a "mean field" region in which the effects of fluctuations are negligible. However as the generation and decay of spiking activity becomes balanced, there is a crossover into the critical fluctuation driven DP region, consistent with measurements in neocortical slice preparations. From the perspective of theoretical neuroscience, the principal contribution of this work is the formulation of a theory of neural activity that goes beyond the mean-field approximation and incorporates the effects of fluctuations and correlations in the critical region. This theory shows that the scaling laws found in many measurements of neocortical activity, in anesthetized, normal and epileptic neocortex, are consistent with the existence of DP and related phase transitions at a critical point. It also shows how such properties lead to a model of the origins of both random and rhythmic brain activity. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Cowan, Jack D.] Univ Chicago, Dept Math, Gordon Ctr Integrat Sci, Chicago, IL 60637 USA. [Buice, Michael A.] NIH NIDDK LBM, Bethesda, MD 20892 USA. RP Cowan, JD (reprint author), Univ Chicago, Dept Math, Gordon Ctr Integrat Sci, E505B,929 E 57th St, Chicago, IL 60637 USA. EM cowan@math.uchicago.edu FU Intramural NIH HHS NR 142 TC 32 Z9 32 U1 2 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD FEB-MAY PY 2009 VL 99 IS 2-3 BP 53 EP 86 DI 10.1016/j.pbiomolbio.2009.07.003 PG 34 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 502NX UT WOS:000270468300001 PM 19695282 ER PT J AU Juruena, MF Ottoni, GL Machado-Vieira, R Carneiro, RM Weingarthner, N Marquardt, AR Fleig, SS Broilo, L Busnello, EA AF Juruena, M. F. Ottoni, G. L. Machado-Vieira, R. Carneiro, R. M. Weingarthner, N. Marquardt, A. R. Fleig, S. S. Broilo, L. Busnello, E. A. TI Bipolar I and II disorder residual symptoms: Oxcarbazepine and carbamazepine as add-on treatment to lithium in a double-blind, randomized trial SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Bipolar disorder; Carbamazepine; Clinical trial; Lithium; Oxcarbazepine; Residual symptoms ID MANIA; GUIDELINES; MOOD AB Bipolar affective disorders often require adjunctive therapy to treat persistent symptoms. In order to evaluate bipolar symptoms inadequately responsive to lithium, we have compared the effects of two structurally related compounds carbamazepine (CBZ) and oxcarbazepine (OXC). We evaluated the efficacy and safety of CBZ and OXC administration in residual symptoms as an adjunctive therapy in Bipolar I (BP I) and Bipolar II (BP II) patients while on lithium maintenance treatment. We selected from 153 bipolar patients in treatment those fulfilling Research Diagnostic Criteria for mania or hypomania, according to the SADS-L and conducted in 52 bipolar patients (27 BP I, 25 BP II) a double-blind, randomized, parallel-group, single centre, clinical trial. Bipolar I and II outpatients, were randomly assigned on a 1:1 ratio to OXC (n = 26) or CBZ (n = 26) for an 8-week period as add-on treatment to the existing lithium regimen. Outcome measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale 21 items (HDRS-21) and Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression severity (CGI-S) and improvement illness (CGI-I). These scales were administered at baseline and at the end of weeks 2, 4 and 8. All the fifty-two patients completed the trial. Overall, females were 35 (65%) and mean (S.D.) age was 39.4 (11.9) years; final doses at the end of week 8 in OXC group was 637.7 (210) mg/day and in the CBZ group 673.5 (179) mg/day; lithium plasma levels were 0.73 (0.25) meq/l and 0.71 (0.28) meq/l, respectively. Both OXC and CBZ were effective in reducing bipolar scores from baseline to endpoint (p<0.01). OXC was more effective than CBZ at weeks 4 and 8 on all 5 outcome measures. OXC resulted in greater significant mean reductions in YMRS, HDRS-21, MADRS, CGI-S and CGI-I scores from baseline to week 4 (p<0.05) and from baseline to week 8 (p<0.001), except YMRS (p<0.01). OXC appeared to be significantly more effective and with better tolerability than CBZ as add-on strategy treatment in BP I and BP II patients. This pilot, randomized clinical trial, suggests the potential usefulness of OXC as adjunctive therapy to lithium both in acute and long-term treatment of bipolar disorder. However, further adequately placebo-controlled trials are needed to expand these findings. (C) 2008 Elsevier Inc. All rights reserved. C1 [Juruena, M. F.] Kings Coll London, Inst Psychiat, Sect Neurobiol Mood Disorders, London WC2R 2LS, England. [Juruena, M. F.; Ottoni, G. L.; Machado-Vieira, R.; Carneiro, R. M.; Weingarthner, N.; Marquardt, A. R.; Fleig, S. S.; Broilo, L.; Busnello, E. A.] Fed Univ Healthy Sci Porto Alegre UFCSPA, Dept Psychiat, Affect Disorders Unit, Porto Alegre, RS, Brazil. [Juruena, M. F.] Bethlem Royal & Maudsley Hosp, Natl Affect Disorders Uni, Affect Disorders Unit Lab, Beckenham, Kent, England. [Machado-Vieira, R.] NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Juruena, MF (reprint author), Av Candido Pereira Lima 416, BR-14040250 Ribeirao Preto, Brazil. EM M.Juruena@iop.kcl.ac.uk RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Juruena, Mario/D-5571-2009; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Juruena, Mario/0000-0001-8558-3396; Juruena, Mario F./0000-0002-4063-2278 FU Novartis Company; 2003-07 CAPES Fellowship Award; 2006-08 NARSAD Young Investigator Award; 2007 NIHR Biomedical Research Centre at South London and Maudsley NHS Trust & Institute of Psychiatry (Kings' College London) FX This trial was sponsored by Novartis Company. M.F. Juruena received 2003-07 CAPES Fellowship Award; 2006-08 NARSAD Young Investigator Award; and 2007 NIHR Biomedical Research Centre at South London and Maudsley NHS Trust & Institute of Psychiatry (Kings' College London). We wish to thank F. Pereira for carrying out the statistical analyses of this trial. NR 32 TC 21 Z9 22 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD FEB 1 PY 2009 VL 33 IS 1 BP 94 EP 99 DI 10.1016/j.pnpbp.2008.10.012 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 405GX UT WOS:000263212200018 PM 19007842 ER PT J AU Zhang, QM Peng, H Gao, F Liu, YW Cheng, H Thompson, J Gao, GF AF Zhang, Qiangmin Peng, Hao Gao, Feng Liu, Yiwei Cheng, Hao Thompson, John Gao, George F. TI Structural insight into the catalytic mechanism of gluconate 5-dehydrogenase from Streptococcus suis: Crystal structures of the substrate-free and quaternary complex enzymes SO PROTEIN SCIENCE LA English DT Article DE Streptococcus suis serotype 2; gluconate 5-dehydrogenase (Ga5DH); quaternary complex; SDR enzymes; catalytic mechanism ID LUNG CARBONYL REDUCTASE; ESCHERICHIA-COLI; HYDROXYSTEROID DEHYDROGENASE; 3-DIMENSIONAL STRUCTURE; GLUCONOBACTER-OXYDANS; ANGSTROM RESOLUTION; SEQUENCE-ANALYSIS; TERNARY COMPLEX; CRYSTALLIZATION; MUTAGENESIS AB Gluconate 5-dehydrogenase (Ga5DH) is an NADP(H)-dependent enzyme that catalyzes a reversible oxidoreduction reaction between D-gluconate and 5-keto-D-gluconate, thereby regulating the flux of this important carbon and energy source in bacteria. Despite the considerable amount of physiological and biochemical knowledge of Ga5DH, there is little physical or structural information available for this enzyme. To this end, we herein report the crystal structures of Ga5DH from pathogenic Streptococcus suis serotype 2 in both substrate-free and liganded (NADP1/D-gluconate/metalion) quaternary complex forms at 2.0 angstrom resolution. Structural analysis reveals that Ga5DH adopts a protein fold similar to that found in members of the short chain dehydrogenase/reductase (SDR) family, while the enzyme itself represents a previously uncharacterized member of this family. In solution, Ga5DH exists as a tetramer that comprised four identical similar to 29 kDa subunits. The catalytic site of Ga5DH shows considerable architectural similarity to that found in other enzymes of the SDR family, but the S. suis protein contains an additional residue (Arg104) that plays an important role in the binding and orientation of substrate. The quaternary complex structure provides the first clear crystallographic evidence for the role of a catalytically important serine residue and also reveals an amino acid tetrad RSYK that differs from the SYK triad found in the majority of SDR enzymes. Detailed analysis of the crystal structures reveals important contributions of Ca(2+) ions to active site formation and of specific residues at the C-termini of subunits to tetramer assembly. Because Ga5DH is a potential target for therapy, our findings provide insight not only of catalytic mechanism, but also suggest a target of structure-based drug design. C1 [Zhang, Qiangmin; Peng, Hao; Gao, Feng; Liu, Yiwei; Cheng, Hao; Gao, George F.] Chinese Acad Sci, Inst Microbiol, Beijing 100101, Peoples R China. [Zhang, Qiangmin; Cheng, Hao] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. [Gao, Feng] China Agr Univ, Coll Life Sci, Beijing 100094, Peoples R China. [Thompson, John] NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Gao, George F.] Chinese Acad Sci, China Japan Joint Lab Mol Immunol & Mol Immunol, Inst Microbiol, Beijing 100101, Peoples R China. RP Gao, GF (reprint author), Chinese Acad Sci, Inst Microbiol, Datun Rd, Beijing 100101, Peoples R China. EM gaof@im.ac.cn FU The National Basic Research Program [973]; Ministry of Science and Technology of China ( MOST); [2005CB523001, 2006BAD06A04]; National Key Technologies R D Program; Ministry of Science and Technology of China ( MOST);; National Natural Science Foundation of China ( NSFC); [30770024, 30525010]; Intramural Research Program of the NIDCR; National Institutes of Health FX The National Basic Research Program ( 973), Ministry of Science and Technology of China ( MOST); Grant number: 2005CB523001; Grant sponsor: National Key Technologies R& D Program, Ministry of Science and Technology of China ( MOST); Grant number: 2006BAD06A04; Grant sponsor: National Natural Science Foundation of China ( NSFC); Grant numbers: 30770024, 30525010; Grant sponsor: Intramural Research Program of the NIDCR, National Institutes of Health. NR 33 TC 10 Z9 11 U1 2 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2009 VL 18 IS 2 BP 294 EP 303 DI 10.1002/pro.32 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429SX UT WOS:000264941500005 PM 19177572 ER PT J AU Lountos, GT Austin, BP Nallamsetty, S Waugh, DS AF Lountos, George T. Austin, Brian P. Nallamsetty, Sreedevi Waugh, David S. TI Atomic resolution structure of the cytoplasmic domain of Yersinia pestis YscU, a regulatory switch involved in type III secretion SO PROTEIN SCIENCE LA English DT Article DE type III secretion; Yersinia; molecular switch; atomic resolution; YscU ID SUBSTRATE-SPECIFICITY; SYSTEM; EXPORT; CLEAVAGE; MODEL; FLHB; PSEUDOTUBERCULOSIS; INJECTISOME; COMPLEXES; MECHANISM AB Crystal structures of cleaved and uncleaved forms of the YscU cytoplasmic domain, an essential component of the type III secretion system (T3SS) in Yersinia pestis, have been solved by single-wavelength anomolous dispersion and refined with X-ray diffraction data extending up to atomic resolution (1.13 angstrom). These crystallographic studies provide structural insights into the conformational changes induced upon auto-cleavage of the cytoplasmic domain of YscU. The structures indicate that the cleaved fragments remain bound to each other. The conserved NPTH sequence that contains the site of the N263-P264 peptide bond cleavage is found on a beta-turn which, upon cleavage, undergoes a major reorientation of the loop away from the catalytic N263, resulting in altered electrostatic surface features at the site of cleavage. Additionally, a significant conformational change was observed in the N-terminal linker regions of the cleaved and noncleaved forms of YscU which may correspond to the molecular switch that influences substrate specificity. The YscU structures determined here also are in good agreement with the auto-cleavage mechanism described for the flagellar homolog FlhB and E. coli EscU. C1 [Lountos, George T.; Austin, Brian P.; Nallamsetty, Sreedevi; Waugh, David S.] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM waughd@ncifcrf.gov RI Lountos, George/B-3983-2015 FU Intramural NIH HHS NR 32 TC 29 Z9 29 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2009 VL 18 IS 2 BP 467 EP 474 DI 10.1002/pro.56 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429SX UT WOS:000264941500021 PM 19165725 ER PT J AU Abou Jamra, R Georgi, A Suliman, H Klein, K Villela, AW Schulze, TG Propping, P Cichon, S Rietschel, M Nothen, MM Schumacher, J AF Abou Jamra, Rami Georgi, Alexander Suliman, Husam Klein, Katrin Villela, Angela Wolf Schulze, Thomas G. Propping, Peter Cichon, Sven Rietschel, Marcella Noethen, Markus M. Schumacher, Johannes TI No association between the D-aspartate oxidase locus and schizophrenia SO PSYCHIATRIC GENETICS LA English DT Article ID LINKAGE C1 [Abou Jamra, Rami; Suliman, Husam; Klein, Katrin; Villela, Angela Wolf; Propping, Peter; Noethen, Markus M.; Schumacher, Johannes] Univ Bonn, Inst Human Genet, D-53111 Bonn, Germany. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-53111 Bonn, Germany. [Georgi, Alexander; Schulze, Thomas G.; Rietschel, Marcella] Cent Inst Mental Hlth, D-6800 Mannheim, Germany. [Schumacher, Johannes] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. RP Abou Jamra, R (reprint author), Univ Bonn, Inst Human Genet, Wilhelmstr 31, D-53111 Bonn, Germany. EM rami.aboujamra@uni-bonn.de RI Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Abou Jamra, Rami/I-4805-2015; Schumacher, Johannes/F-4970-2015 OI Georgi, Alexander/0000-0002-1499-8524; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Abou Jamra, Rami/0000-0002-1542-1399; Nothen, Markus/0000-0002-8770-2464; Schumacher, Johannes/0000-0001-9217-6457 NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD FEB PY 2009 VL 19 IS 1 BP 56 EP 56 DI 10.1097/YPG.0b013e3283118739 PG 1 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 399SZ UT WOS:000262820900009 ER PT J AU Cirulli, F Francia, N Branchi, I Antonucci, MT Aloe, L Suomi, SJ Alleva, E AF Cirulli, Francesca Francia, Nadia Branchi, Igor Antonucci, Maria Teresa Aloe, Luigi Suomi, Stephen J. Alleva, Enrico TI Changes in plasma levels of BDNF and NGF reveal a gender-selective vulnerability to early adversity in rhesus macaques SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Nerve growth actor (NGF); Brain-derived neurotrophic factor (BDNF); Depression; Vulnerability; Gender; Non-human primates ID NERVE GROWTH-FACTOR; NEUROTROPHIC FACTOR BDNF; DEPRESSED-PATIENTS; RAT-BRAIN; SERUM CONCENTRATIONS; MATERNAL SEPARATION; FACTOR EXPRESSION; HUMAN PLATELETS; STRESS; GENE AB Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. Here we tested the hypothesis that peripheral levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are involved in the response to stress and in the pathophysiology of anxiety and depression, might be affected in a non-human primate model of adverse rearing. Mates and females rhesus macaques reared with their mothers (MR) or in peer-only groups (PR) were used as experimental subjects. BDNF, NGF, adrenocorticotropic hormone (ACTH), cortisol and growth hormone (GH) were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA and RIA procedures. In addition, behavior was assessed on PND 7, 14, 21, 30 (Brazelton test) and 60 (home cage observation). Data indicate gender differences in basal levels of BDNF throughout development. Peer-rearing increased significantly BDNF levels only in females. In addition, while all peer-reared subjects showed high levels of stereotypies and self-directed behaviors, behavioral passivity was selectively increased in females. By contrast, NGF levels were increased in response to peer-rearing only in mates, and correlated positively with other "classic" endocrine responses to stress, such as cortisol and GH. Our data identify BDNF and NGF as neuroendocrine markers underlying differential responses to maternal deprivation in mates and females rhesus macaques. The selective changes in BDNF levels in females could help explain the greater vulnerability to mood disorders of this gender reported in humans. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Cirulli, Francesca; Francia, Nadia; Branchi, Igor; Alleva, Enrico] Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, I-00161 Rome, Italy. [Antonucci, Maria Teresa; Aloe, Luigi] CNR, EBRI, Inst Neurobiol & Mol Med, I-00143 Rome, Italy. [Suomi, Stephen J.] NICHD, Comparat Ethol Lab, Poolesville, MD 20837 USA. RP Cirulli, F (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. EM francesca.cirulli@iss.it RI Cirulli, Francesca/B-1581-2013; Alleva, Enrico/B-1630-2013; OI cirulli, francesca/0000-0001-9440-1873; Branchi, Igor/0000-0003-4484-3598 FU Intramural NIH HHS [Z01 HD001106-24] NR 58 TC 46 Z9 47 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD FEB PY 2009 VL 34 IS 2 BP 172 EP 180 DI 10.1016/j.psyneuen.2008.08.020 PG 9 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 408JM UT WOS:000263431300002 PM 18849121 ER PT J AU Lane, RD Waldstein, SR Chesney, MA Jennings, JR Lovallo, WR Kozel, PJ Rose, RM Drossman, DA Schneiderman, N Thayer, JF Cameron, OG AF Lane, Richard D. Waldstein, Shari R. Chesney, Margaret A. Jennings, J. Richard Lovallo, William R. Kozel, Peter J. Rose, Robert M. Drossman, Douglas A. Schneiderman, Neil Thayer, Julian F. Cameron, Oliver G. TI The Rebirth of Neuroscience in Psychosomatic Medicine, Part I: Historical Context, Methods, and Relevant Basic Science SO PSYCHOSOMATIC MEDICINE LA English DT Review DE neuroscience; brain imaging; information transfer systems; autonomic nervous system; neuroendocrinology; psychoneuroimmunology ID ANTERIOR CINGULATE CORTEX; CORTICOTROPIN-RELEASING-FACTOR; BLOOD-PRESSURE REACTIVITY; INDUCED SICKNESS BEHAVIOR; MEDIAL PREFRONTAL CORTEX; AUTONOMIC NERVOUS-SYSTEM; HUMAN BRAIN STRUCTURE; MAJOR DEPRESSION; PSYCHOLOGICAL STRESS; IMMUNE FUNCTION AB Neuroscience was an integral part of psychosomatic medicine at its inception in the early 20th century. Since the mid-20th century, however, psychosomatic research has largely ignored the brain. The field of neuroscience has burgeoned in recent years largely because a variety of powerful new methods have become available. Many of these methods allow for the noninvasive study of the living human brain and thus are potentially available for integration into psychosomatic medicine research at this time. In this first paper we examine various methods available for human neuroscientific investigation and discuss their relative strengths and weaknesses. We next review some basic functional neuroanatomy involving structures that are increasingly being identified as relevant for psychosomatic processes. We then discuss, and provide examples of, flow the brain influences end organs through "information transfer systems," including the autonomic, neuroendocrine, and immune systems. The evidence currently available suggests that neuroscience holds great promise for advancing the goal of understanding the mechanisms by which psychosocial variables influence physical disease outcomes. An increased focus on such mechanistic research in psychosomatic medicine is needed to further its acceptance into the field of medicine. C1 [Lane, Richard D.] Univ Arizona, Dept Psychiat, Tucson, AZ 85724 USA. [Waldstein, Shari R.] Univ Maryland, Dept Psychol, Baltimore, MD 21201 USA. [Waldstein, Shari R.] Baltimore VA Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD USA. [Chesney, Margaret A.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Jennings, J. Richard] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. VA Med Ctr, Behav Sci Labs, Oklahoma City, OK USA. [Kozel, Peter J.] Natl Ctr Complementary & Alternat Med, Div Extramural Activ, NIH, Bethesda, MD USA. [Rose, Robert M.] Mind Brain Body & Hlth Initiat, Galveston, TX USA. [Drossman, Douglas A.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Schneiderman, Neil] Univ Miami, Dept Psychol, Miami, FL USA. [Thayer, Julian F.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. Univ Heidelberg, Mannheim Inst Publ Hlth, Heidelberg, Germany. [Cameron, Oliver G.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Lane, RD (reprint author), Univ Arizona, Dept Psychiat, POB 245002, Tucson, AZ 85724 USA. EM lane@email.arizona.edu NR 192 TC 42 Z9 44 U1 5 U2 27 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD FEB-MAR PY 2009 VL 71 IS 2 BP 117 EP 134 DI 10.1097/PSY.0b013e31819783be PG 18 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 411NT UT WOS:000263657000001 PM 19196808 ER PT J AU Arora, N AF Arora, Neeraj K. TI Importance of patient-centered care in enhancing patient well-being: a cancer survivor's perspective SO QUALITY OF LIFE RESEARCH LA English DT Article DE Patient-centered care; Cancer; Patient experiences; Patient perspective; Quality of care; Patient-physician communication; Cancer survivorship; Well-being; Health-related quality of life ID UNITED-STATES; QUALITY AB In this narrative article, the author, a long-term cancer survivor, reflects on his personal interactions with the healthcare system over a period of 14 years in order to highlight the importance of delivering patient-centered care. He makes a case for why quality of care assessments are incomplete if they focus on clinical indicators of quality alone and exclude systematic assessment of the patient-centered aspects of care from the patient's perspective. The important role played by patient-centered care in reducing patient suffering and enhancing well-being is underscored in this commentary. C1 NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Arora, N (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344,Execut Plaza N 4005, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov NR 5 TC 21 Z9 21 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD FEB PY 2009 VL 18 IS 1 BP 1 EP 4 DI 10.1007/s11136-008-9415-5 PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 402PM UT WOS:000263025600001 PM 19005778 ER PT J AU Morgan, NY Kramer-Marek, G Smith, PD Camphausen, K Capala, J AF Morgan, Nicole Y. Kramer-Marek, Gabriela Smith, Paul D. Camphausen, Kevin Capala, Jacek TI Nanoscintillator Conjugates as Photodynamic Therapy-Based Radiosensitizers: Calculation of Required Physical Parameters SO RADIATION RESEARCH LA English DT Article ID SINGLET OXYGEN LUMINESCENCE; GOLD NANOPARTICLES; IN-VITRO; MAGNETITE NANOPARTICLES; INTRACELLULAR UPTAKE; CANCER-TREATMENT; QUANTUM YIELDS; MLL CELLS; AGENTS; RADIATION AB Morgan, N. Y., Kramer-Marek, G., Smith, P. D., Camphausen, K. and Capala, J. Nanoscintillator Conjugates as Photodynamic Therapy-Based Radiosensitizers: Calculation of Required Physical Parameters. Radiat. Res. 171, 236-244 (2009). The recent demonstration of nanoscale scintillators has led to interest in the combination of radiation and photodynamic therapy. In this model, scintillating nanoparticles conjugated to photosensitizers and molecular targeting agents would enhance the targeting and improve the efficacy of radiotherapy and extend the application of photodynamic therapy to deeply seated tumors. In this study, we calculated the physical parameters required for these nanoparticle conjugates to deliver cytotoxic levels of singlet oxygen at therapeutic radiation doses, drawing on the published literature from several disparate fields. Although uncertainties remain, it appears that the light yield of the nanoscintillators, the efficiency of energy transfer to the photosensitizers, and the cellular uptake of the nanoparticles all need to be fairly well optimized to observe a cytotoxic effect. Even so, the efficacy of the combination therapy will likely be restricted to X-ray energies below 300 keV, which limits the application to brachytherapy. (C) 2009 by Radiation Research Society C1 [Morgan, Nicole Y.] NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. [Kramer-Marek, Gabriela; Camphausen, Kevin; Capala, Jacek] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kramer-Marek, Gabriela] Univ Silesia, A Chelkowski Inst Phys, PL-40007 Katowice, Poland. RP Morgan, NY (reprint author), NIBIB, Lab Bioengn & Phys Sci, NIH, Bldg 13,Room 3N18, Bethesda, MD 20892 USA. EM morgann@mail.nih.gov FU National Institutes of Health; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and National Institute of Biomedical Imaging and Bioengineering. The authors thank Murali Cherukuri and Wei Chen for helpful discussions. NR 34 TC 26 Z9 26 U1 2 U2 20 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 FEB PY 2009 VL 171 IS 2 BP 236 EP 244 DI 10.1667/RR1470.1 PG 9 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 402PB UT WOS:000263024500012 PM 19267550 ER PT J AU Perez-Rodriguez, J Lai, S Ehst, BD Fine, DM Bluemke, DA AF Perez-Rodriguez, Javier Lai, Shenghan Ehst, Benjamin D. Fine, Derek M. Bluemke, David A. TI Nephrogenic Systemic Fibrosis: Incidence, Associations, and Effect of Risk Factor Assessment-Report of 33 Cases SO RADIOLOGY LA English DT Article ID RENAL-INSUFFICIENCY; PERCUTANEOUS TREATMENT; GADOLINIUM; DERMOPATHY; ANGIOGRAPHY; CONTRAST; INVOLVEMENT; TISSUE AB Purpose: To describe the presentation and clinical course of patients with nephrogenic systemic fibrosis (NSF) at a large acute-care hospital, to evaluate the overall incidence of NSF, and to assess the effect of a hospital-wide policy regarding gadolinium-based contrast agent (GBCA) use on NSF incidence. Materials and Methods: A review of all cases of NSF observed at an institution from 2003 to 2008 was conducted. This HIPAA-compliant study was approved by the institutional review board. The informed consent requirement was waived. Demographics, medical history, and associated conditions were recorded. Radiologic procedures were evaluated if they were performed within 1 year prior to NSF onset. GBCA use was assessed by checking the electronic database for each procedure. The incidence of NSF was compared before and after implementation of an institutional policy designed to assess risk of NSF prior to GBCA use. Results: All 33 patients with NSF (mean age, 49 years; age range, 15-78 years) had advanced renal failure (estimated glomerular filtration rate < 15 mL/min/1.73 m(2)) when the GBCA was injected. Twenty-six patients had severe chronic or end-stage renal disease, and seven had acute renal failure. The mean interval between contrast material injection and NSF onset was 29 days +/- 25 (standard deviation) (range, 4-112 days). The overall incidence of NSF was 36.5 cases per 100 000 gadolinium-enhanced magnetic resonance (MR) examinations between 2003 and 2006 and four cases per 100 000 gadolinium-enhanced MR examinations between 2007 and 2008 after screening for NSF risk was instituted (Fisher exact test, P = .001). Five patients developed NSF in the peritransplant period, and four underwent a catheter-based radiographic procedure with administration of a GBCA. Conclusion: Common associations of GBCA MR imaging and NSF were acute and severe chronic renal failure and liver or renal transplantation. Screening procedures performed before MR imaging to determine which patients were at risk of developing NSF appear to reduce the incidence of this complication and further support the belief that NSF is associated with GBCA administration. (C) RSNA, 2009 C1 [Perez-Rodriguez, Javier; Bluemke, David A.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Lai, Shenghan] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Fine, Derek M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21287 USA. [Ehst, Benjamin D.] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97201 USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Room 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov NR 25 TC 113 Z9 115 U1 0 U2 3 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 FEB PY 2009 VL 250 IS 2 BP 371 EP 377 DI 10.1148/radiol.2502080498 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 439QT UT WOS:000265642800009 PM 19188312 ER PT J AU Abbatecola, AM Cherubini, A Guralnik, JM Lacueva, CA Ruggiero, C Maggio, M Bandinelli, S Paolisso, G Ferrucci, L AF Abbatecola, Angela M. Cherubini, Antonio Guralnik, Jack M. Lacueva, Cristina Andres Ruggiero, Carmelinda Maggio, Marcello Bandinelli, Stefania Paolisso, Giuseppe Ferrucci, Luigi TI Plasma Polyunsaturated Fatty Acids and Age-Related Physical Performance Decline SO REJUVENATION RESEARCH LA English DT Article ID OLDER PERSONS; INFLAMMATORY MARKERS; PANCREATIC-CANCER; SKELETAL-MUSCLE; HEALTH; N-3; DISABILITY; INCHIANTI; DISEASE; QUESTIONNAIRE AB Due to supporting evidence that dietary patterns may have a significant role in the maintenance of good physical performance with aging, we tested whether plasma fatty acids, saturated fatty acids (SFA), and polyunsaturated (PUFA) fatty acids are cross-sectionally associated with different physical performance and predict changes in physical performance over a 3-year period. Data were from the InCHIANTI study, a population-based study of older Italians. Plasma fatty acids were measured at enrollment (1998-2000), and outcome variables, Summary Physical Performance Battery (SPPB), and time to walk 7 meters (m) were measured at enrollment and after 3 years (2001-2004). At enrollment, 330 participants had significantly impaired lower extremity performance (defined as a SPPB score <= 9). Adjusting for age, participants with a SPPB score >9 had higher levels of total PUFA, n-3 PUFA, and n-6 PUFA, while significantly lower levels of SFA than those with a SPPB score <9. Baseline SPPB scores were also associated with n-3 PUFA (beta = 0.148, p = 0.031), whereas the 7-m walk time was associated with total PUFA (beta = -0.068, p = 0.008), after adjusting for potential confounders. Of the 884 participants with a SPPB score >9 at baseline, 114 (12.9%) developed impaired lower extremity performance (SPPB <= 9). In fully adjusted logistic models, baseline n-3 PUFA levels were inversely related to the risk of developing a decline in SPPB to >9 (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08-0.53), while the n-6/n-3 ratio was associated with a higher risk of SPPB decline to <= 9 (OR = 5.23; 95% CI = 2.02-13.51). In multivariate regression models, the n-6/n-3 ratio was associated with a longer time to walk 7 m (beta = 0.396, p = 0.037). n-3 PUFA plasma levels, which most likely reflect dietary intake, seem to protect against accelerated decline of physical performance. A higher n-6/n-3 ratio was associated with higher risk of developing poor physical performance and slower walking speed. C1 [Paolisso, Giuseppe] Univ Naples 2, Dept Geriatr Med & Metab Dis, Div Med Interna 4, I-80138 Naples, Italy. [Cherubini, Antonio; Ruggiero, Carmelinda] Univ Perugia, Dept Clin & Expt Med, Inst Gerontol & Geriatr, Perugia, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Lacueva, Cristina Andres] Univ Barcelona, CeRTA, Dept Nutr & Food Sci, E-08007 Barcelona, Spain. [Maggio, Marcello] Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Paolisso, G (reprint author), Univ Naples 2, Dept Geriatr Med & Metab Dis, Div Med Interna 4, Piazza Miraglia 2, I-80138 Naples, Italy. EM giuseppe.paolisso@unina2.it RI Andres-Lacueva, Cristina/J-3377-2012; OI Andres-Lacueva, Cristina/0000-0002-8494-4978; Paolisso, Giuseppe/0000-0002-2137-455X; Cherubini, Antonio/0000-0003-0261-9897 FU Italian Ministry of Health [ICS 110.1/RS97.71]; U. S. National Institute on Aging [N01-AG-916413, N01-AG-821336]; U. S. National Institute on Aging, National Institutes of Health, Baltimore, MD [263 MD 9164 13, 263 MD 821336] FX The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health, and in part by the U. S. National Institute on Aging (contracts N01-AG-916413 and N01-AG-821336), and by the Intramural Research Program of the U. S. National Institute on Aging, National Institutes of Health, Baltimore, MD (contracts 263 MD 9164 13 and 263 MD 821336). None of the sponsoring institutions interfered with the collection, analysis, presentation, or interpretation of the data reported here. All authors had full access to all of the data in the study, and coauthors, Dr. Abbatecola, Dr. Cherubini, Prof. Paolisso, and Dr. Ferrucci designed study protocol and actively participated in writing the manuscript. Co-authors, Dr. Guralnik, Dr. Lacueva, Dr. Ruggiero, Dr. Bandinelli, and Dr. Maggio participated in study protocol design. NR 33 TC 19 Z9 19 U1 0 U2 7 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 J9 REJUV RES JI Rejuv. Res. PD FEB PY 2009 VL 12 IS 1 BP 25 EP 32 DI 10.1089/rej.2008.0799 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 419CX UT WOS:000264197800005 PM 19196012 ER PT J AU Reines, B Cheng, LI Matzinger, P AF Reines, Brandon Cheng, Lily I. Matzinger, Polly TI Unexpected Regeneration in Middle-Aged Mice SO REJUVENATION RESEARCH LA English DT Article ID EAR; STRAINS; TISSUE; MODEL AB Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age. Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes. These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight. C1 [Reines, Brandon; Matzinger, Polly] NIAID, Ghost Lab, T Cell Tolerance & Memory Sect, Lab Cellular & Mol Immunol,NIH, Bethesda, MD 20892 USA. [Cheng, Lily I.] NIAID, Vet Pathol Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. RP Reines, B (reprint author), 4 Ctr Dr,MSC 111, Bethesda, MD 20892 USA. EM BReines@niaid.nih.gov FU NIAID, NIH FX We would like to thank the following people for invaluable help, including: pathologists Georgina Miller, Victoria Hoffman, and Jerry Ward; medical illustrator Ethan Tyler; microscopist Owen Schwartz; data analyst Maxwell Behrens; tool designers Jimmie Powell, Howard Metger, and Frank Sharpnack; and all the members of the Ghost lab. Special thanks to Xinmin Li for supplying a color version of an Excel graph containing hole closure data from his 2001 Heredity paper for us to reanalyze. We would also like to thank Ron Schwartz, Phil Murphy, and Richard Hodes for suggestions on the manuscript. Last, but not least, we thank to Victor Barcelona and Mary Kuta for software guidance. This work was entirely supported by the intramural program of the NIAID, NIH. NR 23 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 J9 REJUV RES JI Rejuv. Res. PD FEB PY 2009 VL 12 IS 1 BP 45 EP 51 DI 10.1089/rej.2008.0792 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 419CX UT WOS:000264197800007 PM 19226206 ER PT J AU Perez, V Sierra, F AF Perez, Viviana Sierra, Felipe TI Biology of aging SO REVISTA MEDICA DE CHILE LA Spanish DT Article DE Aging; Genes; Stem cells ID LIFE-SPAN; CAENORHABDITIS-ELEGANS; CALORIC RESTRICTION; OXIDATIVE STRESS; CELLULAR SENESCENCE; SIGNALING PATHWAY; TUMOR SUPPRESSION; HUMAN-DISEASE; AGE-1 GENE; C-ELEGANS AB The study of biological aging has seen a spectacularly fast progress in the last decade. Besides a better understanding and comprehension of physiological aspects, an important advance has been the identification of at least a hundred different genes which control the process of aging. Their mechanism of action falls within the expectations from a handful of theories which attempt to provide a global explanation of the phenomenon of aging, including free radicals, cell senescence and loss of regenerative capacity through the activation of stem cells. In this review we will concentrate in these biological aspects, with a special emphasis on animal models used to study both the genetics and physiology of aging as well as experimental approaches to test the the aforementioned theories. It should be emphasized that, while the emphasis is in purely biological aspects of the process, the fast pace of aging of the world's population, including Chile, needs a rapid advance also in our understanding of its social and economic implications (Rev Med Chile 2009; 137: 296-302). C1 [Sierra, Felipe] NIA, NIH, Bethesda, MD 20892 USA. [Perez, Viviana] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. RP Sierra, F (reprint author), NIA, NIH, 7201 Wisconsin Ave,Suite 2C231, Bethesda, MD 20892 USA. EM sierrag@nia.nih.gov NR 61 TC 1 Z9 1 U1 2 U2 5 PU SOC MEDICA SANTIAGO PI SANTIAGO 9 PA BERNARDA MORIN 488 PROVIDENCIA, CASILLA 168 CORREO 55, SANTIAGO 9, 00000, CHILE SN 0034-9887 EI 0717-6163 J9 REV MED CHILE JI Rev. Medica Chile PD FEB PY 2009 VL 137 IS 2 BP 296 EP 302 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 454ZL UT WOS:000266723800017 PM 19543655 ER PT J AU Harris-Love, MO Shrader, JA Koziol, D Pahlajani, N Jain, M Smith, M Cintas, HL McGarvey, CL James-Newton, L Pokrovnichka, A Moini, B Cabalar, I Lovell, DJ Wesley, R Plotz, PH Miller, FW Hicks, JE Rider, LG AF Harris-Love, M. O. Shrader, J. A. Koziol, D. Pahlajani, N. Jain, M. Smith, M. Cintas, H. L. McGarvey, C. L. James-Newton, L. Pokrovnichka, A. Moini, B. Cabalar, I. Lovell, D. J. Wesley, R. Plotz, P. H. Miller, F. W. Hicks, J. E. Rider, L. G. TI Distribution and severity of weakness among patients with polymyositis, dermatomyositis and juvenile dermatomyositis SO RHEUMATOLOGY LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; HEALTH ASSESSMENT QUESTIONNAIRE; VALIDATED DISEASE-ACTIVITY; LONG-TERM SURVIVAL; QUALITY-OF-LIFE; MUSCLE STRENGTH; DAMAGE INDEXES; ADULT; MYOSITIS; PROGNOSIS AB Objective. To describe the distribution and severity of muscle weakness using manual muscle testing (MMT) in 172 patients with PM, DM and juvenile DM (JDM). The secondary objectives included characterizing individual muscle group weakness and determining associations of weakness with functional status and myositis characteristics in this large cohort of patients with myositis. Methods. Strength was assessed for 13 muscle groups using the 10-point MMT and expressed as a total score, subscores based on functional and anatomical regions, and grades for individual muscle groups. Patient characteristics and secondary outcomes, such as clinical course, muscle enzymes, corticosteroid dosage and functional status were evaluated for association with strength using univariate and multivariate analyses. Results. A gradient of proximal weakness was seen, with PM weakest, DM intermediate and JDM strongest among the three myositis clinical groups (P 0.05). Hip flexors, hip extensors, hip abductors, neck flexors and shoulder abductors were the muscle groups with the greatest weakness among all three clinical groups. Muscle groups were affected symmetrically. Conclusions. Axial and proximal muscle impairment was reflected in the five weakest muscles shared by our cohort of myositis patients. However, differences in the pattern of weakness were observed among all three clinical groups. Our findings suggest a greater severity of proximal weakness in PM in comparison with DM. C1 [Harris-Love, M. O.; James-Newton, L.; Miller, F. W.; Rider, L. G.] NIEHS, Environm Autoimmun Grp, Off Clin Res, NIH, Bethesda, MD 20892 USA. [Harris-Love, M. O.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Pahlajani, N.; Pokrovnichka, A.; Moini, B.; Cabalar, I.; Plotz, P. H.] NIAMSD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lovell, D. J.] Cincinnati Childrens Hosp, Med Ctr, Div Rheumatol, Cincinnati, OH USA. RP Rider, LG (reprint author), NIEHS, Environm Autoimmun Grp, Off Clin Res, NIH, CRC 4-2352,MSC 1301,10 Ctr Dr, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov RI Harris-Love, Michael/J-1359-2014; OI Harris-Love, Michael/0000-0002-1842-3269; Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Rehabilitation Medicine Department; NIH Clinical Center FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Rehabilitation Medicine Department and the NIH Clinical Center. NR 45 TC 45 Z9 47 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD FEB PY 2009 VL 48 IS 2 BP 134 EP 139 DI 10.1093/rheumatology/ken441 PG 6 WC Rheumatology SC Rheumatology GA 395IT UT WOS:000262518500009 PM 19074186 ER PT J AU Rangel-Santos, A Wakim, VL Jacob, CM Pastorino, AC Cunha, JM Collanieri, AC Niemela, JE Grumach, AS Duarte, AJS Moraes-Vasconcelos, D Oliveira, JB AF Rangel-Santos, A. Wakim, V. L. Jacob, C. M. Pastorino, A. C. Cunha, J. M. Collanieri, A. C. Niemela, J. E. Grumach, A. S. Duarte, A. J. S. Moraes-Vasconcelos, D. Oliveira, J. B. TI Molecular Characterization of Patients with X-linked Hyper-IgM Syndrome: Description of Two Novel CD40L Mutations SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID LIGAND; IMMUNODEFICIENCY; PROTEINS AB Type 1, X-linked Hyper-IgM syndrome (HIGM1) is caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). CD40L is expressed in activated T cells and interacts with CD40 receptor expressed on B lymphocytes and dendritic cells. Affected patients present cellular and humoral immune defects, with infections by intracellular, opportunistic and extracellular pathogens. In the present study we investigated the molecular defects underlying disease in four patients with HIGM1. We identified four distinct CD40L mutations, two of them which have not been previously described. P1 harboured the novel p.G227X mutation which abolished CD40L expression. P2 had a previously described frame shift deletion in exon 2 (p.I53fsX65) which also prevented protein expression. P3 demonstrated the previously known p.V126D change in exon 4, affecting the TNF homology (TNFH) domain. Finally, P4 evidenced the novel p.F229L mutation also located in the TNFH domain. In silico analysis of F229L predicted the change to be pathological, affecting the many hydrophobic interactions of this residue. Precise molecular diagnosis in HIGM syndrome allows reliable detection of carriers, making genetic counselling and prenatal diagnosis possible. C1 [Oliveira, J. B.] NIH, Immunl Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Rangel-Santos, A.; Collanieri, A. C.; Grumach, A. S.; Duarte, A. J. S.; Moraes-Vasconcelos, D.; Oliveira, J. B.] Univ Sao Paulo, Fac Med, Lab Med Invest Unit 56, Dept Dermatol,LIM 56, Sao Paulo, Brazil. [Wakim, V. L.] Univ Fed Rio de Janeiro, BR-21941 Rio De Janeiro, Brazil. [Jacob, C. M.; Pastorino, A. C.] Univ Sao Paulo, Fac Med, Allergy & Immunol Serv, Dept Pediat, Sao Paulo, Brazil. RP Oliveira, JB (reprint author), NIH, Immunl Serv, Dept Lab Med, Ctr Clin, EUA Bldg 10,Room 2C410,10 Ctr Dr, Bethesda, MD 20892 USA. EM oliveirajb@cc.nih.gov RI Duarte, Alberto/D-4382-2012; Moraes-Vasconcelos, Dewton/G-2209-2012; Cunha, Jose Marcos/J-7030-2014; Rangel Santos, Andreia/E-9985-2016; OI Cunha, Jose Marcos/0000-0003-3264-0929; Niemela, Julie/0000-0003-4197-3792; Oliveira, Joao/0000-0001-9388-8173; Grumach, Anete/0000-0002-9803-0309 NR 21 TC 5 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD FEB PY 2009 VL 69 IS 2 BP 169 EP 173 DI 10.1111/j.1365-3083.2008.02198.x PG 5 WC Immunology SC Immunology GA 397XA UT WOS:000262694400011 PM 19170966 ER PT J AU Maurex, L Zaboli, G Wiens, S Asberg, M Leopardi, R Ohman, A AF Maurex, Liselotte Zaboli, Ghazal Wiens, Stefan Asberg, Marie Leopardi, Rosario Ohman, Arne TI Emotionally controlled decision-making and a gene variant related to serotonin synthesis in women with borderline personality disorder SO SCANDINAVIAN JOURNAL OF PSYCHOLOGY LA English DT Article DE Borderline personality disorder; tryptophan hydroxylase-1 gene; serotonin; decision-making; Iowa Gambling Task ID TRYPTOPHAN-HYDROXYLASE GENE; IOWA GAMBLING TASK; DSM-III-R; SUICIDAL-BEHAVIOR; IMPULSIVITY; ASSOCIATION; DEFICITS; FAMILY; CORTEX AB Maurex, L., Zaboli, G., Wiens, S., angstrom sberg, M., Leopardi, R. & ohman, A. (2008). Emotionally controlled decision-making and a gene variant related to serotonin synthesis in women with borderline personality disorder. Scandinavian Journal of Psychology, 50, 5-10. The Iowa Gambling Task (IGT) was used to examine (i) social decision-making in women with borderline personality disorder (BPD), and (ii) the relationship between impaired decision-making and the tryptophan hydroxylase-1 (TPH-1) gene, involved in serotonin synthesis. Forty-two women with BPD and a history of suicide attempts were genotyped, and the frequency of a TPH-1 haplotype previously uniquely associated with BPD was calculated. The BPD group scored significantly lower than a control group in the IGT. Furthermore, the TPH-1 haplotype displayed a significantly higher frequency in BPD participants with impaired decision making, compared to BPD participants with normal scores. These findings suggest that impaired decision-making as determined by the IGT is a feature of BPD and may be (i) associated with serotonin dysfunction, and (ii) possibly relevant for suicidal behavior. C1 [Maurex, Liselotte; Wiens, Stefan; Ohman, Arne] Karolinska Inst, Dept Clin Neurosci, Psychol Sect, S-17177 Stockholm, Sweden. [Zaboli, Ghazal; Leopardi, Rosario] Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17177 Stockholm, Sweden. [Zaboli, Ghazal; Leopardi, Rosario] Karolinska Inst, Ctr Mol Med, S-17177 Stockholm, Sweden. [Wiens, Stefan] Stockholm Univ, Dept Psychol, Stockholm, Sweden. [Ohman, Arne] Ctr Adv Study Behav Sci, Stanford, CA 94305 USA. [Ohman, Arne] Stockholm Brain Inst, Stockholm, Sweden. [Ohman, Arne] Univ Florida, NIMH, Ctr Res Emot & Attent, Gainesville, FL 32611 USA. [Asberg, Marie] Karolinska Inst, Dept Clin Sci, S-17177 Stockholm, Sweden. RP Ohman, A (reprint author), Karolinska Inst, Dept Clin Neurosci, Psychol Sect, S-17177 Stockholm, Sweden. EM Arne.Ohman@ki.se NR 41 TC 23 Z9 26 U1 1 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0036-5564 J9 SCAND J PSYCHOL JI Scand. J. Psychol. PD FEB PY 2009 VL 50 IS 1 BP 5 EP 10 DI 10.1111/j.1467-9450.2008.00689.x PG 6 WC Psychology, Multidisciplinary SC Psychology GA 394XY UT WOS:000262487700003 PM 18826425 ER PT J AU Lemelin, ET Roux, AVD Franklin, TG Carnethon, M Lutsey, PL Ni, HY O'Meara, E Shrager, S AF Lemelin, Emily T. Roux, Ana V. Diez Franklin, Tracy G. Carnethon, Mercedes Lutsey, Pamela L. Ni, Hanyu O'Meara, Ellen Shrager, Sandi TI Life-course socioeconomic positions and subclinical atherosclerosis in the multi-ethnic study of atherosclerosis SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Socioeconomic position; Subclinical disease; Life-course; USA; Neighborhood; Atherosclerosis; Ethnicity; Gender ID CORONARY-HEART-DISEASE; INTIMA-MEDIA-THICKNESS; CARDIOVASCULAR-DISEASE; CAROTID ATHEROSCLEROSIS; MYOCARDIAL-INFARCTION; NEIGHBORHOOD DEPRIVATION; HEALTH RESEARCH; SOCIAL-CLASS; RISK; WOMEN AB A major limitation of past work on the social patterning of atherosclerosis has been the reliance on measures of neighborhood or individual-level socioeconomic position (SEP) assessed at a single point in time in adulthood. Risk of chronic disease is thought to accumulate throughout the life-course, so the use of a measure for a single point in time may result in inaccurate estimates of the social patterning of subclinical disease. Using data from the US Multi-Ethnic Study of Atherosclerosis (MESA), we examined the relation between childhood SEP [CSEP] (father or caretaker's education), adulthood SEP [ASEP] (a summary score of income, education, and wealth), and 20-year average exposure to neighborhood poverty [NSEP] (residential addresses geocoded and linked to census data) and the prevalence of subclinical atherosclerosis, as assessed by common carotid intimal-medial thickness (IMT) in mid to late adulthood. Participants were 45-84 years of age at baseline and were sampled from six study sites in the United States. After adjustment for age, CSEP and ASEP were both inversely and independently associated with IMT in men. All three indicators CSEP, ASEP, and NSEP were inversely and independently associated with IMT in women. Associations were somewhat reduced after adjustment for cardiovascular risk factors, suggesting that these factors may play a mediating role. There was evidence of heterogeneity in effects of NSEP by gender, and in the effects of ASEP and NSEP by race/ethnicity. Our results contribute to the growing body of work that shows that SEP at multiple points in the life-course, and at the individual and neighborhood level, contributes to the development of atherosclerosis. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Lemelin, Emily T.; Roux, Ana V. Diez; Franklin, Tracy G.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48104 USA. [Carnethon, Mercedes] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Lutsey, Pamela L.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Ni, Hanyu] NHLBI, NIH, Bethesda, MD 20892 USA. [O'Meara, Ellen] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Shrager, Sandi] Univ Washington, Collaborat Hlth Studies Coordinating Ctr, Washington, DC USA. RP Lemelin, ET (reprint author), Univ Michigan, Dept Epidemiol, 1214 S Univ, Ann Arbor, MI 48104 USA. EM elemelin@nshd.mrc.ac.uk; adiezrou@umich.edu; greentl@umich.edu; carnethon@northwestern.edu; lutsey@epi.umn.edu; hn79e@nih.gov; eomeara@u.washington.edu; sandis@u.washington.edu FU NHLBI NIH HHS [N01-HC-95161, N01-HC-95163, N01-HC-95165, N01-HC-95169, N01 HC048049, N01-HC-95159, N01-HC-95160, N01-HC-95162, N01-HC-95164, R01-HL071759] NR 58 TC 37 Z9 39 U1 1 U2 9 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 FEB PY 2009 VL 68 IS 3 BP 444 EP 451 DI 10.1016/j.socscimed.2008.10.038 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 408GX UT WOS:000263424600008 PM 19081660 ER PT J AU Shaw, PA Pepe, MS Alonzo, TA Etzioni, R AF Shaw, Pamela A. Pepe, Margaret S. Alonzo, Todd A. Etzioni, Ruth TI Methods for Assessing Improvement in Specificity When a Biomarker is Combined With a Standard Screening Test SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE Diagnostic tests; Relative accuracy; ROC curve; Specificity; Study design AB Biomarkers that can be used in combination with established screening tests to reduce false positive rates are in considerable demand. In this article, we present methods for evaluating the diagnostic performance of combination tests that require positivity on a biomarker test in addition to a standard screening test. These methods rely on relative true-and false-positive rates to measure the loss in sensitivity and gain in specificity associated with the combination relative to the standard test. Inference about the relative rates follows from noting their interpretation as conditional probabilities. These methods are extended to evaluate combinations with continuous biomarker tests by introducing a new statistical entity, the relative receiver operating characteristic (rROC) curve. The rROC curve plots the relative true positive rate versus the relative false positive rate as the biomarker threshold for positivity varies. Inference can be made by applying existing ROC methodology. We illustrate the methods with two examples: a breast cancer biomarker study proposed by the Early Detection Research Network (EDRN) and a prostate cancer case-control study examining the ability of free prostate-specific antigen (PSA) to improve the specificity of the standard PSA test. C1 [Shaw, Pamela A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Pepe, Margaret S.; Etzioni, Ruth] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Alonzo, Todd A.] Univ So Calif, Dept Biostat, Keck Sch Med, Arcadia, CA 91006 USA. RP Shaw, PA (reprint author), NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM shawpa@niaid.nih.gov; mspepe@u.washington.edu; talonzo@childrensoncologygroup.org; retzioni@fhcrc.org FU Intramural NIH HHS [Z99 AI999999] NR 24 TC 5 Z9 5 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD FEB PY 2009 VL 1 IS 1 BP 18 EP 25 DI 10.1198/sbr.2009.0002 PG 8 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA V17ZI UT WOS:000207974700003 PM 20054437 ER PT J AU Nambi, V Hoogeveen, RC Chambless, L Hu, YJ Bang, HJ Coresh, J Ni, HY Boerwinkle, E Mosley, T Sharrett, R Folsom, AR Ballantyne, CM AF Nambi, Vijay Hoogeveen, Ron C. Chambless, Lloyd Hu, Yijuan Bang, Heejung Coresh, Josef Ni, Hanyu Boerwinkle, Eric Mosley, Thomas Sharrett, Richey Folsom, Aaron R. Ballantyne, Christie M. TI Lipoprotein-Associated Phospholipase A(2) and High-Sensitivity C-Reactive Protein Improve the Stratification of Ischemic Stroke Risk in the Atherosclerosis Risk in Communities (ARIC) Study SO STROKE LA English DT Article DE CRP; Lp-PLA(2); risk; stroke ID CORONARY-HEART-DISEASE; MIDDLE-AGED MEN; PRIMARY PREVENTION; BLOOD CHOLESTEROL; PREDICTIVE MODELS; EVENTS; COHORT; WOMEN; INFLAMMATION; SIMVASTATIN AB Background and Purpose-Inflammation plays a critical role in the development of vascular disease, and increased levels of the inflammatory biomarkers, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), and high-sensitivity C-reactive protein (hs-CRP) have been shown to be associated with an increased risk for ischemic stroke. Methods-In a prospective case-cohort (n = 949) study in 12 762 apparently healthy, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, we first examined whether Lp-PLA(2) and hs-CRP levels improved the area under the receiver operator characteristic curve (AUC) for 5-year ischemic stroke risk. We then examined how Lp-PLA(2) and hs-CRP levels altered classification of individuals into low-, intermediate-, or high-risk categories compared with traditional risk factors. Results-In a model using traditional risk factors alone, the AUC adjusted for optimism was 0.732, whereas adding hs-CRP improved the AUC to 0.743, and adding Lp-PLA(2) significantly improved the AUC to 0.752. Addition of hs-CRP and Lp-PLA(2) together in the model improved the AUC to 0.761, and the addition of the interaction between Lp-PLA(2) and hs-CRP further significantly improved the AUC to 0.774. With the use of traditional risk factors to assess 5-year risk for ischemic stroke, 86% of participants were categorized as low risk (<2%); 11%, intermediate risk (2% to 5%); and 3%, high risk (>5%). The addition of hs-CRP, Lp-PLA(2), and their interaction to the model reclassified 4%, 39%, and 34% of the low-, intermediate- and high-risk categories, respectively. Conclusion-Lp-PLA(2) and hs-CRP may be useful in individuals classified as intermediate risk for ischemic stroke by traditional risk factors. (Stroke. 2009; 40: 376-381.) C1 [Nambi, Vijay; Hoogeveen, Ron C.; Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Sect Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Nambi, Vijay; Hoogeveen, Ron C.; Ballantyne, Christie M.] Methodist DeBakey Heart Ctr, Ctr Cardiovasc Dis Prevent, Houston, TX USA. [Chambless, Lloyd; Hu, Yijuan] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Bang, Heejung] Cornell Univ, Weill Med Coll, Dept Publ Hlth, Div Biostat & Epidemiol, New York, NY 10021 USA. [Coresh, Josef; Sharrett, Richey] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Ni, Hanyu] NIH, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Houston Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Houston Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Mosley, Thomas] Univ Mississippi, Dept Med, Jackson, MS 39216 USA. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP Ballantyne, CM (reprint author), Baylor Coll Med, Dept Med, Sect Atherosclerosis & Vasc Med, 6565 Fannin,MS STE-B-160 A-601, Houston, TX 77030 USA. EM cmb@bcm.tmc.edu FU NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; GlaxoSmithKline, Research Triangle Park, NC FX The National Heart, Lung, and Blood Institute (NHLBI) participated in the design and conduct of the study, and the NHLBI Project Office participated in the preparation and review of the manuscript. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the (NHLBI, Bethesda, Md. This research was also supported by an unrestricted research grant from GlaxoSmithKline, Research Triangle Park, NC. NR 45 TC 39 Z9 50 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 FEB PY 2009 VL 40 IS 2 BP 376 EP 381 DI 10.1161/STROKEAHA.107.513259 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 399FD UT WOS:000262784900007 PM 19095974 ER PT J AU Guo, SZ Arai, K Stins, MF Chuang, DM Lo, EH AF Guo, Shuzhen Arai, Ken Stins, Monique F. Chuang, De-Maw Lo, Eng H. TI Lithium Upregulates Vascular Endothelial Growth Factor in Brain Endothelial Cells and Astrocytes SO STROKE LA English DT Article DE growth factor; neuroprotection; neurovascular unit; stroke recovery ID GLYCOGEN-SYNTHASE KINASE-3; NEUROPROTECTION; VEGF; INHIBITION; INDUCTION; SURVIVAL; NEURONS; MODEL AB Background and Purpose-We recently reported that delayed lithium therapy can improve stroke recovery in rats by augmenting neurovascular remodeling. We tested the hypothesis that lithium can promote the expression of growth factors in brain endothelial cells and astrocytes. Methods-Human brain microvascular endothelial cells and primary rat cortical astrocytes were exposed to lithium chloride in serum-free medium. We examined 2 representative growth factors: brain-derived neurotrophic factor and vascular endothelial growth factor (VEGF). Cell lysates were collected for Western blot analysis. Conditioned media was analyzed with enzyme-linked immunosorbent assay. SB-216763 and LY294002 were used to assess the roles of the glycogen synthase kinase-3 beta (GSK-3 beta) and PI3-K signaling in the lithium-induced responses. Results-No consistent responses were observed for brain-derived neurotrophic factor. However, lithium (0.2 to 20 mmol/L) increased the phosphorylation of GSK-3 beta and promoted VEGF secretion in a concentration-dependent manner in both endothelial and astrocyte cells. For endothelial cells, the potent GSK-3 beta inhibitor SB-216763 upregulated VEGF, whereas inhibition of PI3-K with LY294002 suppressed lithium-induced responses in both phospho-GSK-3 beta and VEGF. In contrast, neither inhibition of GSK-3 beta nor inhibition of PI3-K had any detectable effects on VEGF levels in astrocytes. Conclusions-Lithium promotes VEGF expression through PI3-K/GSK-3 beta-dependent and-independent pathways in brain endothelium and astrocytes, respectively. This growth factor signaling mechanism may contribute to lithium's reported ability to promote neurovascular remodeling after stroke. (Stroke. 2009;40:652-655.) C1 [Chuang, De-Maw] NIMH, Mol Neurobiol Sect, Bethesda, MD 20892 USA. [Stins, Monique F.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Boston, MA 02114 USA. RP Lo, EH (reprint author), MGH East 149-2401, Charlestown, MA 02129 USA. EM Lo@helix.mgh.harvard.edu FU American Heart Association Bugher; National Institutes of Health [R01-NS48422, R01-NS53560, P50-NS10828, P01-NS55104] FX Supported in part by an American Heart Association Bugher award and National Institutes of Health grants R01-NS48422, R01-NS53560, P50-NS10828, and P01-NS55104. NR 18 TC 36 Z9 39 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2009 VL 40 IS 2 BP 652 EP 655 DI 10.1161/STROKEAHA.108.524504 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 399FD UT WOS:000262784900050 PM 18974377 ER PT J AU Gray, TR Kelly, T LaGasse, LL Smith, LM Derauf, C Haning, W Grant, P Shah, R Arria, A Strauss, A Lester, BM Huestis, MA AF Gray, Teresa R. Kelly, Tamsin LaGasse, Linda L. Smith, Lynne M. Derauf, Chris Haning, William Grant, Penny Shah, Rizwan Arria, Amelia Strauss, Arthur Lester, Barry M. Huestis, Marilyn A. TI Novel Biomarkers of Prenatal Methamphetamine Exposure in Human Meconium SO THERAPEUTIC DRUG MONITORING LA English DT Article DE methamphetamine; meconium; in utero ID PERFORMANCE LIQUID-CHROMATOGRAPHY; LIFE-STYLE; INFANT DEVELOPMENT; MASS-SPECTROMETRY; MAJOR METABOLITES; URINARY-EXCRETION; HAIR ANALYSIS; DRUG-USE; AMPHETAMINE; PREGNANCY AB Meconium analysis can detect fetal exposure to drugs taken by the mother during pregnancy. Methamphetamine (MAMP) and amphetamine (AMP) have previously been observed in meconium of MAMP-exposed neonates; the presence of other metabolites has not been investigated. Detection of such analytes may lead to more sensitive identification and thus improved medical treatment of affected infants. Forty-three MAMP-positive meconium specimens were analyzed for newly identified MAMP biomarkers, p-hydroxymethamphetamine, p-hydroxyamphetamine, and norephedrine. Due to MAMP adulteration in illicit ecstasy and to simultaneously monitor 3,4-methylenedioxymethamphetaniine and MAMP prenatal exposure, 3,4-methylenedioxymethamphetamine, its metabolites, and related sympathomimetic amines were assayed. MAMP AM-P, and unconjugated p-hydroxyrnethamphetamine were the most prevalent and abundant analytes present in meconium; however, unconjugated p-hydroxyamphetarnine and norephedrine also were identified. It is possible that one of these additional analytes could be important for predicting toxicity or maternal or neonatal outcome measures in fetuses exposed to MAMP at specific gestational ages or with different metabolic capabilities. Although these new biomarkers were present in lower concentrations than MAMP and AMP in the meconium of previously confirmed specimens, additional research will determine if inclusion of these analytes can increase identification of MAMP-exposed neonates. Novel methamphetamine biomarker concentrations were characterized in meconium of infants exposed in utero to MAMP C1 [Gray, Teresa R.; Kelly, Tamsin; Huestis, Marilyn A.] NIDA, Intramural Res Program, Natl Inst Hlth, Baltimore, MD USA. [Kelly, Tamsin] Curtin Univ Technol, Dept Appl Chem, Perth, WA, Australia. [LaGasse, Linda L.; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Study Children Risk, Brown Ctr, Providence, RI 02912 USA. [LaGasse, Linda L.; Lester, Barry M.] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Smith, Lynne M.] Harbor UCLA Med Ctr, Los Angeles Biomed Inst, Dept Pediat, Torrance, CA 90509 USA. [Smith, Lynne M.] Univ Calif Los Angeles, David Geffen Sch Med, Torrance, CA USA. [Derauf, Chris] Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96822 USA. [Haning, William] Univ Hawaii, John A Burns Sch Med, Dept Psychiat, Honolulu, HI 96822 USA. [Grant, Penny] Univ Oklahoma, Dept Pediat, Tulsa, OK USA. [Shah, Rizwan] Blank Childrens Hosp, Dept Pediat, Des Moines, IA USA. [Arria, Amelia] Univ Maryland, Ctr Subst Abuse Res, College Pk, MD 20742 USA. [Strauss, Arthur] Long Beach Mem Med Ctr, Dept Pediat, Long Beach, CA USA. RP Huestis, MA (reprint author), 251 Bayview Blvd,Suite 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI Kelly, Tamsin/A-2456-2009; OI Kelly, Tamsin/0000-0002-8946-9686; Arria, Amelia/0000-0002-6360-9265 FU Intramural Research Program, National Institutes of Health; National Institute on Drug Abuse FX This research was funded by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse. The authors thank the US Drug Testing Laboratory for donating authentic MAMP-positive meconium specimens. NR 40 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD FEB PY 2009 VL 31 IS 1 BP 70 EP 75 PG 6 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 400OX UT WOS:000262879000008 PM 19125148 ER PT J AU Bueno, DF Kerkis, I Costa, AM Martins, MT Kobayashi, GS Zucconi, E Fanganiello, RD Salles, FT Almeida, AB do Amaral, CER Alonso, N Passos-Bueno, MR AF Bueno, Daniela Franco Kerkis, Irina Costa, Andre Mendonca Martins, Marilia T. Kobayashi, Gerson Shigeru Zucconi, Eder Fanganiello, Roberto Dalto Salles, Felipe T. Almeida, Ana Beatriz Raposo do Amaral, Cassio Eduardo Alonso, Nivaldo Passos-Bueno, Maria Rita TI New Source of Muscle-Derived Stem Cells with Potential for Alveolar Bone Reconstruction in Cleft Lip and/or Palate Patients SO TISSUE ENGINEERING PART A LA English DT Article ID SKELETAL-MUSCLE; TISSUE; GRAFTS; OSTEOPLASTY; DEFECTS; REPAIR; ADULT AB Cleft lip and palate (CLP), one of the most frequent congenital malformations, affects the alveolar bone in the great majority of the cases, and the reconstruction of this defect still represents a challenge in the rehabilitation of these patients. One of the current most promising strategy to achieve this goal is the use of bone marrow stem cells (BMSC); however, isolation of BMSC or iliac bone, which is still the mostly used graft in the surgical repair of these patients, confers site morbidity to the donor. Therefore, in order to identify a new alternative source of stem cells with osteogenic potential without conferring morbidity to the donor, we have used orbicular oris muscle (OOM) fragments, which are regularly discarded during surgery repair (cheiloplasty) of CLP patients. We obtained cells from OOM fragments of four unrelated CLP patients (CLPMDSC) using previously described preplating technique. These cells, through flow cytometry analysis, were mainly positively marked for five mesenchymal stem cell antigens (CD29, CD90, CD105, SH3, and SH4), while negative for hematopoietic cell markers, CD14, CD34, CD45, and CD117, and for endothelial cell marker, CD31. After induction under appropriate cell culture conditions, these cells were capable to undergo chondrogenic, adipogenic, osteogenic, and skeletal muscle cell differentiation, as evidenced by immunohistochemistry. We also demonstrated that these cells together with a collagen membrane lead to bone tissue reconstruction in a critical-size cranial defects previously induced in non-immunocompromised rats. The presence of human DNA in the new bone was confirmed by PCR with human-specific primers and immunohistochemistry with human nuclei antibodies. In conclusion, we showed that cells from OOM have phenotypic and behavior characteristics similar to other adult stem cells, both in vitro and in vivo. Our findings suggest that these cells represent a promising source of stem cells for alveolar bone grafting treatment, particularly in young CLP patients. C1 [Bueno, Daniela Franco] Univ Sao Paulo, Inst Biosci, Ctr Human Genome, BR-05508090 Sao Paulo, Brazil. [Kerkis, Irina] Butantan Inst, Dept Genet, Sao Paulo, Brazil. [Costa, Andre Mendonca; Alonso, Nivaldo] Univ Sao Paulo, Fac Med, Dept Plast Surg, BR-05508090 Sao Paulo, Brazil. [Costa, Andre Mendonca] State Univ Hlth Sci Alagoas, Dept Plast Surg, Alagoas, Brazil. [Martins, Marilia T.] Univ Sao Paulo, Dept Oral Pathol, BR-05508090 Sao Paulo, Brazil. [Salles, Felipe T.; Almeida, Ana Beatriz] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Raposo do Amaral, Cassio Eduardo] SOBRAPAR, Campinas, SP, Brazil. RP Bueno, DF (reprint author), Univ Sao Paulo, Inst Biosci, Ctr Human Genome, Rua Matao 277, BR-05508090 Sao Paulo, Brazil. EM passos@ib.usp.br RI Salles, Felipe/H-7544-2013; Celulas tronco, Inct/I-1921-2013; Cetgen, Inct/I-2412-2013; Trierveiler, Marilia/N-7359-2015; Raposo Amaral, Cassio Eduardo/D-1397-2013; Passos-Bueno, Maria Rita/I-6796-2016; Kobayashi, Gerson/H-4017-2013; OI Trierveiler, Marilia/0000-0002-8517-2105; Raposo Amaral, Cassio Eduardo/0000-0001-6201-0827; Passos-Bueno, Maria Rita/0000-0002-9248-3008; Kobayashi, Gerson/0000-0002-6520-5774; Zucconi, Eder/0000-0002-5904-4564; Bueno, Daniela F/0000-0001-5932-6134 FU FAPESP/CEPID; CNPq FX The authors would like to express their gratitude to Professor Cassio Raposo do Amaral (1943-2005) for his incentive and fruitful ideas on new insights in rehabilitating craniofacial malformation; Professor Mayana Zatz for her incentive on stem cells research, Dr. Bechara Kachar, M. D., who allowed the use of his facility at NIH; Dr. Mariz Vainzof for the muscle antibodies; Mrs. Constancia Urbani for secretarial assistance, and the following colleagues for assistance: Carlos Maranduba, Ph. D.; Alexandre Kerkis, Ph. D.; Fernanda S. Jehee, Ph. D.; Rogerio Castilho, Ph. D.; Marta Canovas, Erika Yeh, and Natassia Vieira. FAPESP/CEPID and CNPq sponsored this study. NR 36 TC 28 Z9 32 U1 1 U2 10 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 FEB PY 2009 VL 15 IS 2 BP 427 EP 435 DI 10.1089/ten.tea.2007.0417 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 403BR UT WOS:000263057300022 PM 18816169 ER PT J AU Kaczmarek, M Cachau, RE Topol, IA Kasprzak, KS Ghio, A Salnikow, K AF Kaczmarek, Monika Cachau, Raul E. Topol, Igor A. Kasprzak, Kazimierz S. Ghio, Andy Salnikow, Konstantin TI Metal Ions-Stimulated Iron Oxidation in Hydroxylases Facilitates Stabilization of HIF-1 alpha Protein SO TOXICOLOGICAL SCIENCES LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; PROLYL 4-HYDROXYLASE ACTIVITY; SOLUBLE TRANSITION-METALS; AIRWAY EPITHELIAL-CELLS; L-ASCORBIC-ACID; OIL FLY-ASH; PROLINE HYDROXYLATION; CRYSTAL-STRUCTURE; A549 CELLS; HIF-ALPHA AB The exposure of cells to several metal ions stabilizes HIF-1 alpha protein. However, the molecular mechanisms are not completely understood. They may involve inhibition of hydroxylation by either substitution of iron by metal ions or by iron oxidation in the hydroxylases. Here we provide evidence supporting the latter mechanism. We show that HIF-1 alpha stabilization in human lung epithelial cells occurred following exposure to various metal and metalloid ions, including those that cannot substitute for iron in the hydroxylases. In each case addition of the reducing agent ascorbic acid (AA)* abolished HIF-1 alpha protein stabilization. To better understand the role of iron oxidation in hydroxylase inhibition and to define the role of AA in the enzyme recovery we applied molecular modeling techniques. Our results indicate that the energy required for iron substitution by Ni(II) in the enzyme is high and unlikely to be achieved in a biological system. Additionally, computer modeling allowed us to identify a tridentate coordination of AA with the enzyme-bound iron, which explains the specific demand for AA as the iron reductant. Thus, the stabilization of HIF-1 alpha by numerous metal ions that cannot substitute for iron in the enzyme, the alleviation of this effect by AA, and our computer modeling data support the hypothesis of iron oxidation in the hydroxylases following exposure to metal ions. C1 [Kaczmarek, Monika; Kasprzak, Kazimierz S.; Salnikow, Konstantin] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. [Cachau, Raul E.; Topol, Igor A.] NCI, SAIC Frederick Inc, Adv Biomed Comp Ctr, Adv Technol Program, Frederick, MD 21701 USA. [Ghio, Andy] US EPA, Res Triangle Pk, NC 27711 USA. RP Salnikow, K (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538,Room 205 E, Frederick, MD 21701 USA. EM salnikok@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; National Institutes of Health [N01-CO-12400] FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and National Cancer Institute, National Institutes of Health, under contract no. (N01-CO-12400). NR 50 TC 17 Z9 18 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2009 VL 107 IS 2 BP 394 EP 403 DI 10.1093/toxsci/kfn251 PG 10 WC Toxicology SC Toxicology GA 398HK UT WOS:000262723000010 PM 19074761 ER PT J AU Jiang, T Bell, DR Clode, S Fan, MQ Fernandes, A Foster, PMD Loizou, G MacNicoll, A Miller, BG Rose, M Tran, L White, S AF Jiang, Tao Bell, David R. Clode, Sally Fan, Ming Qi Fernandes, Alwyn Foster, Paul M. D. Loizou, George MacNicoll, Alan Miller, Brian G. Rose, Martin Tran, Lang White, Shaun TI A Truncation in the Aryl Hydrocarbon Receptor of the CRL:WI(Han) Rat Does Not Affect the Developmental Toxicity of TCDD SO TOXICOLOGICAL SCIENCES LA English DT Article ID MALE WISTAR(HAN) RAT; AH-RECEPTOR; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN TCDD; MATERNAL EXPOSURE; RESISTANT RAT; MICE LACKING; IN-UTERO; BINDING; HYDROXYLASE; EXPRESSION AB The aryl hydrocarbon receptor (AhR) is required for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and so the AhR of CRL:WI and CRL:WI(Han) rats was characterized. Western blot showed AhR proteins of similar to 110 and similar to 97 kDa in individual rats from both strains. The AhR cDNA from a CRL:WI(Han) rat with the similar to 110-kDa protein revealed a sequence that was identical to that of the CRL:WI and SD rat. However, cloning of the AhR from a rat with the similar to 97-kDa protein revealed a point mutation, and five variants encoding two C-terminally truncated variants of the AhR protein, arising from a point mutation in the intron/exon junction and consequent differential splicing. These C-terminally truncated variants were expressed and shown to give rise to a protein of similar to 97 kDa; the recombinant AhR bound TCDD with an affinity that was not statistically different from the full-length protein. A single-nucleotide polymorphism assay was developed, and showed that both alleles were represented in a Hardy-Weinberg equilibrium in samples of CRL:WI and CRL:WI(Han) populations; both alleles are abundant. Rats from two studies of TCDD developmental toxicity were genotyped, and the association with toxicity investigated using statistical analysis. There was no plausible evidence that the AhR allele had a significant effect on the toxic endpoints examined. These data show that the two AhR alleles are common in two strains of Wistar rat, and that the AhR alleles had no effect on TCDD-induced developmental toxicity in two independent studies. C1 [Jiang, Tao; Bell, David R.; Fan, Ming Qi] Univ Nottingham, Sch Biol, Nottingham NG7 2RD, England. [Fernandes, Alwyn; MacNicoll, Alan; Rose, Martin; White, Shaun] Environm Food & Hlth, Cent Sci Lab, York YO41 1LZ, N Yorkshire, England. [Foster, Paul M. D.] NIEHS, Res Triangle Pk, NC 27709 USA. [Loizou, George] Hlth & Safety Lab, Buxton SK17 9JN, Derby, England. [Miller, Brian G.; Tran, Lang] Inst Occupat Med, Edinburgh EH14 4AP, Midlothian, Scotland. RP Bell, DR (reprint author), Univ Nottingham, Sch Biol, Univ Pk, Nottingham NG7 2RD, England. EM david.bell@nottingham.ac.uk OI Rose, Martin/0000-0001-7071-180X FU Food Standards Agency [T01034] FX Food Standards Agency (T01034). NR 40 TC 3 Z9 3 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2009 VL 107 IS 2 BP 512 EP 521 DI 10.1093/toxsci/kfn252 PG 10 WC Toxicology SC Toxicology GA 398HK UT WOS:000262723000021 PM 19056935 ER PT J AU Kienhuis, AS van de Poll, MCG Wortelboer, H van Herwijnen, M Gottschalk, R Dejong, CHC Boorsma, A Paules, RS Kleinjans, JCS Stierum, RH van Delft, JHM AF Kienhuis, Anne S. van de Poll, Marcel C. G. Wortelboer, Heleen van Herwijnen, Marcel Gottschalk, Ralph Dejong, Cornelis H. C. Boorsma, Andre Paules, Richard S. Kleinjans, Jos C. S. Stierum, Rob H. van Delft, Joost H. M. TI Parallelogram Approach Using Rat-Human In Vitro and Rat In Vivo Toxicogenomics Predicts Acetaminophen-induced Hepatotoxicity in Humans SO TOXICOLOGICAL SCIENCES LA English DT Article ID GENE-EXPRESSION; HUMAN HEPATOCYTES; CYTOCHROME-P450 EXPRESSION; DRUG-METABOLISM; LIVER; TOXICITY; MECHANISMS; MICROARRAY; REVEALS; MODELS AB The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. The present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo. C1 [Kienhuis, Anne S.; van Herwijnen, Marcel; Gottschalk, Ralph; Kleinjans, Jos C. S.; van Delft, Joost H. M.] Univ Maastricht, Dept Hlth Risk Anal & Toxicol, NL-6200 MD Maastricht, Netherlands. [Kienhuis, Anne S.; Wortelboer, Heleen; Boorsma, Andre; Stierum, Rob H.] TNO Qual Life, Business Unit Biosci, Zeist, Netherlands. [van de Poll, Marcel C. G.; Dejong, Cornelis H. C.] Univ Maastricht, Nutr & Toxicol Res Inst NUTRIM, NL-6200 MD Maastricht, Netherlands. [van de Poll, Marcel C. G.; Dejong, Cornelis H. C.] Univ Hosp Maastricht, Dept Surg, Maastricht, Netherlands. [Paules, Richard S.] NIEHS, Microarray Grp, Res Triangle Pk, NC 27709 USA. RP Kienhuis, AS (reprint author), Univ Maastricht, Dept Hlth Risk Anal & Toxicol, POB 616, NL-6200 MD Maastricht, Netherlands. EM anne.kienhuis@rivm.nl RI Kleinjans, Jos/E-7241-2015 FU Netherlands Organization for Health Research and Development, program Alternatives to Animal Experiments [3170.0049]; Dutch Ministry of Economic Affairs FX The Netherlands Organization for Health Research and Development, program Alternatives to Animal Experiments (3170.0049); the Dutch Ministry of Economic Affairs. NR 37 TC 27 Z9 28 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2009 VL 107 IS 2 BP 544 EP 552 DI 10.1093/toxsci/kfn237 PG 9 WC Toxicology SC Toxicology GA 398HK UT WOS:000262723000024 PM 19008212 ER PT J AU Nadadur, SS Haykal-Coates, N Mudipalli, A Costa, DL AF Nadadur, Srikanth S. Haykal-Coates, Najwa Mudipalli, Anuradha Costa, Daniel L. TI Endothelial effects of emission source particles: Acute toxic response gene expression profiles SO TOXICOLOGY IN VITRO LA English DT Article DE Endothelial; Particulate matter; Vascular effects ID OIL FLY-ASH; PARTICULATE AIR-POLLUTION; TRANSITION-METALS; EPIDEMIOLOGIC EVIDENCE; ULTRAFINE PARTICLES; RESPIRATORY-TRACT; OXIDATIVE-STRESS; DIESEL EXHAUST; LUNG INJURY; MATTER AB Air pollution epidemiology has established a strong association between exposure to ambient particulate matter (PM) and cardiovascular outcomes. Experimental studies in both humans and laboratory animals Support varied biological mechanisms including endothelial dysfunction as potentially a central step to the elicitation of cardiovascular events. We therefore hypothesized that relevant early molecular alterations on endothelial cells should be assessable in vitro upon acute exposure to PM components previously shown to be involved in health outcomes. Using a model emission PM, residual oil fly ash and one of its predominant constituents (vanadium-V), we focused oil the development of gene expression profiles to fingerprint that particle and its constituents to explore potential biomarkers for PM-induced endothelial dysfunction. Here we present differential gene expression and transcription factor activation Profiles in human vascular endothelial cells exposed to a non-cytotoxic dose of fly ash or V following semi-global gene expression profiling of similar to 8000 genes. Both fly ash and it's prime constituent, V, induced alterations in genes involved in passive and active transport of solutes across the membrane; voltage-dependent ion pumps: induction of extracellular matrix proteins and adhesion molecules: and activation of numerous kinases involved in signal transduction pathways. These preliminary data suggest that cardiovascular effects associated with exposure to PM may be mediated by perturbations in endothelial cell permeability, membrane integrity; and ultimately endothelial dysfunction. Published by Elsevier Ltd. C1 [Nadadur, Srikanth S.; Haykal-Coates, Najwa; Costa, Daniel L.] US EPA, ORD, Natl Hlth Environm Effects Res Lab, Pulm Toxicol Branch,Expt Toxicol Div, Res Triangle Pk, NC 27711 USA. [Mudipalli, Anuradha] US EPA, ORD, Natl Ctr Environm Assessment, Res Triangle Pk, NC 27711 USA. RP Nadadur, SS (reprint author), NIEHS, Cellular & Organ Syst Pathobiol Branch, Div Extramural Res & Training, POB 12233,MD EC 23, Res Triangle Pk, NC 27709 USA. EM Nadadurs@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 53 TC 16 Z9 19 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD FEB PY 2009 VL 23 IS 1 BP 67 EP 77 DI 10.1016/j.tiv.2008.10.004 PG 11 WC Toxicology SC Toxicology GA 402LS UT WOS:000263015800009 PM 19000753 ER PT J AU Rismanchi, N Puertollano, R Blackstone, C AF Rismanchi, Neggy Puertollano, Rosa Blackstone, Craig TI STAM Adaptor Proteins Interact with COPII Complexes and Function in ER-to-Golgi Trafficking SO TRAFFIC LA English DT Article DE Brefeldin A; endocytosis; Golgi fragmentation; Sec31; VHS domain; VSV-G ID ENDOPLASMIC-RETICULUM; GAMMA-ADAPTIN; SIGNALING PATHWAYS; MAMMALIAN-CELLS; EARLY ENDOSOME; JANUS KINASES; LIVING CELLS; EXIT SITES; VHS DOMAIN; HRS AB Signal-transducing adaptor molecules (STAMs) are involved in growth factor and cytokine signaling as well as receptor degradation, and they form complexes with a number of endocytic proteins, including Hrs and Eps15. In this study, we demonstrate that STAM proteins also localize prominently to early exocytic compartments and profoundly regulate Golgi morphology. Upon STAM overexpression in cells, the Golgi apparatus becomes extensively fragmented and dispersed, but when STAMs are depleted, the Golgi becomes highly condensed. Under both scenarios, vesicular stomatitis virus G protein-green fluorescent protein trafficking to the plasma membrane is markedly inhibited, and recovery of Golgi morphology after Brefeldin A treatment is substantially impaired in STAM-depleted cells. Furthermore, STAM proteins interact with coat protein II (COPII) proteins, probably at endoplasmic reticulum (ER) exit sites, and Sar1 activity is required to maintain the localization of STAMs at discrete sites. Thus, in addition to their roles in signaling and endocytosis, STAMs function prominently in ER-to-Golgi trafficking, most likely through direct interactions with the COPII complex. C1 [Rismanchi, Neggy; Blackstone, Craig] NINDS, Cellular Neurol Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Rismanchi, Neggy] Penn State Univ, Coll Med, Dept Neural & Behav Sci, Hershey, PA 17033 USA. [Puertollano, Rosa] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), NINDS, Cellular Neurol Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU NINDS and NHLBI; National Institutes of Health FX We thank James Nagle and Deborah Kauffman (NINDS DNA Sequencing Facility) for DNA sequencing, Carolyn Smith for assistance with confocal microscopy, Jung-Hwa Tao-Cheng for assistance with electron microscopy and Chuang-Rung Chang for helpful discussions. This work was supported by the Intramural Research Programs of the NINDS and NHLBI, National Institutes of Health. NR 44 TC 13 Z9 14 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD FEB PY 2009 VL 10 IS 2 BP 201 EP 217 DI 10.1111/j.1600-0854.2008.00856.x PG 17 WC Cell Biology SC Cell Biology GA 395FW UT WOS:000262511000007 PM 19054391 ER PT J AU Hayashi, T Rizzuto, R Hajnoczky, G Su, TP AF Hayashi, Teruo Rizzuto, Rosario Hajnoczky, Gyorgy Su, Tsung-Ping TI MAM: more than just a housekeeper SO TRENDS IN CELL BIOLOGY LA English DT Review ID RAT-LIVER MITOCHONDRIA; SMOOTH ENDOPLASMIC-RETICULUM; PERMEABILIZED ANIMAL-CELLS; SIGMA(1) BINDING-SITES; HAMSTER OVARY CELLS; TRISPHOSPHATE RECEPTORS; MEDIATED APOPTOSIS; MEMBRANE-FRACTION; PLASMA-MEMBRANE; CA2+ AB The physical association between the endoplasmic reticulum (ER) and mitochondria, which is known as the mitochondria-associated ER membrane (MAM), has important roles in various cellular 'housekeeping' functions including the non-vesicular transports of phospholipids. It has recently become clear that the MAM also enables highly efficient transmission of Ca(2+) from the ER to mitochondria to stimulate oxidative metabolism and, conversely, might enable the metabolically energized mitochondria to regulate the ER Ca(2+) homeostasis. Recent studies have shed light on molecular chaperones such as calnexin, calreticulin, ERp44, ERp57, grp75 and the sigma-1 receptor at the MAM, which regulate the association between the two organelles. The MAM thus integrates signal transduction with metabolic pathways to regulate the communication and functional interactions between the ER and mitochondrion. C1 [Hayashi, Teruo; Su, Tsung-Ping] Natl Inst Drug Abuse, Cellular Pathobiol Sect, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Rizzuto, Rosario] Univ Ferrara, Dept Expt & Diagnost Med, Sect Gen Pathol, ER GenTech Lab, I-44100 Ferrara, Italy. [Rizzuto, Rosario] Univ Ferrara, Interdisciplinary Ctr Study Inflammat, I-44100 Ferrara, Italy. [Hajnoczky, Gyorgy] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RP Su, TP (reprint author), Natl Inst Drug Abuse, Cellular Pathobiol Sect, Cellular Neurobiol Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, 333 Cassell Dr, Baltimore, MD 21224 USA. EM tsu@mail.nih.gov OI Rizzuto, Rosario/0000-0001-7044-5097 FU National Institute on Drug Abuse; National Institutes of Health; Department of Health and Human Services of the USA FX This work supported in part by the Intramural Research Program of the National Institute on Drug Abuse, the National Institutes of Health and the Department of Health and Human Services of the USA. NR 65 TC 312 Z9 321 U1 3 U2 23 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 FEB PY 2009 VL 19 IS 2 BP 81 EP 88 DI 10.1016/j.tcb.2008.12.002 PG 8 WC Cell Biology SC Cell Biology GA 413DS UT WOS:000263773700005 PM 19144519 ER PT J AU Roy, SW Irimia, M AF Roy, Scott William Irimia, Manuel TI Mystery of intron gain: new data and new models SO TRENDS IN GENETICS LA English DT Review ID DIATOM THALASSIOSIRA-PSEUDONANA; CHORDATE OIKOPLEURA-DIOICA; CODON USAGE BIAS; GROUP-II INTRONS; REVERSE-TRANSCRIPTION; SPLICEOSOMAL INTRONS; CRYPTOCOCCUS-NEOFORMANS; EUKARYOTIC EVOLUTION; GENES; GENOME AB Despite their ubiquity, the mechanisms and evolutionary forces responsible for the origins of spliceosomal introns remain mysterious. Recent molecular evidence supports the idea that intronic RNAs can reverse splice into RNA transcripts, a crucial step for an influential model of intron gain. However, a paradox attends this model because the rate of intron gain is expected to be orders of magnitude lower than the rate of intron loss in general, in contrast to findings from several lineages. We suggest two possible resolutions to this paradox, based on steric considerations and on the possibility of cooption by specific introns of retroelement transposition pathways, respectively. In addition, we introduce two potential mechanisms for intron creation, based on hybrid RNA-DNA reverse splicing and on template switching errors by reverse transcriptase. C1 [Roy, Scott William] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Irimia, Manuel] Univ Barcelona, Fac Biol, Dept Genet, E-08028 Barcelona, Spain. RP Roy, SW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. EM royscott@ncbi.nlm.nih.gov RI Irimia, Manuel/E-3040-2010; OI Irimia, Manuel/0000-0002-2179-2567 FU Spanish Ministerio of Educacion y Ciencia [BFU2005-00252]; National Library of Medicine at National Institutes of Health FX M.I. was funded by the Spanish Ministerio of Educacion y Ciencia, through a FPI grant (BFU2005-00252) and S.W.R. by the Intramural Research Program of the National Library of Medicine at National Institutes of Health. We thank Eugene Koonin and Jordi Garcia-Fernandez for support. NR 63 TC 45 Z9 45 U1 3 U2 13 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD FEB PY 2009 VL 25 IS 2 BP 67 EP 73 DI 10.1016/j.tig.2008.11.004 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 415IF UT WOS:000263926800003 PM 19070397 ER PT J AU Aronova, MA Kim, YC Pivovarova, NB Andrews, SB Leapman, RD AF Aronova, M. A. Kim, Y. C. Pivovarova, N. B. Andrews, S. B. Leapman, R. D. TI Quantitative EFTEM mapping of near physiological calcium concentrations in biological specimens SO ULTRAMICROSCOPY LA English DT Article DE Energy-filtered transmission electron microscopy (EFTEM); Electron energy-loss spectroscopy (EELS); Plural scattering; Elemental mapping; Calcium; Detection limits ID ENERGY-LOSS SPECTROSCOPY; SPATIAL DISTRIBUTIONS; LOSS SPECTRA; ELECTRON; MITOCHONDRIA; PHOSPHORUS; MICROANALYSIS; NEURONS; FILTER; TOMOGRAPHY AB Although electron energy-loss spectroscopy (EELS) in the scanning transmission electron microscope (STEM) provides high sensitivity for measuring the important element, calcium, in biological specimens, the technique has been difficult to apply routinely, because of long acquisition times required. Here we describe a refinement of the complementary analytical technique of energy-filtered transmission electron microscopy (EFTEM), which enables rapid imaging of large cellular regions and measurement of calcium concentrations approaching physiological levels. Extraction of precise quantitative information is possible by averaging large numbers of pixels that are contained in organelles of interest. We employ a modified two-window approach in which the behavior of the background signal in the EELS spectrum can be modeled as a function of specimen thickness t expressed in terms of the inelastic mean free path lambda. By acquiring pairs of images, one above and one below the Ca L(2.3) edge, together with zero-loss and unfiltered images, which are used to determine a relative thickness (t/lambda) map, it is possible to correct the Ca L(2.3) signal for plural scattering. We have evaluated the detection limits of this technique by considering several sources of systematic errors and applied this method to determine mitochondrial total calcium concentrations in freeze-dried cryosections of rapidly frozen stimulated neurons. By analyzing 0.1 mu m(2) areas of specimen regions that do not contain calcium, it was found that the standard deviation in the measurement of Ca concentrations was about 20 mmol/kg dry weight, corresponding to a Ca:C atomic fraction of approximately 2 x 10(-4). Calcium concentrations in peripheral mitochondria of recently depolarized, and therefore stimulated and Ca loaded, frog sympathetic neurons were in reasonable agreement with previous data. Published by Elsevier B.V. C1 [Aronova, M. A.; Leapman, R. D.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. [Kim, Y. C.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Pivovarova, N. B.; Andrews, S. B.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bldg 13,Rm 3N17,9000 Rockville Pike, Bethesda, MD 20892 USA. EM leapmanr@mail.nih.gov FU National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering and the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 40 TC 19 Z9 19 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD FEB PY 2009 VL 109 IS 3 BP 201 EP 212 DI 10.1016/j.ultramic.2008.10.003 PG 12 WC Microscopy SC Microscopy GA 420HQ UT WOS:000264280200001 PM 19118952 ER PT J AU Sousa, AA Hohmann-Marriott, MF Zhang, G Leapman, RD AF Sousa, A. A. Hohmann-Marriott, M. F. Zhang, G. Leapman, R. D. TI Monte Carlo electron-trajectory simulations in bright-field and dark-field STEM: Implications for tomography of thick biological sections SO ULTRAMICROSCOPY LA English DT Article DE Scanning transmission electron microscopy; STEM; Electron tomography; Monte Carlo simulation; Thick sections ID AMORPHOUS SPECIMENS; SPATIAL-RESOLUTION; IMAGE-FORMATION; ENERGY-LOSS; MICROSCOPY; RECONSTRUCTION; SCATTERING; CONTRAST; LABELS; CELLS AB A Monte Carlo electron-trajectory calculation has been implemented to assess the optimal detector configuration for scanning transmission electron microscopy (STEM) tomography of thick biological sections. By modeling specimens containing 2 and 3 at% osmium in a carbon matrix, it was found that for 1-mu m-thick samples the bright-field (BF) and annular dark-field (ADF) signals give similar contrast and signal-to-noise ratio provided the ADF inner angle and BF outer angle are chosen optimally. Spatial resolution in STEM imaging of thick sections is compromised by multiple elastic scattering which results in a spread of scattering angles and thus a spread in lateral distances of the electrons leaving the bottom surface. However, the simulations reveal that a large fraction of these multiply scattered electrons are excluded from the BF detector, which results in higher spatial resolution in BF than in high-angle ADF images for objects situated towards the bottom of the sample. The calculations imply that STEM electron tomography of thick sections should be performed using a BF rather than an ADF detector. This advantage was verified by recording simultaneous BF and high-angle ADF STEM tomographic tilt series from a stained 600-nm-thick section of C elegans. It was found that loss of spatial resolution occurred markedly at the bottom surface of the specimen in the ADF STEM but significantly less in the BF STEM tomographic reconstruction. Our results indicate that it might be feasible to use BF STEM tomography to determine the 3D structure of whole eukaryotic microorganisms prepared by freeze-substitution, embedding, and sectioning. Published by Elsevier B.V. C1 [Sousa, A. A.; Hohmann-Marriott, M. F.; Zhang, G.; Leapman, R. D.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bldg 13,Rm 3N17,13 S Dr, Bethesda, MD 20892 USA. EM leapmanr@mail.nih.gov FU National institute of Biomedical Imaging and Bioengineering, National Institutes of Health; National Institute of Standards and Technology and NIBIB, NIH FX This work was supported by the Intramural Research Program of the National institute of Biomedical Imaging and Bioengineering, National Institutes of Health. MFHM would like to acknowledge support of a US National Research Council Postdoctoral Associateship co-funded by the National Institute of Standards and Technology and NIBIB, NIH. NR 38 TC 25 Z9 25 U1 0 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD FEB PY 2009 VL 109 IS 3 BP 213 EP 221 DI 10.1016/j.ultramic.2008.10.005 PG 9 WC Microscopy SC Microscopy GA 420HQ UT WOS:000264280200002 PM 19110374 ER PT J AU Robey, RW To, KKK Polgar, O Dohse, M Fetsch, P Dean, M Bates, SE AF Robey, Robert W. To, Kenneth K. K. Polgar, Orsolya Dohse, Marius Fetsch, Patricia Dean, Michael Bates, Susan E. TI ABCG2: A perspective SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE ABCG2; BCRP; Drug-resistance; ABC transporter; Chemotherapy; Pharmacology ID CANCER-RESISTANCE-PROTEIN; BLOOD-BRAIN-BARRIER; MULTIDRUG TRANSPORTER ABCG2; LIMITS FETAL DISTRIBUTION; HIGH-AFFINITY INTERACTION; HEMATOPOIETIC STEM-CELLS; CHRONIC MYELOID-LEUKEMIA; NORMAL HUMAN TISSUES; BREAST-CANCER; P-GLYCOPROTEIN AB ABCG2, or breast cancer resistance protein (BCRP), is an ABC transporter that has been the subject of intense study since its discovery a decade ago. With high normal tissue expression in the brain endothelium, gastrointestinal tract, and placenta, ABCG2 is believed to be important in the protection from xenobiotics, regulating oral bioavailability, forming part of the blood-brain barrier, the blood-testis barrier, and the maternal-fetal barrier. Notably, ABCG2 is often expressed in stem cell populations, where it likely plays a role in xenobiotic protection. However, clues to its epigenetic regulation in various cell populations are only beginning to emerge. While ABCG2 overexpression has been demonstrated in cancer cells after in vitro drug treatment, endogenous ABCG2 expression in certain cancers is likely a reflection of the differentiated phenotype of the cell of origin and likely contributes to intrinsic drug resistance. Notably, research into the transporter's role in cancer drug resistance and its development as a therapeutic target in cancer has lagged. Substrates and inhibitors of the transporter have been described, among them chemotherapy drugs, tyrosine kinase inhibitors, antivirals, HMG-CoA reductase inhibitors, carcinogens, and flavonoids. This broad range of substrates complements the efficiency of ABCG2 as a transporter in laboratory studies and suggests that, while there are redundant mechanisms of xenobiotic protection, the protein is important in normal physiology. indeed, emerging studies in pharmacology and toxicology assessing polymorphic variants in man, in combination with murine knockout models have confirmed its dynamic role. Work in pharmacology may eventually lead us to a greater understanding of the physiologic role of ABCG2. (C) 2008 Published by Elsevier B.V. C1 [Robey, Robert W.; To, Kenneth K. K.; Polgar, Orsolya; Dohse, Marius; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fetsch, Patricia] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dean, Michael] Natl Canc Inst, Lab Genom Divers, Frederick, MD 21702 USA. RP Bates, SE (reprint author), 9000 Rockville Pike,Bldg 10 Rm 13N, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI Dean, Michael/G-8172-2012; To, Kenneth /M-4500-2013 OI Dean, Michael/0000-0003-2234-0631; To, Kenneth /0000-0003-2755-0283 FU Intramural NIH HHS [Z99 CA999999] NR 159 TC 213 Z9 223 U1 3 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD JAN 31 PY 2009 VL 61 IS 1 BP 3 EP 13 DI 10.1016/j.addr.2008.11.003 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 414HT UT WOS:000263855200002 PM 19135109 ER PT J AU Pistell, PJ Nelson, CM Miller, MG Spangler, EL Ingram, DK Devan, BD AF Pistell, Paul J. Nelson, Chris M. Miller, Marshall G. Spangler, Edward L. Ingram, Donald K. Devan, Bryan D. TI Striatal lesions interfere with acquisition of a complex maze task in rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Striatum; Maze; Learning; Excitotoxic lesion; Rats ID 14-UNIT T-MAZE; FIMBRIA-FORNIX LESIONS; CAUDATE-PUTAMEN LESIONS; NITRIC-OXIDE; WATER MAZE; LEARNING IMPAIRMENT; DORSAL STRIATUM; PHOSPHODIESTERASE INHIBITION; RETENTION PERFORMANCE; DOUBLE DISSOCIATION AB The 14-unit T-maze has proven to be a valuable tool for investigating age-associated memory impairment (AAMI). While another task widely used to evaluate AAMI, the water maze, is primarily used to evaluate allocentric hippocampal-dependent spatial memory, the 14-unit T-maze can assess egocentric procedural memory. Although several brain structures, e.g. hippocampus, parietal cortex have been implicated in, acquisition and retention performance in the 14-unit T-maze, there has been no evaluation of the involvement of the striatum, a brain region implicated in procedural learning and memory. The current study revealed that excitotoxic lesions of the medial or lateral striatum significantly impaired acquisition, as measured by errors and latency, on this task without disruption of motor function. These results indicate that the 14-unit T-maze most likely is requires a large egocentric procedural learning component, and previously observed AAMI may involve age-related dysfunction of the striatum. Published by Elsevier B.V. C1 [Pistell, Paul J.; Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. [Pistell, Paul J.; Nelson, Chris M.; Miller, Marshall G.; Spangler, Edward L.; Ingram, Donald K.; Devan, Bryan D.] NIA, Behav Neurosci Sect, Lab Expt Gerontol, NIH,Gerontol Res Ctr, Baltimore, MD 21224 USA. [Devan, Bryan D.] Towson Univ, Dept Psychol, Lab Comparat Neuropsychol, Towson, MD 21252 USA. RP Pistell, PJ (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Paul.Pistell@pbrc.edu FU Intramural Research Program of the NIH, National Institute on Aging [Z01AG00302-24, 1P20 RR02/1945]; CNRU [1P30 DK072476]; NIDDK FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging (Z01AG00302-24). Christopher Quigley provided assistance with the histological preparation. Histological analysis of the lesions utilized the facilities of the Cell Biology and Bioimaging Core facilities at the Pennington Biomedical Research Center supported by NIH Grant 1P20 RR02/1945 and a CNRU center grant # 1P30 DK072476 sponsored by NIDDK. NR 48 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 30 PY 2009 VL 197 IS 1 BP 138 EP 143 DI 10.1016/j.bbr.2008.08.015 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 396MU UT WOS:000262596600018 PM 18789359 ER PT J AU So, JH Chun, HS Bae, YK Kim, HS Park, YM Huh, TL Chitnis, AB Kim, CH Yeo, SY AF So, Ju-Hoon Chun, Hang-Suk Bae, Yong-Ki Kim, Hyun-Seo Park, Yeoll-Mae Huh, Tae-Lin Chitnis, Ajay B. Kim, Cheol-Hee Yeo, Sang-Yeob TI Her4 is necessary for establishing peripheral projections of the trigeminal ganglia in zebrafish SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Her4; Zebrafish; Notch signaling; Trigeminal ganglia; Neural progenitor; Peripheral projections ID EARLY NEUROGENESIS; DROSOPHILA-MELANOGASTER; EMBRYONIC ZEBRAFISH; NOTCH; GENE; PROTEINS; HOMOLOG; DELTA; SUPPRESSOR; EXPRESSION AB Transcripts of notch and its target genes have been detected in some differentiating neurons. However, the role of Notch in neuronal differentiation remains poorly defined. Here, we show that a subset of differentiating sensory neurons in the trigeminal ganglia express her4. Expression of her4 requires Notch signaling during neurogenesis but not during differentiation, when peripheral projections of the trigeminal ganglia are established. These projections develop poorly in her4 morphants. While many components of the canonical Notch signaling pathway are not required for late her4 expression or peripheral axon outgrowth in trigeminal neurons, simultaneous knock-down of Notch receptors prevents establishment of these peripheral projections. These observations suggest that Her4 and Notch play a role in peripheral outgrowth of sensory neurons. (C) 2008 Elsevier Inc. All rights reserved. C1 [Kim, Hyun-Seo; Park, Yeoll-Mae; Yeo, Sang-Yeob] Hanbat Natl Univ, Dept Biotechnol, Div Appl Chem & Biotechnol, Taejon 305719, South Korea. [Chun, Hang-Suk; Huh, Tae-Lin] Kyungpook Natl Univ, Dept Gen Engn, Taegu 702701, South Korea. [Bae, Yong-Ki] Natl Canc Ctr, Res Inst, Div Basic & Appl Sci, Canc Expt Resources Branch, Gyeonggi Do 410769, South Korea. [Chitnis, Ajay B.] NICHD, Sect Neural Dev Dynam, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [So, Ju-Hoon; Kim, Cheol-Hee] Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. RP Yeo, SY (reprint author), Hanbat Natl Univ, Dept Biotechnol, Div Appl Chem & Biotechnol, Taejon 305719, South Korea. EM yeosy@hanbat.ac.kr FU Korean Government (MOEHRD, Basic Research Promotion Fund) [KRF-2007-313-C00603] FX The authors thank members of the Chitnis, Hull, Kim, and Yeo laboratories. We are indebted to V.T. Cunliffe for providing the hdac1 MO. This work was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2007-313-C00603). NR 20 TC 6 Z9 6 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 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 30 PY 2009 VL 379 IS 1 BP 22 EP 26 DI 10.1016/j.bbrc.2008.11.149 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 401DA UT WOS:000262917500005 PM 19084503 ER PT J AU Tai, CH Vincent, JJ Kim, C Lee, B AF Tai, Chin-Hsien Vincent, James J. Kim, Changhoon Lee, Byungkook TI SE: an algorithm for deriving sequence alignment from a pair of superimposed structures SO BMC BIOINFORMATICS LA English DT Article CT 9th Asia Pacific Bioinformatics Conference CY JAN 13-16, 2009 CL Tsinghua Univ, Beijing, PEOPLES R CHINA HO Tsinghua Univ ID PROTEIN-STRUCTURE ALIGNMENT; GLUTAMINE-SYNTHETASE; UCSF CHIMERA; DATABASE; ACCURACY; FAMILIES AB Background: Generating sequence alignments from superimposed structures is an important part of many structure comparison programs. The accuracy of the alignment affects structure recognition, classification and possibly function prediction. Many programs use a dynamic programming algorithm to generate the sequence alignment from superimposed structures. However, this procedure requires using a gap penalty and, depending on the value of the penalty used, can introduce spurious gaps and misalignments. Here we present a new algorithm, Seed Extension (SE), for generating the sequence alignment from a pair of superimposed structures. The SE algorithm first finds "seeds", which are the pairs of residues, one from each structure, that meet certain stringent criteria for being structurally equivalent. Three consecutive seeds form a seed segment, which is extended along the diagonal of the alignment matrix in both directions. Distance and the amino acid type similarity between the residues are used to resolve conflicts that arise during extension of more than one diagonal. The manually curated alignments in the Conserved Domain Database were used as the standard to assess the quality of the sequence alignments. Results: SE gave an average accuracy of 95.9% over 582 pairs of superimposed proteins tested, while CHIMERA, LSQMAN, and DP extracted from SHEBA, which all use a dynamic programming algorithm, yielded 89.9%, 90.2% and 91.0%, respectively. For pairs of proteins with low sequence or structural similarity, SE produced alignments up to 18% more accurate on average than the next best scoring program. Improvement was most pronounced when the two superimposed structures contained equivalent helices or beta-strands that crossed at an angle. When the SE algorithm was implemented in SHEBA to replace the dynamic programming routine, the alignment accuracy improved by 10% on average for structure pairs with RMSD between 2 and 4 angstrom. SE also used considerably less CPU time than DP. Conclusion: The Seed Extension algorithm is fast and, without using a gap penalty, produces more accurate sequence alignments from superimposed structures than three other programs tested that use dynamic programming algorithm. C1 [Tai, Chin-Hsien; Vincent, James J.; Kim, Changhoon; Lee, Byungkook] NCI, Mol Modeling & Bioinformat Sect, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Vincent, James J.] Univ Vermont, Dept Biol, Vermont Genet Network, Burlington, VT 05405 USA. RP Lee, B (reprint author), NCI, Mol Modeling & Bioinformat Sect, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM taic@mail.nih.gov; jjv5@uvm.edu; kimchan@mail.nih.gov; bklee@mail.nih.gov FU Intramural NIH HHS NR 21 TC 6 Z9 6 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JAN 30 PY 2009 VL 10 AR S4 DI 10.1186/1471-2105-10-S1-S4 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 439BN UT WOS:000265601900004 PM 19208141 ER PT J AU Azzato, EM Morton, LM Bergen, AW Wang, SS Chatterjee, N Kvale, P Yeager, M Hayes, RB Chanock, SJ Caporaso, NE AF Azzato, Elizabeth M. Morton, Lindsay M. Bergen, Andrew W. Wang, Sophia S. Chatterjee, Nilanjan Kvale, Paul Yeager, Meredith Hayes, Richard B. Chanock, Stephen J. Caporaso, Neil E. TI SLC6A3 and body mass index in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial SO BMC MEDICAL GENETICS LA English DT Article ID DOPAMINE TRANSPORTER GENE; AFRICAN-AMERICAN SMOKERS; GENOME-WIDE ASSOCIATION; UNITED-STATES; ANOREXIA-NERVOSA; VARIABLE NUMBER; VNTR POLYMORPHISMS; SMOKING-CESSATION; CIGARETTE-SMOKING; ADULT OBESITY AB Background: To investigate the contribution of the dopamine transporter to dopaminergic reward-related behaviors and anthropometry, we evaluated associations between polymorphisms at the dopamine transporter gene(SLC6A3) and body mass index (BMI), among participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Methods: Four polymorphisms (rs6350, rs6413429, rs6347 and the 3' variable number of tandem repeat (3' VNTR) polymorphism) at the SLC6A3 gene were genotyped in 2,364 participants selected from the screening arm of PLCO randomly within strata of sex, age and smoking history. Height and weight at ages 20 and 50 years and baseline were assessed by questionnaire. BMI was calculated and categorized as underweight, normal, overweight and obese (< 18.5, 18.5-24.9, 25.0-29.9, or >= 30 kg/m(2), respectively). Odds ratios (ORs) and 95% confidence intervals (CIs) of SLC6A3 genotypes and haplotypes were computed using conditional logistic regression. Results: Compared with individuals having a normal BMI, obese individuals at the time of the baseline study questionnaire were less likely to possess the 3' VNTR variant allele with 9 copies of the repeated sequence in a dose-dependent model (** is referent; OR(*9) = 0.80, OR(99) = 0.47, P(trend) = 0.005). Compared with individuals having a normal BMI at age 50, overweight individuals (A-C-G-* is referent; OR(A-C-G-9) = 0.80, 95% CI 0.65-0.99, p = 0.04) and obese individuals (A-C-G-* is referent; OR(A-C-G-9) = 0.70, 95% CI 0.49-0.99, p = 0.04) were less likely to possess the haplotype with the 3' variant allele (A-C-G-9). Conclusion: Our results support a role of genetic variation at the dopamine transporter gene, SLC6A3, as a modifier of BMI. C1 [Azzato, Elizabeth M.; Morton, Lindsay M.; Wang, Sophia S.; Chatterjee, Nilanjan; Hayes, Richard B.; Caporaso, Neil E.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Azzato, Elizabeth M.] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England. [Bergen, Andrew W.] SRI Int, Hlth Sci Ctr, Menlo Pk, CA 94025 USA. [Kvale, Paul] Henry Ford Hlth Syst, Detroit, MI USA. [Yeager, Meredith; Chanock, Stephen J.] SAIC Frederick Inc, NCI Frederick, Core Genotyping Facil, Div Canc Epidemiol & Genet,Adv Technol Program, Frederick, MD USA. RP Azzato, EM (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. EM ema32@cam.ac.uk; mortonli@mail.nih.gov; andrew.bergen@sri.com; wangso@mail.nih.gov; chattern@mail.nih.gov; pkvale1@hfhs.org; my76y@nih.gov; hayesr@mail.nih.gov; sc83a@nih.gov; caporasn@epndce.nci.nih.gov RI Morton, Lindsay/B-5234-2015; Azzato, Elizabeth/A-1902-2009; OI Morton, Lindsay/0000-0001-9767-2310; Bergen, Andrew/0000-0002-1237-7644; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute; National Institutes of Health [N01-CO-12400]; Clinical Research Training Program; NIH and Pfizer Inc; NCI; NIH/University of Cambridge; National Cancer Institute [U01 DA020830] 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 U. S. Government. EMA was funded through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc) and is currently funded through the NCI and the NIH/University of Cambridge Graduate Partnership Program. AWB was supported by the Intramural Research Program of the National Cancer Institute and is supported by U01 DA020830. NR 59 TC 4 Z9 4 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 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JAN 30 PY 2009 VL 10 AR 9 DI 10.1186/1471-2350-10-9 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 418MW UT WOS:000264153300001 PM 19183461 ER PT J AU Mueller, M Peters, FT Huestis, MA Ricaurte, GA Maurer, HH AF Mueller, Melanie Peters, Frank T. Huestis, Marilyn A. Ricaurte, George A. Maurer, Hans H. TI Simultaneous liquid chromatographic-electrospray ionization mass spectrometric quantification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its metabolites 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine and 3,4-methylenedioxyamphetamine in squirrel monkey and human plasma after acidic conjugate cleavage SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE MDMA; Metabolites; LC-ESI-MS; Human plasma; Validation; Acidic hydrolysis ID FORENSIC TOXICOLOGY; DOPING CONTROL; AMPHETAMINE; NEUROTOXICITY; DRUGS; PHARMACOLOGY; GLUTATHIONE; ANIMALS; ASSAY AB 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a psychoactive drug with abuse liability and neurotoxic potential. Specimen preparation of a recently presented LC-MS assay with electrospray ionization for quantifying MDMA and its main metabolites in squirrel monkey plasma was modified to include acidic hydrolysis to obtain total 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. Method re-validation for squirrel monkey plasma and full validation for human plasma showed selectivity for all analytes. Recoveries were >= 71.0%. Changed specimen preparation or matrix did not affect accuracy or precision. No instability was observed after repeated freezing or in processed samples. Plasma MDMA and metabolites quantification, derived pharmacokinetic and toxicokinetic data and neurotoxicity research will benefit from this validated method. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Mueller, Melanie; Peters, Frank T.; Maurer, Hans H.] Univ Saarland, Inst Expt & Clin Pharmacol & Toxicol, Dept Expt & Clin Toxicol, D-66421 Homburg, Saar, Germany. [Mueller, Melanie; Ricaurte, George A.] Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Maurer, HH (reprint author), Univ Saarland, Inst Expt & Clin Pharmacol & Toxicol, Dept Expt & Clin Toxicol, D-66421 Homburg, Saar, Germany. EM hans.maurer@uks.eu FU USPHS [DA05707] FX The authors thank Armin A. Weber for his technical support. This work was supported by USPHS grant DA05707. NR 27 TC 11 Z9 13 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD JAN 30 PY 2009 VL 184 IS 1-3 BP 64 EP 68 DI 10.1016/j.forsciint.2008.12.002 PG 5 WC Medicine, Legal SC Legal Medicine GA 408IV UT WOS:000263429600012 PM 19131196 ER PT J AU Barros, SA Srimaroeng, C Perry, JL Walden, R Dembla-Rajpal, N Sweet, DH Pritchard, JB AF Barros, Scott A. Srimaroeng, Chutima Perry, Jennifer L. Walden, Ramsey Dembla-Rajpal, Neetu Sweet, Douglas H. Pritchard, John B. TI Activation of Protein Kinase C zeta Increases OAT1 (SLC22A6)- and OAT3 (SLC22A8)-mediated Transport SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ORGANIC ANION TRANSPORT; BREAST-CANCER CELLS; SUBSTRATE-SPECIFICITY; CELLULAR PHYSIOLOGY; SULFATE TRANSPORT; PROXIMAL TUBULES; LLC-PK1 CELLS; PDZ; KIDNEY; MEMBRANE AB Organic anion transporters (OATs) play a pivotal role in the clearance of small organic anions by the kidney, yet little is known about how their activity is regulated. A yeast two-hybrid assay was used to identify putative OAT3-associated proteins in the kidney. Atypical protein kinase C zeta(PKC zeta) was shown to bind to OAT3. Binding was confirmed in immunoprecipitation assays. The OAT3/PKC zeta interaction was investigated in rodent renal cortical slices from fasted animals. Insulin, an upstream activator of PKC zeta, increased both OAT3-mediated uptake of estrone sulfate (ES) and PKC zeta activity. Both effects were abolished by a PKC zeta-specific pseudosubstrate inhibitor. Increased ES transport was not observed in renal slices from OAT3-null mice. Transport of the shared OAT1/OAT3 substrate, p-aminohippurate, behaved similarly, except that stimulation was reduced, not abolished, in the OAT3-null mice. This suggested that OAT1 activity was also modified by PKC zeta, subsequently confirmed using an OAT1-specific substrate, adefovir. Inhibition of PKC zeta also blocked the increase in ES uptake seen in response to epidermal growth factor and to activation of protein kinase A. Thus, PKC zeta acted downstream of the epidermal growth factor to protein kinase A signaling pathway. Activation of transport was accompanied by an increase in V(max) and was blocked by microtubule disruption, indicating that activation may result from trafficking of OAT3 into the plasma membrane. These data demonstrate that PKC zeta activation up-regulates OAT1 and OAT3 function, and that protein-protein interactions play a central role controlling these two important renal drug transporters. C1 [Barros, Scott A.; Srimaroeng, Chutima; Perry, Jennifer L.; Walden, Ramsey; Dembla-Rajpal, Neetu; Pritchard, John B.] NIEHS, NIH, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Sweet, Douglas H.] Med Univ S Carolina, Dept Pharmaceut Sci, Charleston, SC 29425 USA. RP Pritchard, JB (reprint author), 111 TW Alexander Dr,MD F1-03, Res Triangle Pk, NC 27709 USA. EM pritcha3@niehs.nih.gov RI Sweet, Douglas/H-7914-2013 OI Sweet, Douglas/0000-0002-8911-9184 FU National Institutes of Health Intramural Research Program from the NIEHS FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program from the NIEHS. 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. 1 Both authors contributed equally to this study. NR 30 TC 23 Z9 23 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 30 PY 2009 VL 284 IS 5 BP 2672 EP 2679 DI 10.1074/jbc.M808078200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 397ZL UT WOS:000262700900009 PM 19028678 ER PT J AU Burns, KE Liu, WT Boshoff, HIM Dorrestein, PC Barry, CE AF Burns, Kristin E. Liu, Wei-Ting Boshoff, Helena I. M. Dorrestein, Pieter C. Barry, Clifton E. TI Proteasomal Protein Degradation in Mycobacteria Is Dependent upon a Prokaryotic Ubiquitin-like Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUBERCULOSIS PROTEASOME; 20S PROTEASOME; GENE; FAMILY; IDENTIFICATION; RHODOCOCCUS; PRECURSOR; COMPLEX; KIN AB The striking identification of an apparent proteasome core in Mycobacteria and allied actinomycetes suggested that additional elements of this otherwise strictly eukaryotic system for regulated protein degradation might be conserved. The genes encoding this prokaryotic proteasome are clustered in an operon with a short open reading frame that encodes a small protein of 64 amino acids resembling ubiquitin with a carboxyl-terminal di-glycine-glutamine motif ( herein called Pup for prokaryotic ubiquitin-like protein). Expression of a polyhistidine-tagged Pup followed by pulldown revealed that a broad spectrum of proteins were post-translationally modified by Pup. Two-dimensional gel electrophoresis allowed us to conclusively identify two targets of this modification as myoinositol-1-phosphate synthase and superoxide dismutase. Deletion of the penultimate di-glycine motif or the terminal glutamine completely abrogated modification of cellular proteins with Pup. Further mass spectral analysis demonstrated that Pup was attached to a lysine residue on its target protein via the carboxyl-terminal glutamine with deamidation of this residue. Finally, we showed that cell lysates of wild type ( but not a proteasome mutant) efficiently degraded Pup-modified proteins. These data therefore establish that, despite differences in both sequence and target linkage, Pup plays an analogous role to ubiquitin in targeting proteins to the proteasome for degradation. C1 [Burns, Kristin E.; Boshoff, Helena I. M.; Barry, Clifton E.] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Liu, Wei-Ting; Dorrestein, Pieter C.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmacol, La Jolla, CA 92093 USA. [Liu, Wei-Ting; Dorrestein, Pieter C.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Chem & Biochem, La Jolla, CA 92093 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@mail.nih.gov RI Dorrestein, Pieter/D-5012-2012; Barry, III, Clifton/H-3839-2012 FU National Institutes of Health; Intramural Research Program, NIAID FX This work was supported, in whole or in part, by the National Institutes of Health, Intramural Research Program, NIAID. 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 29 TC 77 Z9 88 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 JAN 30 PY 2009 VL 284 IS 5 BP 3069 EP 3075 DI 10.1074/jbc.M808032200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 397ZL UT WOS:000262700900051 PM 19028679 ER PT J AU Topol, LL Chen, W Song, H Day, TF Yang, YZ AF Topol, Lilia Chen, Wen Song, Hai Day, Timothy F. Yang, Yingzi TI Sox9 Inhibits Wnt Signaling by Promoting beta-Catenin Phosphorylation in the Nucleus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AUTOSOMAL SEX REVERSAL; F-BOX PROTEIN; I-KAPPA-B; GLYCOGEN-SYNTHASE KINASE-3; SYNOVIAL JOINT FORMATION; COLON-CARCINOMA CELLS; CRANIAL NEURAL CREST; SRY-RELATED GENE; CAMPOMELIC DYSPLASIA; CHONDROCYTE DIFFERENTIATION AB Chondrocyte fate determination and maintenance requires Sox9, an intrinsic transcription factor, but is inhibited by Wnt/beta-catenin signaling activated by extrinsic Wnt ligands. Here we explored the underlying molecular mechanism by which Sox9 antagonizes the Wnt/beta-catenin signaling in chondrocyte differentiation. We found that Sox9 employed two distinct mechanisms to inhibit Wnt/beta-catenin signaling: the Sox9 N terminus is necessary and sufficient to promote beta-catenin degradation, whereas the C terminus is required to inhibit beta-catenin transcriptional activity without affecting its stability. Sox9 binds to beta-catenin and components of the beta-catenin "destruction complex," glycogen synthase kinase 3 and beta-transducin repeat containing protein, to promote their nuclear localization. Independent of its DNA binding ability, nuclear localization of Sox9 is both necessary and sufficient to enhance beta-catenin phosphorylation and its subsequent degradation. Thus, one mechanism whereby Sox9 regulates chondrogenesis is to promote efficient beta-catenin phosphorylation in the nucleus. This mechanism may be broadly employed by other intrinsic cell fate determining transcription factors to promptly turn off extrinsic inhibitory Wnt signaling mediated by beta-catenin. C1 [Topol, Lilia; Chen, Wen; Song, Hai; Day, Timothy F.; Yang, Yingzi] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Yang, YZ (reprint author), 49 Convent Dr,MSC 4472, Bethesda, MD 20892 USA. EM yingzi@mail.nih.gov FU National Institutes of Health; NHGRI FX This work was supported, in whole or in part, by the National Institutes of Health, NHGRI intramural research program. 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 61 TC 88 Z9 97 U1 1 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 JAN 30 PY 2009 VL 284 IS 5 BP 3323 EP 3333 DI 10.1074/jbc.M808048200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 397ZL UT WOS:000262700900075 PM 19047045 ER PT J AU Orr, SJ Quigley, L McVicar, DW AF Orr, Selinda J. Quigley, Laura McVicar, Daniel W. TI In vivo expression of signaling proteins in reconstituted NK cells SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Natural Killer cells; IL2R gamma(c); PI3K ID RECEPTOR-GAMMA CHAIN; GENE-TRANSFER; PATHWAYS; MICE AB Natural Killer cells are cells of the innate immune system that are important for the recognition and clearance of virally infected cells or tumors. Examination of the development and signaling of these cells has been severely hampered due to an inability to over-express proteins in these cells. We developed a novel technique to generate NK cells in vivo, all of which express a gene of interest. IL2R gamma(-/-)(c)/Rag2(-/-) mice do not develop NK cells due to the lack of IL15 signaling. We infected bone marrow from IL2R gamma(-/-)(c)/Rag2(-/-) mice with a retroviral construct encoding EGFP and IL2 gamma(c). connected by an IRES. NK cells selectively developed through expression of IL2R gamma(c) and 100% of these NK cells were found to be EGFP(+). In order to test the utilization of this method to examine the function of biologically relevant proteins, constitutively active PI3K p110 gamma and p110 delta isoforms were over-expressed in this system. Constitutively active p110 gamma revealed profound effects on NK cell development and function in vivo while p110 delta had little effect. Published by Elsevier B.V. C1 [Orr, Selinda J.; Quigley, Laura; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. RP McVicar, DW (reprint author), NCI, Canc & Inflammat Program, Bldg 560,Rm 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 Intramural NIH HHS [Z99 CA999999, Z01 BC010300-10] NR 12 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JAN 30 PY 2009 VL 340 IS 2 BP 158 EP 163 DI 10.1016/j.jim.2008.10.014 PG 6 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 400LS UT WOS:000262870100009 PM 19028500 ER PT J AU Lang, AE Angel, M Bhatia, K Chen, R Fahn, S Hallett, M Schrag, A Thompson, P AF Lang, Anthony E. Angel, Michael Bhatia, Kailash Chen, Roberta Fahn, Stanley Hallett, Market Schrag, Anette Thompson, Philip TI Myoclonus in Complex Regional Pain Syndrome SO MOVEMENT DISORDERS LA English DT Letter ID PSYCHOGENIC MOVEMENT-DISORDERS; REFLEX SYMPATHETIC DYSTROPHY; GENERALIZED TONIC DYSTONIA; TRAUMA INDUCE DYSTONIA; FIXED DYSTONIA; TREMOR C1 [Lang, Anthony E.; Angel, Michael; Chen, Roberta] Univ Toronto, Div Neurol, Toronto, ON, Canada. [Bhatia, Kailash] Sobell Dept Movement Neurosci, London, England. [Fahn, Stanley] Neurol Inst, Dept Neurol, New York, NY 10032 USA. [Hallett, Market] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Schrag, Anette] UCL, Inst Neurol Royal Free Campus, Dept Clin Neurosci, London, England. [Thompson, Philip] Univ Adelaide, Univ Dept Med, Adelaide, SA, Australia. [Thompson, Philip] Royal Adelaide Hosp, Dept Neurol, Adelaide, SA 5000, Australia. RP Lang, AE (reprint author), Univ Toronto, Div Neurol, Toronto, ON, Canada. EM lang@uhnres.utoronto.ca RI Schrag, Anette/B-4181-2011; Chen, Robert/B-3899-2009 OI Schrag, Anette/0000-0002-9872-6680; Chen, Robert/0000-0002-8371-8629 NR 22 TC 10 Z9 10 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN 30 PY 2009 VL 24 IS 2 BP 314 EP 316 DI 10.1002/mds.22355 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 401SO UT WOS:000262962600031 PM 18973259 ER PT J AU Best, RB Hummer, G AF Best, Robert B. Hummer, Gerhard TI BIOCHEMISTRY Unfolding the Secrets of Calmodulin SO SCIENCE LA English DT Editorial Material ID C-TERMINAL DOMAIN; SINGLE PROTEIN; DYNAMICS; MOLECULE; BINDING C1 [Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Hummer, Gerhard] NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 FU Intramural NIH HHS [Z01 DK029033-08] NR 16 TC 6 Z9 6 U1 1 U2 8 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 JAN 30 PY 2009 VL 323 IS 5914 BP 593 EP 594 DI 10.1126/science.1169555 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 400JB UT WOS:000262862800030 PM 19179519 ER PT J AU Venteicher, AS Abreu, EB Meng, ZJ McCann, KE Terns, RM Veenstra, TD Terns, MP Artandi, SE AF Venteicher, Andrew S. Abreu, Eladio B. Meng, Zhaojing McCann, Kelly E. Terns, Rebecca M. Veenstra, Timothy D. Terns, Michael P. Artandi, Steven E. TI A Human Telomerase Holoenzyme Protein Required for Cajal Body Localization and Telomere Synthesis SO SCIENCE LA English DT Article ID SMALL NUCLEOLAR RNPS; DYSKERATOSIS-CONGENITA; RNA; ACCUMULATION; HOMOLOG; BODIES; PURIFICATION; RECRUITMENT; BIOGENESIS; SHARE AB Telomerase is a ribonucleoprotein ( RNP) complex that synthesizes telomere repeats in tissue progenitor cells and cancer cells. Active human telomerase consists of at least three principal subunits, including the telomerase reverse transcriptase, the telomerase RNA ( TERC), and dyskerin. Here, we identify a holoenzyme subunit, TCAB1 ( telomerase Cajal body protein 1), that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. TCAB1 associates with active telomerase enzyme, established telomerase components, and small Cajal body RNAs that are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevents TERC from associating with Cajal bodies, disrupts telomerase- telomere association, and abrogates telomere synthesis by telomerase. Thus, TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells. C1 [Venteicher, Andrew S.; McCann, Kelly E.; Artandi, Steven E.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Venteicher, Andrew S.; Artandi, Steven E.] Stanford Univ, Sch Med, Program Biophys, Stanford, CA 94305 USA. [Abreu, Eladio B.; Terns, Rebecca M.; Terns, Michael P.] Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA. [Abreu, Eladio B.; Terns, Rebecca M.; Terns, Michael P.] Univ Georgia, Dept Genet, Athens, GA 30602 USA. [Meng, Zhaojing; Veenstra, Timothy D.] NCI, Lab Proteom & Analyt Technol, Adv Technol Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. [McCann, Kelly E.; Artandi, Steven E.] Stanford Univ, Sch Med, Program Canc Biol, Stanford, CA 94305 USA. RP Artandi, SE (reprint author), Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. EM sartandi@stanford.edu RI Terns, Michael/N-6435-2016 FU Medical Scientist Training Program [GM07365]; NCI [CA104676, NO1-CO-12400, CA111691, CA125453]; Leukemia and Lymphoma Society Specialized Centers of Research [7007-09] FX This work was supported by Medical Scientist Training Program grant GM07365 (A.S.V.) and NCI grant CA104676 (M.P.T. and R.M.T.), with a Supplement to Promote Diversity in Health- Related Research (E.B.A.). This project has been funded in part with federal funds from the NCI under contract NO1-CO-12400 (T.D.V.). This work was supported by NCI grants CA111691 and CA125453 (S.E.A.) and by Leukemia and Lymphoma Society Specialized Centers of Research grant 7007-09 (S.E.A.). NR 23 TC 236 Z9 252 U1 2 U2 18 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 JAN 30 PY 2009 VL 323 IS 5914 BP 644 EP 648 DI 10.1126/science.1165357 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 400JB UT WOS:000262862800046 PM 19179534 ER PT J AU Langevin, SM Lin, D Matsuo, K Gao, CM Takezaki, T Stolzenberg-Solomon, RZ Vasavi, M Hasan, Q Taioli, E AF Langevin, S. M. Lin, D. Matsuo, K. Gao, C. M. Takezaki, T. Stolzenberg-Solomon, R. Z. Vasavi, M. Hasan, Q. Taioli, E. TI Review and pooled analysis of studies on MTHFR C677T polymorphism and esophageal cancer SO TOXICOLOGY LETTERS LA English DT Review DE Methylenetetrahydrofolate reductase; Esophagus; Genetic epidemiology; Case control studies ID METHYLENETETRAHYDROFOLATE-REDUCTASE GENE; SQUAMOUS-CELL CARCINOMA; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; CHINESE POPULATION; DNA METHYLATION; FOLATE STATUS; NEOADJUVANT CHEMOTHERAPY; COLORECTAL-CANCER; COMMON MUTATION; CARDIA CANCER AB Esophageal cancer has been associated with tobacco and alcohol consumption, gastric reflux, exposure to nitrosamines from food or other environmental sources, and diets lacking folate. Susceptibility to esophageal cancer may be modified by functional polymorphisms in genes along the folate metabolic pathway, such as methylenetetrahydrofolate reductase (MTHFR). The C677T polymorphism is the most common functional variant, leading to a reduction in enzyme activity. We report a pooled analysis of 5 studies on the association of MTHFR C677T polymorphism and esophageal cancer, including 725 cases and 1531 controls. A significant association between the MTHFR 677 TT genotype and esophageal cancer was observed (OR = 2.63, 95% CI: 1.75-3.94), although there was significant heterogeneity between studies. A sensitivity analysis excluded one study: the association between 7 genotype and esophageal cancer was still present, although of reduced magnitude (OR = 1.57, 95% CI: 0.96-2.56). A significant interaction between smoking and TT genotype on esophageal cancer risk was observed, while no interaction was observed between alcohol consumption and genotype. (C) 2008 Published by Elsevier Ireland Ltd. C1 [Langevin, S. M.; Taioli, E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Langevin, S. M.; Taioli, E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Lin, D.] Chinese Acad Med Sci, Inst Canc, Dept Etiol & Carcinogenesis, Beijing 100021, Peoples R China. [Matsuo, K.] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Gao, C. M.] Jiangsu Prov Inst Canc Res, Dept Epidemiol, Nanjing, Peoples R China. [Takezaki, T.] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Int Isl & Community Med, Kagoshima 890, Japan. [Stolzenberg-Solomon, R. Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vasavi, M.; Hasan, Q.] Kamineni Hosp, Dept Genet & Mol Med, Hyderabad, Andhra Pradesh, India. [Hasan, Q.] Bhagwan Mahavir Med Res Ctr, Dept Genet, Hyderabad, Andhra Pradesh, India. RP Taioli, E (reprint author), Suny Downstate Med Ctr, Grad Program Publ Hlth, SUNY Downstate Sch Publ Hlth, Dept Epidemiol & Biostat, 450 Clarkson Ave,Box 43, Brooklyn, NY 11203 USA. EM emanuela.taioli@downstate.edu OI Langevin, Scott/0000-0001-7031-1216; Matsuo, Keitaro/0000-0003-1761-6314 FU National Institutes of Health [P30CA047904-19S1]; NIH/NCI SPORE in Head and Neck Cancer [5P50CA097190-02] FX Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS); the authors thank Barbara M. Stadterman, GSEC administrator, for her support (National Institutes of Health grant P30CA047904-19S1; NIH/NCI SPORE in Head and Neck Cancer 5P50CA097190-02). NR 64 TC 34 Z9 37 U1 0 U2 8 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 JAN 30 PY 2009 VL 184 IS 2 BP 73 EP 80 DI 10.1016/j.toxlet.2008.09.003 PG 8 WC Toxicology SC Toxicology GA 405JU UT WOS:000263219900001 PM 18840514 ER PT J AU Yuditskaya, S Tumblin, A Hoehn, GT Wang, GH Drake, SK Xu, XL Ying, SX Chi, AH Remaley, AT Shen, RF Munson, PJ Suffredini, AF Kato, GJ AF Yuditskaya, Susan Tumblin, Ashaunta Hoehn, Gerard T. Wang, Guanghui Drake, Steven K. Xu, Xiuli Ying, Saixia Chi, Amy H. Remaley, Alan T. Shen, Rong-Fong Munson, Peter J. Suffredini, Anthony F. Kato, Gregory J. TI Proteomic identification of altered apolipoprotein patterns in pulmonary hypertension and vasculopathy of sickle cell disease SO BLOOD LA English DT Article ID NITRIC-OXIDE BIOAVAILABILITY; SERUM AMYLOID-A; VASCULAR FUNCTION; FREE HEMOGLOBIN; LUNG-DISEASE; RISK; ACTIVATION; CHILDREN; PLASMA; ANEMIA AB Pulmonary arterial hypertension (PAH) is emerging as a major complication and independent risk factor for death among adults with sickle cell disease (SCD). Using surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS), we searched for biomarkers of PAH in plasma specimens from 27 homozygous sickle cell anemia (HbSS) patients with PAH and 28 without PAH. In PAH patients, analysis consistently showed lower abundance of a 28.1-kDa peak (P <.001), identified by high-resolution mass spectrometry as the oxidant-scavenging protein apolipoprotein A-I (apoA-I), which correlated with clinical assays of apoA-I (r = .58, P <.001) and high-density lipoprotein (HDL) levels (r = .50, P = .001). Consistent with endothelial dysfunction that may mediate this effect in PAH, HbSS patients with lower apoA-I levels also displayed impaired vasodilatory responses to acetylcholine (mean +/- SEM, 189% +/- 34% [n = 13] vs 339% +/- 51% [n = 13], P <.001). As a group, patients with SCD demonstrated significantly lower apoA-I levels than African-American control subjects. The PAH cohort was further characterized by high levels of apolipoproteins A-II and B and serum amyloid A, and low levels of haptoglobin dimers and plasminogen. These results imply a relationship of apolipoproteins to the development of PAH vasculopathy in SCD, potentially involving an unexpected mechanistic parallel to atherosclerosis, another proliferative vasculopathy. (Blood. 2009;113:1122-1128) C1 [Yuditskaya, Susan; Tumblin, Ashaunta; Xu, Xiuli; Chi, Amy H.; Remaley, Alan T.; Kato, Gregory J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Hoehn, Gerard T.; Wang, Guanghui; Drake, Steven K.; Suffredini, Anthony F.; Kato, Gregory J.] NHLBI, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Ying, Saixia; Munson, Peter J.] NHLBI, Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. [Shen, Rong-Fong] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, 10 Ctr Dr,MSC 1476,Bldg 10 CRC,Room 5-5140, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU National Institutes of Health (NIH); Clinical Research Training Program (CRTP); Pfizer Pharmaceuticals Group (NewYork, NY) FX This research was supported by intramural research funds from the National Institutes of Health (NIH). S. Y. andA. T. were supported by the Clinical Research Training Program (CRTP), a public-private partnership supported jointly by the NIH and a grant to the Foundation for the NIH from Pfizer Pharmaceuticals Group (NewYork, NY). NR 49 TC 38 Z9 39 U1 0 U2 0 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 JAN 29 PY 2009 VL 113 IS 5 BP 1122 EP 1128 DI 10.1182/blood-2008-03-142604 PG 7 WC Hematology SC Hematology GA 400RD UT WOS:000262885300020 PM 19023114 ER PT J AU Rizzo, JD Curtis, RE Socie, G Sobocinski, KA Gilbert, E Landgren, O Travis, LB Travis, WD Flowers, MED Friedman, DL Horowitz, MM Wingard, JR Deeg, HJ AF Rizzo, J. Douglas Curtis, Rochelle E. Socie, Gerard Sobocinski, Kathleen A. Gilbert, Ethel Landgren, Ola Travis, Lois B. Travis, William D. Flowers, Mary E. D. Friedman, Debra L. Horowitz, Mary M. Wingard, John R. Deeg, H. Joachim TI Solid cancers after allogeneic hematopoietic cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; LONG-TERM SURVIVORS; 2ND MALIGNANT NEOPLASMS; CHILDHOOD-CANCER; BREAST-CANCER; THYROID-CANCER; WORKING PARTY; RISK-FACTORS; CHILDREN AB Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend <.001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non-squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction <.01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients. (Blood. 2009; 113:1175-1183) C1 [Rizzo, J. Douglas; Sobocinski, Kathleen A.; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplantat Res, Milwaukee, WI 53226 USA. [Curtis, Rochelle E.; Gilbert, Ethel; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Socie, Gerard] Hop St Louis, Paris, France. [Travis, Lois B.] James P Willmot Canc Ctr, Rochester, NY USA. [Travis, William D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Flowers, Mary E. D.; Friedman, Debra L.; Deeg, H. Joachim] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Wingard, John R.] Univ Florida, Shands Hosp, Gainesville, FL USA. RP Rizzo, JD (reprint author), Med Coll Wisconsin, Ctr Int Blood & Marrow Transplantat Res, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM rizzo@mcw.edu FU NCI NIH HHS [U24-CA76518, U24 CA076518]; NHLBI NIH HHS [5U01HL069294, U01 HL069294]; PHS HHS [HHSH234200637015C] NR 43 TC 163 Z9 167 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 JAN 29 PY 2009 VL 113 IS 5 BP 1175 EP 1183 DI 10.1182/blood-2008-05-158782 PG 9 WC Hematology SC Hematology GA 400RD UT WOS:000262885300026 PM 18971419 ER PT J AU Chun, CZ Kaur, S Samant, GV Wang, L Pramanik, K Garnaas, MK Li, KG Field, L Mukhopadhyay, D Ramchandran, R AF Chun, Chang Z. Kaur, Sukhbir Samant, Ganesh V. Wang, Ling Pramanik, Kallal Garnaas, Maija K. Li, Keguo Field, Lyndsay Mukhopadhyay, Debabrata Ramchandran, Ramani TI Snrk-1 is involved in multiple steps of angioblast development and acts via notch signaling pathway in artery-vein specification in vertebrates SO BLOOD LA English DT Article ID EMBRYONIC VASCULAR DEVELOPMENT; ENDOTHELIAL-CELLS; ZEBRAFISH; OVEREXPRESSION; VASCULOGENESIS; MALFORMATIONS; ANGIOGENESIS; EXPRESSION; GRIDLOCK; PROTEIN AB In vertebrates, molecular mechanisms dictate angioblasts' migration and subsequent differentiation into arteries and veins. In this study, we used a microarray screen to identify a novel member of the sucrose nonfermenting related kinase (snrk-1) family of serine/threonine kinases expressed specifically in the embryonic zebrafish vasculature and investigated its function in vivo. Using gain- and loss-of-function studies in vivo, we show that Snrk-1 plays an essential role in the migration, maintenance, and differentiation of angioblasts. The kinase function of Snrk-1 is critical for migration and maintenance, but not for the differentiation of angioblasts. In vitro, snrk-1 knockdown endothelial cells show only defects in migration. The snrk-1 gene acts down-stream or parallel to notch and upstream of gridlock during artery-vein specification, and the human gene compensates for zebrafish snrk-1 knockdown, suggesting evolutionary conservation of function. (Blood. 2009; 113: 1192-1199) C1 [Chun, Chang Z.; Samant, Ganesh V.; Pramanik, Kallal; Garnaas, Maija K.; Li, Keguo; Ramchandran, Ramani] Med Coll Wisconsin, Dept Pediat, Translat & Biomed Res Ctr, CRI Dev Vasc Biol Program, Milwaukee, WI 53226 USA. [Kaur, Sukhbir] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Ling; Mukhopadhyay, Debabrata] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN USA. [Field, Lyndsay] Univ Massachusetts Dartmouth, N Dartmouth, MA USA. RP Ramchandran, R (reprint author), Med Coll Wisconsin, Dept Pediat, Translat & Biomed Res Ctr, CRI Dev Vasc Biol Program, CRI C3420,8701Watertown Plank Rd,POB 26509, Milwaukee, WI 53226 USA. EM rramchan@mcw.edu FU National Institutes of Health [HL072178, HL70567]; Medical College of Wisconsin, Milwaukee FX This study was supported in part by research funding from National Institutes of Health (NIH, Bethesda, MD) grants HL072178 and HL70567 (D.M.) and by seed funds from the Children's Research Institute at the Medical College of Wisconsin, Milwaukee (R.R.). R. R. is a recipient of the National Cancer Institute (NCI, Bethesda, MD) Scholar Award. G. S. is a recipient of the State of Wisconsin Breast Cancer Research Tax Write-off Program Award. L. W. is a fellow of American Heart Association (Washington, DC). NR 23 TC 15 Z9 15 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 JAN 29 PY 2009 VL 113 IS 5 BP 1192 EP 1199 DI 10.1182/blood-2008-06-162156 PG 8 WC Hematology SC Hematology GA 400RD UT WOS:000262885300028 PM 18723694 ER PT J AU Calvo, E Pham, VM Marinotti, O Andersen, JF Ribeiro, JMC AF Calvo, Eric Pham, Van M. Marinotti, Osvaldo Andersen, John F. Ribeiro, Jose M. C. TI The salivary gland transcriptome of the neotropical malaria vector Anopheles darlingi reveals accelerated evolution of genes relevant to hematophagy SO BMC GENOMICS LA English DT Review ID ADULT FEMALE MOSQUITO; PLATELET-AGGREGATION INHIBITOR; LEECH HIRUDO-MEDICINALIS; RICH SECRETORY PROTEINS; AEDES-AEGYPTI; TRIATOMA-INFESTANS; LUTZOMYIA-LONGIPALPIS; STEPHENSI MOSQUITO; SEQUENCE ALIGNMENT; ANTIBODY-RESPONSE AB Background: Mosquito saliva, consisting of a mixture of dozens of proteins affecting vertebrate hemostasis and having sugar digestive and antimicrobial properties, helps both blood and sugar meal feeding. Culicine and anopheline mosquitoes diverged similar to 150 MYA, and within the anophelines, the New World species diverged from those of the Old World similar to 95 MYA. While the sialotranscriptome (from the Greek sialo, saliva) of several species of the Cellia subgenus of Anopheles has been described thoroughly, no detailed analysis of any New World anopheline has been done to date. Here we present and analyze data from a comprehensive salivary gland (SG) transcriptome of the neotropical malaria vector Anopheles darlingi (subgenus Nyssorhynchus). Results: A total of 2,371 clones randomly selected from an adult female An. darlingi SG cDNA library were sequenced and used to assemble a database that yielded 966 clusters of related sequences, 739 of which were singletons. Primer extension experiments were performed in selected clones to further extend sequence coverage, allowing for the identification of 183 protein sequences, 114 of which code for putative secreted proteins. Conclusion: Comparative analysis of sialotranscriptomes of An. darlingi and An. gambiae reveals significant divergence of salivary proteins. On average, salivary proteins are only 53% identical, while housekeeping proteins are 86% identical between the two species. Furthermore, An. darlingi proteins were found that match culicine but not anopheline proteins, indicating loss or rapid evolution of these proteins in the old world Cellia subgenus. On the other hand, several well represented salivary protein families in old world anophelines are not expressed in An. darlingi. C1 [Calvo, Eric; Pham, Van M.; Andersen, John F.; Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Marinotti, Osvaldo] Univ Calif Irvine, Dept Biochem & Mol Biol, Irvine, CA 92697 USA. RP Ribeiro, JMC (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM eric.calvo@fda.hhs.gov; vpham@niaid.nih.gov; omarinot@uci.edu; jandersen@niaid.nih.gov; jribeiro@niaid.nih.gov OI Marinotti, Osvaldo/0000-0002-7173-7160; Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Dr. Bruno Arca for valuable discussions, and NIAID intramural editor Brenda Rae Marshall for assistance. NR 158 TC 47 Z9 51 U1 2 U2 9 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 JAN 29 PY 2009 VL 10 AR 57 DI 10.1186/1471-2164-10-57 PG 27 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 418BP UT WOS:000264122500003 PM 19178717 ER PT J AU Mullighan, CG Su, XP Zhang, JH Radtke, I Phillips, LAA Miller, CB Ma, J Liu, W Cheng, C Schulman, BA Harvey, RC Chen, I Clifford, RJ Carroll, WL Reaman, G Bowman, WP Devidas, M Gerhard, DS Yang, WJ Relling, MV Shurtleff, SA Campana, D Borowitz, MJ Pui, C Smith, M Hunger, SP Willman, CL Downing, JR AF Mullighan, Charles G. Su, Xiaoping Zhang, Jinghui Radtke, Ina Phillips, Letha A. A. Miller, Christopher B. Ma, Jing Liu, Wei Cheng, Cheng Schulman, Brenda A. Harvey, Richard C. Chen, I-Ming Clifford, Robert J. Carroll, William L. Reaman, Gregory Bowman, W. Paul Devidas, Meenakshi Gerhard, Daniela S. Yang, Wenjian Relling, Mary V. Shurtleff, Sheila A. Campana, Dario Borowitz, Michael J. Pui, Ching-Hon Smith, Malcolm Hunger, Stephen P. Willman, Cheryl L. Downing, James R. CA Childrens Oncology Grp TI Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MINIMAL RESIDUAL DISEASE; TOTAL THERAPY; IKAROS GENE; CHILDHOOD; CHILDREN; EXPRESSION; TRANSCRIPTION; MICROARRAY; LINEAGE; CELLS AB Background: Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. Methods: We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL. Results: More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. Conclusions: Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL. N Engl J Med 2009;360:470-80. C1 [Mullighan, Charles G.; Su, Xiaoping; Radtke, Ina; Phillips, Letha A. A.; Miller, Christopher B.; Shurtleff, Sheila A.; Campana, Dario; Downing, James R.] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Ma, Jing] St Jude Childrens Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Liu, Wei; Cheng, Cheng] St Jude Childrens Hosp, Dept Biostat, Memphis, TN 38105 USA. [Yang, Wenjian; Relling, Mary V.] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Schulman, Brenda A.] St Jude Childrens Hosp, Dept Biol Struct, Memphis, TN 38105 USA. [Campana, Dario; Pui, Ching-Hon] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [Zhang, Jinghui] NCI, Ctr Biomed Informat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Clifford, Robert J.] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Gerhard, Daniela S.] NCI, Off Canc Genom, NIH, Bethesda, MD 20892 USA. [Smith, Malcolm] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Schulman, Brenda A.] Johns Hopkins Med Inst, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Borowitz, Michael J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Harvey, Richard C.; Chen, I-Ming; Willman, Cheryl L.] Univ New Mexico, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. [Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Reaman, Gregory] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Bowman, W. Paul] Cook Childrens Med Ctr, Dept Hematol & Oncol, Ft Worth, TX USA. [Devidas, Meenakshi] Univ Florida, Coll Med, Dept Epidemiol & Hlth Policy Res, Gainesville, FL USA. [Devidas, Meenakshi] Childrens Oncol Grp, Gainesville, FL USA. [Hunger, Stephen P.] Univ Colorado, Denver Sch Med, Aurora, CO USA. [Hunger, Stephen P.] Childrens Hosp, Aurora, CO USA. RP Downing, JR (reprint author), St Jude Childrens Hosp, Dept Pathol, 262 Danny Thomas Pl,MS 271, Memphis, TN 38105 USA. EM james.downing@stjude.org OI Mullighan, Charles/0000-0002-1871-1850 FU Children's Oncology Group Chair's Award [CA098543]; Strategic Partnering to Evaluate Cancer Signatures Program [CA114762]; National Cancer Institute; National Institute of General Medical Sciences Pharmacogenetics Research Network and Database [U01 GM61393, U01GM61374]; Cancer Center [21765]; National Institutes of Health [R01 CA86011, N01-C0-12400]; Leukemia and Lymphoma Society Specialized Center of Research [7388-06]; CureSearch National Childhood Cancer Foundation; National Health and Medical Research Council (Australia); Australia) C. J. Martin Traveling Fellowship; American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; NCI; Becton Dickinson Biosciences; Xanthus Pharmaceuticals FX We thank Zhongling Cai and Claire Boltz for technical assistance and Stephen Smale for helpful discussions. NR 34 TC 531 Z9 560 U1 2 U2 13 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 JAN 29 PY 2009 VL 360 IS 5 BP 470 EP 480 DI 10.1056/NEJMoa0808253 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 399PS UT WOS:000262812400006 PM 19129520 ER PT J AU Subak, LL Wing, R West, DS Franklin, F Vittinghoff, E Creasman, JM Richter, HE Myers, D Burgio, KL Gorin, AA Macer, J Kusek, JW Grady, D AF Subak, Leslee L. Wing, Rena West, Delia Smith Franklin, Frank Vittinghoff, Eric Creasman, Jennifer M. Richter, Holly E. Myers, Deborah Burgio, Kathryn L. Gorin, Amy A. Macer, Judith Kusek, John W. Grady, Deborah CA PRIDE Investigators TI Weight Loss to Treat Urinary Incontinence in Overweight and Obese Women. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; MIDDLE-AGED WOMEN; CARDIOVASCULAR-DISEASE; STRESS-INCONTINENCE; STYLE INTERVENTION; RISK-FACTORS; FOLLOW-UP; SURGERY; HEALTH AB Background: Obesity is an established and modifiable risk factor for urinary incontinence, but conclusive evidence for a beneficial effect of weight loss on urinary incontinence is lacking. Methods: We randomly assigned 338 overweight and obese women with at least 10 urinary-incontinence episodes per week to an intensive 6-month weight-loss program that included diet, exercise, and behavior modification (226 patients) or to a structured education program (112 patients). Results: The mean (+/-SD) age of the participants was 53+/-11 years. The body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) and the weekly number of incontinence episodes as recorded in a 7-day diary of voiding were similar in the intervention group and the control group at baseline (BMI, 36+/-6 and 36+/-5, respectively; incontinence episodes, 24+/-18 and 24+/-16, respectively). The women in the intervention group had a mean weight loss of 8.0% (7.8 kg), as compared with 1.6% (1.5 kg) in the control group (P<0.001). After 6 months, the mean weekly number of incontinence episodes decreased by 47% in the intervention group, as compared with 28% in the control group (P=0.01). As compared with the control group, the intervention group had a greater decrease in the frequency of stress-incontinence episodes (P=0.02), but not of urge-incontinence episodes (P=0.14). A higher proportion of the intervention group than of the control group had a clinically relevant reduction of 70% or more in the frequency of all incontinence episodes (P<0.001), stress-incontinence episodes (P=0.009), and urge-incontinence episodes (P=0.04). Conclusions: A 6-month behavioral intervention targeting weight loss reduced the frequency of self-reported urinary-incontinence episodes among overweight and obese women as compared with a control group. A decrease in urinary incontinence may be another benefit among the extensive health improvements associated with moderate weight reduction. (ClinicalTrials.gov number, NCT00091988.) N Engl J Med 2009;360:481-90. C1 [Subak, Leslee L.; Vittinghoff, Eric; Creasman, Jennifer M.; Macer, Judith; Grady, Deborah] Univ Calif San Francisco, Womens Hlth Clin Res Ctr, San Francisco, CA 94115 USA. [Wing, Rena] Miriam Hosp, Providence, RI 02906 USA. [Wing, Rena; Myers, Deborah] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [West, Delia Smith] Univ Arkansas Med Sci, Coll Publ Hlth, Little Rock, AR 72205 USA. [Franklin, Frank; Richter, Holly E.; Burgio, Kathryn L.] Univ Alabama Birmingham, Birmingham, AL USA. [Burgio, Kathryn L.] Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, Birmingham, AL USA. [Gorin, Amy A.] Univ Connecticut, Storrs, CT USA. [Kusek, John W.] NIDDKD, Bethesda, MD 20892 USA. [Grady, Deborah] San Francisco VA Med Ctr, San Francisco, CA USA. RP Subak, LL (reprint author), Univ Calif San Francisco, Womens Hlth Clin Res Ctr, 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM subakl@obgyn.ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK067860, U01 DK067861, U01 DK067862]; Office of Research on Women's Health; Pfizer; Bionovo; Astellas; GlaxoSmithKline FX Supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01 DK067860, U01 DK067861, and U01 DK067862) and from the Office of Research on Women's Health.; Dr. Subak reports serving on an advisory board for Pfizer and receiving grant support from Pfizer; Dr. Grady, receiving grant support from Bionovo; Dr. Kusek, owning stock in Eli Lilly, Pfizer, and deCODE Genetics; and Dr. Burgio, serving on an advisory board for Pfizer, receiving grant support from Pfizer, and receiving advisory-board fees from Astellas and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported.; The views expressed are those of the authors and do not necessarily represent the official views of the NIDDK or the National Institutes of Health. NR 36 TC 200 Z9 206 U1 1 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 29 PY 2009 VL 360 IS 5 BP 481 EP 490 DI 10.1056/NEJMoa0806375 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 399PS UT WOS:000262812400007 PM 19179316 ER PT J AU Kohn, DB Candotti, F AF Kohn, Donald B. Candotti, Fabio TI Gene Therapy Fulfilling Its Promise. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SEVERE COMBINED IMMUNODEFICIENCY; BONE-MARROW; DISEASE; VECTOR; CELLS; TRANSPLANTATION; GENOTOXICITY C1 [Kohn, Donald B.] Childrens Hosp Los Angeles, Div Res Immunol Bone Marrow Transplantat, Los Angeles, CA 90027 USA. [Kohn, Donald B.] Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA 90033 USA. [Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Kohn, DB (reprint author), Childrens Hosp Los Angeles, Div Res Immunol Bone Marrow Transplantat, Los Angeles, CA 90027 USA. RI Kohn, Donald/N-5085-2016 OI Kohn, Donald/0000-0003-1840-6087 NR 16 TC 61 Z9 62 U1 0 U2 1 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 JAN 29 PY 2009 VL 360 IS 5 BP 518 EP 521 DI 10.1056/NEJMe0809614 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 399PS UT WOS:000262812400014 PM 19179320 ER PT J AU Ping, PP AF Ping, Peipei TI Getting to the Heart of Proteomics. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, NHLBI, Program Project Myocardial Ischemia Injury & Prot, Los Angeles, CA 90095 USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, NHLBI, Program Project Myocardial Ischemia Injury & Prot, Los Angeles, CA 90095 USA. FU NHLBI NIH HHS [R37 HL063901, P01 HL080111-04, P01 HL080111, R01 HL101228] NR 5 TC 19 Z9 19 U1 0 U2 4 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 JAN 29 PY 2009 VL 360 IS 5 BP 532 EP 534 DI 10.1056/NEJMcibr0808487 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 399PS UT WOS:000262812400018 PM 19179323 ER PT J AU Guigon, CJ Zhao, L Willingham, MC Cheng, SY AF Guigon, C. J. Zhao, L. Willingham, M. C. Cheng, S-Y TI PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer SO ONCOGENE LA English DT Article DE thyroid cancer; Pten; carcinogenesis; mouse model; mutations ID PROTEIN-KINASE-B; COWDEN-DISEASE; GERMLINE MUTATIONS; PHOSPHOINOSITIDE 3-KINASE; TRANSCRIPTION FACTORS; SUPPRESSOR GENE; LIGAND-BINDING; BETA-RECEPTOR; HORMONE; RESISTANCE AB Inactivation and silencing of PTEN have been observed in multiple cancers, including follicular thyroid carcinoma. PTEN (phosphatase and tensin homologue deleted from chromosome 10) functions as a tumour suppressor by opposing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Despite correlative data, how deregulated PTEN signalling leads to thyroid carcinogenesis is not known. Mice harbouring a dominant-negative mutant thyroid hormone receptor beta (TR beta(PV/PV) mice) spontaneously develop follicular thyroid carcinoma and distant metastases similar to human cancer. To elucidate the role of PTEN in thyroid carcinogenesis, we generated TR beta(PV/PV) mice haploinsufficient for Pten (TR beta(PV/PV)Pten(+/-) mouse). PTEN deficiency accelerated the progression of thyroid tumour and increased the occurrence of metastasis spread to the lung in TR beta(PV/PV)Pten(+/-) mice, thereby significantly reducing their survival as compared with TR beta(PV/PV)Pten(+/+) mice. AKT activation was further increased by two-fold in TR beta(PV/PV)Pten(+/-) mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)-p70S6K signalling and decreased activity of the forkhead family member FOXO3a. Consistently, cyclin D1 expression was increased. Apoptosis was decreased as indicated by increased expression of nuclear factor-kappa B (NF-kappa B) and decreased caspase-3 activity in the thyroids of TR beta(PV/PV)Pten(+/-) mice. Our results indicate that PTEN deficiency resulted in increased cell proliferation and survival in the thyroids of TR beta(PV/PV)Pten(+/-) mice. Altogether, our study provides direct evidence to indicate that in vivo, PTEN is a critical regulator in the follicular thyroid cancer progression and invasiveness. C1 [Cheng, S-Y] NCI, Gene Regulat Sect, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Willingham, M. C.] Wake Forest Univ, Dept Pathol, Winston Salem, NC 27109 USA. RP Cheng, SY (reprint author), NCI, Gene Regulat Sect, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Center for Cancer Research; National Cancer Institute; National Institutes of Health FX ;We thank Dr Hao Ying for assistance in the determination of thyroid function tests. This research was supported by the Intramural Research Program of Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 37 TC 48 Z9 48 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 29 PY 2009 VL 28 IS 4 BP 509 EP 517 DI 10.1038/onc.2008.407 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 400KM UT WOS:000262866500005 PM 18997818 ER PT J AU Kitagaki, J Yang, Y Saavedra, JE Colburn, NH Keefer, LK Perantoni, AO AF Kitagaki, J. Yang, Y. Saavedra, J. E. Colburn, N. H. Keefer, L. K. Perantoni, A. O. TI Nitric oxide prodrug JS-K inhibits ubiquitin E1 and kills tumor cells retaining wild-type p53 SO ONCOGENE LA English DT Article DE JS-K; nitric oxide (NO); ubiquitin; tumor; apoptosis; p53 ID IN-VITRO; BETA-CATENIN; APOPTOSIS; CANCER; DESTRUCTION; TRANSLATION; GLUTATHIONE; PATHWAYS; SYSTEM; GROWTH AB Nitric oxide (NO) is a major effector molecule in cancer prevention. A number of studies have shown that NO prodrug JS-K (O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxy-carbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate) induces apoptotic cell death in vitro and in vivo, indicating that it is a promising new therapeutic for cancer. However, the mechanism of its tumor-killing activity remains unclear. Ubiquitin plays an important role in the regulation of tumorigenesis and cell apoptosis. Our earlier report has shown that inactivation of the ubiquitin system through blocking E1(ubiquitin-activating enzyme) activity preferentially induces apoptosis in p53-expressing transformed cells. As E1 has an active cysteine residue that could potentially interact with NO, we hypothesized that JS-K could inactivate E1 activity. E1 activity was evaluated by detecting ubiquitin-E1 conjugates through immunoblotting. JS-K strikingly inhibits the ubiquitin-E1 thioester formation in cells in a dose-dependent manner with an IC(50) of approximately 2 mu M, whereas a JS-K analog that cannot release NO did not affect these levels in cells. Moreover, JS-K decreases total ubiquitylated proteins and increases p53 levels, which is mainly regulated by ubiquitin and proteasomal degradation. Furthermore, JS-K preferentially induces cell apoptosis in p53-expressing transformed cells. These findings indicate that JS-K inhibits E1 activity and kills transformed cells harboring wild-type p53. C1 [Kitagaki, J.; Yang, Y.; Perantoni, A. O.] Natl Canc Inst Frederick, Canc & Dev Biol Lab, Ctr Canc Res, Natl Inst Hlth, Frederick, MD 21702 USA. [Saavedra, J. E.] Natl Canc Inst Frederick, Basic Res Program, SAIC Frederick, Ctr Canc Res,Natl Inst Hlth, Frederick, MD 21702 USA. [Colburn, N. H.] Natl Canc Inst Frederick, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Keefer, L. K.] Natl Canc Inst Frederick, Comparat Carcinogenesis Lab, Ctr Canc Res, Natl Inst Hlth, Frederick, MD 21702 USA. RP Perantoni, AO (reprint author), Natl Canc Inst Frederick, Canc & Dev Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bldg 538,Rm 221,1050 Boyles St, Frederick, MD 21702 USA. EM yangyili@ncifcrf.gov; peranton@ncifcrf.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NIH; National Cancer Institute; Center for Cancer Research; National Cancer Institute [NOI-CO-12400] FX We are grateful to the NIH Fellows Editorial Board for revisions of this paper. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by National Cancer Institute Contract No. NOI-CO-12400 to SAIC Inc. JK was a fellow of the Japanese Society for the Promotion of Science. NR 26 TC 26 Z9 27 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 29 PY 2009 VL 28 IS 4 BP 619 EP 624 DI 10.1038/onc.2008.401 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 400KM UT WOS:000262866500015 PM 18978812 ER PT J AU Lee, CH Kuo, WC Beri, S Kapre, S Joshi, JS Bouveret, N LaForce, FM Frasch, CE AF Lee, Che-Hung Kuo, Wen-Chun Beri, Suresh Kapre, Subash Joshi, Jayant S. Bouveret, Nancy LaForce, F. Marc Frasch, Carl E. TI Preparation and characterization of an immunogenic meningococcal group A conjugate vaccine for use in Africa SO VACCINE LA English DT Article DE Vaccine; Conjugate; Polysaccharide ID NEISSERIA-MENINGITIDIS SEROGROUP; SUB-SAHARAN AFRICA; CAPSULAR POLYSACCHARIDE; O-ACETYLATION; GROUP-B; ANTIBODY; IMMUNIZATION; PERSISTENCE; PREVENTION; EPIDEMIC AB Periodic epidemics of group A meningococcal (Mn A) meningitis continue to occur in sub-Saharan Africa. For its prevention, a Mn A polysaccharide (PS)-tetanus toxoid (TT) conjugate vaccine was developed using reductive amination of polysaccharicle aldehydes and toxoid hydrazides. In mouse immunization studies, a schedule of three bi-weekly s.c. immunizations of 0.1 or 1 mu g of the conjugate (PS content) without an adjuvant induced serum antibody levels of >10,000 units/mL measured by enzyme-linked immunosorbent assay (ELISA) as compared to similar to 100 units/mL in PS control mice. The elicited antibodies were active in bactericidal assays using either baby rabbit or human complement (titers >1500 compared to similar to 200 for the PS control group). The synthesis process is reproducible and scalable, and has been successfully used for manufacturing a Mn A PS-TT conjugate vaccine based on a paradigm of shared manufacturing with transfer of new technology [Jodar L, LaForce FM, Ceccarini C, Aguado T, Granoff DM. Meningococcal conjugate vaccine for Africa: a model for development of new vaccine for the poorest countries. Lancet 2003, 361:1092-4]. A phase 1 clinical trial of the manufactured Men A-TT conjugate vaccine has been successfully carried out in adults in India, and a phase 2 clinical trial in young children is currently underway in Africa. Published by Elsevier Ltd. C1 [Frasch, Carl E.] US FDA, Lab Bacterial Polysaccharides, HFM 428, DBPAP,OVRR,CBER,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Beri, Suresh; Kapre, Subash; Joshi, Jayant S.] Serum Inst India Ltd, Pune, Maharashtra, India. [Bouveret, Nancy; LaForce, F. Marc] Meningitis Vaccine Project, Ferney Voltaire, France. RP Lee, CH (reprint author), US FDA, Lab Bacterial Polysaccharides, HFM 428, DBPAP,OVRR,CBER,Ctr Biol Evaluat & Res, NIH Campus,Bldg 29,Room 404,29 Lincoln Ave, Bethesda, MD 20892 USA. EM robert.lee@fda.hhs.gov FU CRADA FX The authors are grateful to Dr. Dan Granoff and his laboratory for performing bactericidal assay with human complement. We thank Ms. Britany Bowen for her technical support, Mr. Scot Noris for recording the NMR spectra of native and activated Mn A PS, and Drs. Margaret Bash, Chao-Ming Tsai and Willie Vann for their review and comments of this manuscript. This research is supported in part by a CRADA between CBER and PATH. NR 35 TC 39 Z9 43 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN 29 PY 2009 VL 27 IS 5 BP 726 EP 732 DI 10.1016/j.vaccine.2008.11.065 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 405II UT WOS:000263216100019 PM 19063929 ER PT J AU Demeter, LM Jiang, H Mukherjee, AL Morse, GD DiFrancesco, R DiCenzo, R Dykes, C Sista, P Bacheler, L Klingman, K Rinehart, A Albrecht, M AF Demeter, Lisa M. Jiang, Hongyu Mukherjee, A. Lisa Morse, Gene D. DiFrancesco, Robin DiCenzo, Robert Dykes, Carrie Sista, Prakash Bacheler, Lee Klingman, Karin Rinehart, Alex Albrecht, Mary TI A randomized trial of therapeutic drug monitoring of protease inhibitors in antiretroviral-experienced, HIV-1-infected patients SO AIDS LA English DT Article; Proceedings Paper CT 15th Conference on Retroviruses and Opportunistic Infections CY FEB 03-06, 2008 CL Boston, MA DE antiretroviral therapy; clinical trials; HIV drug resistance; pharmacokinetics; protease inhibitors; therapeutic drug monitoring ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEAVILY PRETREATED PATIENTS; HIV-INFECTED PATIENTS; VIROLOGICAL RESPONSE; LOPINAVIR-RITONAVIR; SUSCEPTIBILITY SCORES; QUOTIENT; AMPRENAVIR; RESISTANCE; PHARMACOKINETICS AB Objective: Whether therapeutic drug monitoring of protease inhibitors improves outcomes in HIV-infected patients is controversial. We evaluated this strategy in a randomized, open-label clinical trial, using a normalized inhibitory quotient (NIQ), which incorporates drug exposure and viral drug resistance. NIQs <= 1 may predict poor outcome and identify patients who could benefit from dose escalation. Design/methods: Eligible patients had a viral load >1000 copies/ml on a failing regimen, and began a new protease inhibitor containing regimen at entry. All FDA-approved protease inhibitors available during the study recruitment (June 2002-May 2006) were allowed. One hundred and eighty-three participants with NIQ <= 1, oil the basis of their week 2 protease inhibitor trough concentration and pre-entry drug resistance test, were randomized at week 4 to standard of care (SOC) or protease inhibitor dose escalation (TDM). The primary endpoint was change in log(10) plasma HIV-1 RNA concentration from randomization to 20 weeks later. Results: Ninety-one patients were randomized to SOC and 92 to TDM. NIQs increased more in the TDM arm compared to SOC (+69 versus +25%, P=0.01). Despite this, TDM and SOC arms showed no difference in Outcome (+0.09 versus +0.02 log(10), P=0.17). In retrospective Subgroup analyses, patients with less HIV resistance to their protease inhibitors benefited from TDM (P=0.002), as did black and Hispanic patients (P=0.035 and 0.05, respectively). Differences between black and white patients persisted when accounting for protease inhibitor susceptibility. Conclusions: There was no overall benefit of TDM. In post hoc subgroup analyses, TDM appeared beneficial in black and Hispanic patients, and in patients whose virus retained some susceptibility to the protease inhibitors in their regimen. (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Demeter, Lisa M.; DiCenzo, Robert; Dykes, Carrie] Univ Rochester, Sch Med & Dent, Div Infect Dis, Rochester, NY USA. [Jiang, Hongyu; Mukherjee, A. Lisa] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Morse, Gene D.; DiFrancesco, Robin; DiCenzo, Robert] SUNY Buffalo, Dept Pharm Practice, Buffalo, NY USA. [Sista, Prakash; Bacheler, Lee] VircoLab Inc, Durham, NC USA. [Albrecht, Mary] Beth Israel Deaconess Med Ctr, Div Infect Dis, Bethesda, MD USA. [Klingman, Karin] NIH, Div Aids, Bethesda, MD 20892 USA. [Rinehart, Alex] Tibotec Therapeut, Bridgewater, NJ USA. RP Demeter, LM (reprint author), 601 Elmwood Ave,Box 689, Rochester, NY 14642 USA. EM lisa_demeter@urmc.rochester.edu FU NCRR NIH HHS [M01 RR000032, M01 RR000044, M01 RR000044-440787, M01 RR000047, M01 RR000051, M01 RR000096, RR-00032, RR-00044, RR-00047, RR-00051, RR-00075, RR-00096]; NIAID NIH HHS [U01 AI069511, AI-25859, AI-27665, AI-27761, AI-32782, AI-32783, AI-34853, AI-38855, AI-38858, AI-46370, AI-68634, AI-68636, AI-69411, AI-69415, AI-69419, AI-69423, AI-69424, AI-69428, AI-69432, AI-69434, AI-69439, AI-69450, AI-69452, AI-69471, AI-69472, AI-69474, AI-69477, AI-69484, AI-69494, AI-69495, AI-69501, AI-69511, AI-69513, AI-69532, AI-69556, P30 AI045008, P30-AI-45008, U01 AI025859, U01 AI027659, U01 AI027659-18, U01 AI027665, U01 AI032782, U01 AI032783, U01 AI034853, U01 AI038855, U01 AI038858, U01 AI038858-09, U01 AI046370, U01 AI068634, U01 AI068636, U01 AI068636-04, U01 AI069411, U01 AI069415, U01 AI069419, U01 AI069423, U01 AI069424, U01 AI069428, U01 AI069432, U01 AI069434, U01 AI069439, U01 AI069450, U01 AI069452, U01 AI069471, U01 AI069472, U01 AI069474, U01 AI069477, U01 AI069484, U01 AI069494, U01 AI069495, U01 AI069501, U01 AI069511-03, U01 AI069513, U01 AI069532, U01 AI069556, UM1 AI068634, UM1 AI068636, UM1 AI069411, UM1 AI069415, UM1 AI069419, UM1 AI069423, UM1 AI069424, UM1 AI069428, UM1 AI069432, UM1 AI069434, UM1 AI069439, UM1 AI069450, UM1 AI069452, UM1 AI069471, UM1 AI069472, UM1 AI069474, UM1 AI069477, UM1 AI069484, UM1 AI069494, UM1 AI069495, UM1 AI069501, UM1 AI069511, UM1 AI069513, UM1 AI069532, UM1 AI069556] NR 30 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 28 PY 2009 VL 23 IS 3 BP 357 EP 368 DI 10.1097/QAD.0b013e32831f9148 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 406WH UT WOS:000263325100010 PM 19114860 ER PT J AU Lanoy, E Dores, GM Madeleine, MM Toro, JR Fraumeni, JF Engels, EA AF Lanoy, Emilie Dores, Graca M. Madeleine, Margaret M. Toro, Jorge R. Fraumeni, Joseph F., Jr. Engels, Eric A. TI Epidemiology of nonkeratinocytic skin cancers among persons with AIDS in the United States SO AIDS LA English DT Article DE AIDS; appendageal carcinoma; epidemiology; melanoma; Merkel cell carcinoma; sebaceous carcinoma; skin cancer ID HUMAN-IMMUNODEFICIENCY-VIRUS; MUIR-TORRE-SYNDROME; SQUAMOUS-CELL CARCINOMA; CUTANEOUS HUMAN PAPILLOMAVIRUSES; ORGAN TRANSPLANT RECIPIENTS; SEBACEOUS GLAND CARCINOMA; SUN-EXPOSED SKIN; MICROSATELLITE INSTABILITY; HIV-INFECTION; RISK-FACTORS AB Objective: Immunosuppression may increase risk for some skin cancers. We evaluated skin cancer epidemiology among persons with AIDS. Design: We linked data from population-based US AIDS and cancer registries to evaluate risk of nonkeratinocytic skin cancers (melanoma, Merkel cell carcinoma, and appendageal carcinomas, including sebaceous carcinoma) in 497 142 persons with AIDS. Methods: Standardized incidence ratios (SIRs) were calculated to relate skin cancer risk to that in the general population. We used logistic regression to compare risk according to demographic factors, CD4 cell count, and a geographic index of ultraviolet radiation exposure. Results: From 60 months before to 60 months after AIDS onset, persons with AIDS had elevated risks of melanoma (SIR=1.3, 95% confidence interval 1.1-1.4, n=292 cases) and, more strongly, of Merkel cell carcinoma (SIR=11, 95% confidence interval 6.3-17, n=17) and sebaceous carcinoma (SIR=8.1, 95% confidence interval 3.2-17, n=7). Risk for appendageal carcinomas increased with progressive time relative to AIDS onset (P trend 0.03). Risk of these skin cancers was higher in non-Hispanic whites than other racial/ethnic groups, and melanoma risk was highest among men who have sex with men. Melanoma risk was unrelated to CD4 cell count at AIDS onset (P=0.32). Risks for melanoma and appendageal carcinomas rose with increasing ultraviolet radiation exposure (P trend <10 (4) and P trend -10 (3), respectively). Conclusion: Among persons with AIDS, there is a modest excess risk of melanoma, which is not strongly related to immunosuppression and may relate to ultraviolet radiation exposure. In contrast, the greatly increased risks for Merkel cell and sebaceous carcinoma suggest an etiologic role for immunosuppression. (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Lanoy, Emilie; Dores, Graca M.; Toro, Jorge R.; Fraumeni, Joseph F., Jr.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Lanoy, Emilie] Univ Paris 06, INSERM, U720, Paris, France. [Lanoy, Emilie] Univ Paris 06, UPMC, UMR S720, Paris, France. [Dores, Graca M.] US Dept Vet Affairs, Med Ctr, Med Serv, Oklahoma City, OK USA. [Madeleine, Margaret M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7076, Rockville, MD 20892 USA. EM engelse@exchange.nih.gov RI Lanoy, Emilie/A-8541-2011 OI Lanoy, Emilie/0000-0002-4789-7770 FU Intramural Research Program of the National Cancer Institute FX We are grateful for the contributions of many staff members at the HIV/AIDS and cancer registries who collected the data, prepared data files for the mathces, and facilitated the record linkages.; E.L. and E.A.E. designed the study and conducted the statistical analyses. G.M.D., J.R.T, and J.F.F contributed expertise regarding, skin cancer. All authors contributed expertise regarding epidemiology methods and participated in the interpretation of the data. M.M.M. and E.A.E. provided data for the study. E.L. and E.A.E. drafted the article, and all authors contributed to critical revision of the article.; The study was supported by the Intramural Research Program of the National Cancer Institute. NR 42 TC 36 Z9 36 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 28 PY 2009 VL 23 IS 3 BP 385 EP 393 DI 10.1097/QAD.0b013e3283213046 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 406WH UT WOS:000263325100013 PM 19114864 ER PT J AU Trucksess, MW Whitaker, TB Weaver, CM Slate, A Giesbrecht, FG Rader, JI Betz, JM AF Trucksess, Mary W. Whitaker, Thomas B. Weaver, Carol M. Slate, Andrew Giesbrecht, Francis G. Rader, Jeanne I. Betz, Joseph M. TI Sampling and Analytical Variability Associated with the Determination of Total Aflatoxins and Ochratoxin A in Powdered Ginger Sold As a Dietary Supplement in Capsules SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE Sampling; analytical uncertainty; aflatoxins; ochratoxin A; ginger capsules; dietary supplements ID PART I; MYCOTOXINS; GINSENG; FOODS AB The U.S. Food and Drug Administration is studying the need to monitor dietary supplements for mycotoxins such as total aflatoxins and ochratoxin A. An effective mycotoxin-monitoring program requires knowledge of the sampling and analytical variability associated with the determination of total aflatoxins (AF) and ochratoxin A (OTA) in dietary supplements. Three lots of ginger sold as a powder in capsule form and packaged in individual bottles were analyzed for both AF and OTA. The total variability associated with measuring AF and OTA in powdered ginger was partitioned into bottle-to-bottle, within bottle, and analytical variances. The variances were estimated using a nested design. For AF and OTA, the within-bottle variance associated with the 5 g laboratory sample size was the largest component of variability accounting for about 43% and 85% of the total variance, respectively; the analytical variance accounted for about 34% and 9% of the total variability, respectively; and the bottle-to-bottle variance accounted for about 23% and 7% of the total variance, respectively. When the total variance is converted into the coefficient of variation (CV or standard deviation relative to the mean concentration), the CV is lower for AF (16.9%) than OTA (24.7%). C1 [Trucksess, Mary W.; Weaver, Carol M.; Rader, Jeanne I.] US FDA, College Pk, MD USA. [Whitaker, Thomas B.] N Carolina State Univ, USDA, Raleigh, NC 27695 USA. [Slate, Andrew] N Carolina State Univ, Dept Biol & Agr Engn, Raleigh, NC 27695 USA. [Giesbrecht, Francis G.] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Trucksess, MW (reprint author), US FDA, College Pk, MD USA. NR 12 TC 11 Z9 11 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JAN 28 PY 2009 VL 57 IS 2 BP 321 EP 325 DI 10.1021/jf8017854 PG 5 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 397LU UT WOS:000262665000001 PM 19105639 ER PT J AU Thomsen, M Hall, FS Uhl, GR Caine, SB AF Thomsen, Morgane Hall, F. Scott Uhl, George R. Caine, S. Barak TI Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cocaine; drug abuse; DAT; SERT; knock-out mouse; progressive ratio ID PLACE PREFERENCE; DEFICIENT MICE; REWARD; AMPHETAMINE; MODULATION; RECEPTORS; MONKEYS; LACKING; RAT AB There has been much interest in the relative importance of dopamine and serotonin transporters in the abuse-related-effects of cocaine. We tested the hypotheses that mice lacking the dopamine transporter (DAT(-/-)), the serotonin transporter (SERT(-/-)), or both (DAT(-/-) SERT(-/-)) exhibit decreased reinforcing effects of cocaine. We also assessed whether observed effects on self-administration are specific to cocaine or if operant behavior maintained by food or a direct dopamine agonist are similarly affected. We used a broad range of experimental conditions that included acquisition without previous training, behavior established with food training and subsequent testing with food, cocaine or a direct dopamine agonist as reinforcers, fixed ratio and progressive ratio schedules of reinforcement, and a reversal procedure. Wild-type mice readily acquired cocaine self-administration and showed dose-response curves characteristic of the schedule of reinforcement that was used. While some DAT(-/-) mice appeared to acquire cocaine self-administration transiently, almost all DAT(-/-) mice failed to self-administer cocaine reliably. Food-maintained behaviors were not decreased by the DAT mutation, and IV self-administration of a direct dopamine agonist was robust in the DAT(-/-) mice. In contrast to those mice, cocaine's reinforcing effects were not diminished in SERT(-/-) mice under any of the conditions tested, except for impaired initial acquisition of both food- and cocaine-maintained behavior. These findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine. C1 [Thomsen, Morgane; Caine, S. Barak] Harvard Univ, Sch Med, McLean Hosp, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Thomsen, M (reprint author), Harvard Univ, Sch Med, McLean Hosp, Alcohol & Drug Abuse Res Ctr, 115 Mill St, Belmont, MA 02478 USA. EM mthomsen@mclean.harvard.edu RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU National Institute on Drug Abuse (NIDA)-National Institutes of Health (NIH) [DA12142, DA14644, DA17323, DA14528, DA07252]; NIDA Intramural Research-NIH-Department of Health and Human Services FX This work was supported by grants from National Institute on Drug Abuse (NIDA)-National Institutes of Health (NIH) (DA12142, DA14644, DA17323, DA14528, DA07252) and in part from intramural funding from the NIDA Intramural Research-NIH-Department of Health and Human Services (G. R. U., F. S. H.). We thank Joon Y. Boon, Jennifer Dohrmann, Jill Berkowitz, and Dana Angood for expert technical assistance. NR 25 TC 62 Z9 65 U1 2 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 28 PY 2009 VL 29 IS 4 BP 1087 EP 1092 DI 10.1523/JNEUROSCI.4037-08.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 400HQ UT WOS:000262859000020 PM 19176817 ER PT J AU Weickert, TW Goldberg, TE Callicott, JH Chen, Q Apud, JA Das, S Zoltick, BJ Egan, MF Meeter, M Myers, C Gluck, MA Weinberger, DR Mattay, VS AF Weickert, Thomas W. Goldberg, Terry E. Callicott, Joseph H. Chen, Qiang Apud, Jose A. Das, Sumitra Zoltick, Brad J. Egan, Michael F. Meeter, Martijn Myers, Catherine Gluck, Mark A. Weinberger, Daniel R. Mattay, Venkata S. TI Neural Correlates of Probabilistic Category Learning in Patients with Schizophrenia SO JOURNAL OF NEUROSCIENCE LA English DT Article DE schizophrenia; prefrontal cortex; caudate; parahippocampus; learning; cognition ID PARKINSONS-DISEASE; N-ACETYLASPARTATE; STRIATAL DOPAMINE; COGNITIVE SKILL; BASAL GANGLIA; WHITE-MATTER; TASK; BRAIN; MEMORY; ACTIVATION AB Functional neuroimaging studies of probabilistic category learning in healthy adults report activation of cortical-striatal circuitry. Based on previous findings of normal learning rate concurrent with an overall performance deficit in patients with schizophrenia, we hypothesized that relative to healthy adults, patients with schizophrenia would display preserved caudate nucleus and abnormal prefrontal cortex activation during probabilistic category learning. Forty patients with schizophrenia receiving antipsychotic medication and 25 healthy participants were assessed on interleaved blocks of probabilistic category learning and control tasks while undergoing blood oxygenation level-dependent functional magnetic resonance imaging. In addition to the whole sample of patients with schizophrenia and healthy adults, a subset of patients and healthy adults matched for good learning was also compared. In the whole sample analysis, patients with schizophrenia displayed impaired performance in conjunction with normal learning rate relative to healthy adults. The matched comparison of patients and healthy adults classified as good learners revealed greater caudate and dorsolateral prefrontal cortex activity in the healthy adults and greater activation in a more rostral region of the dorsolateral prefrontal, cingulate, parahippocampal and parietal cortex in patients. These results demonstrate that successful probabilistic category learning can occur in the absence of normal frontal-striatal function. Based on analyses of the patients and healthy adults matched on learning and performance, a minority of patients with schizophrenia achieve successful probabilistic category learning and performance levels through differential activation of a circumscribed neural network which suggests a compensatory mechanism in patients showing successful learning. C1 [Weickert, Thomas W.] Univ New S Wales, Prince Wales Med Res Inst, Randwick, NSW 2031, Australia. [Weickert, Thomas W.; Goldberg, Terry E.; Callicott, Joseph H.; Chen, Qiang; Apud, Jose A.; Das, Sumitra; Zoltick, Brad J.; Egan, Michael F.; Weinberger, Daniel R.; Mattay, Venkata S.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Goldberg, Terry E.] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY 11004 USA. [Meeter, Martijn] Vrije Univ Amsterdam, Dept Cognit Psychol, NL-1081 BT Amsterdam, Netherlands. [Myers, Catherine] Rutgers State Univ, Dept Psychol, Newark, NJ 07102 USA. [Gluck, Mark A.] Rutgers State Univ, Ctr Mol & Behav Neurosci, Newark, NJ 07102 USA. RP Weickert, TW (reprint author), Univ New S Wales, Prince Wales Med Res Inst, Randwick, NSW 2031, Australia. EM t.weickert@unsw.edu.au RI Callicott, Joseph/C-9102-2009; Meeter, Martijn/A-2926-2009; OI Callicott, Joseph/0000-0003-1298-3334; Meeter, Martijn/0000-0002-5112-6717; Myers, Catherine/0000-0002-2776-4823 FU National Institutes of Health-National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institutes of Health-National Institute of Mental Health. NR 55 TC 40 Z9 41 U1 2 U2 9 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 JAN 28 PY 2009 VL 29 IS 4 BP 1244 EP 1254 DI 10.1523/JNEUROSCI.4341-08.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 400HQ UT WOS:000262859000035 PM 19176832 ER PT J AU Wylie, BJ Schwieters, CD Oldfield, E Rienstra, CM AF Wylie, Benjamin J. Schwieters, Charles D. Oldfield, Eric Rienstra, Chad M. TI Protein Structure Refinement Using C-13 alpha Chemical Shift Tensors SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; INDIVIDUAL CARBON SITES; MAGIC-ANGLE; C-13 NMR; AB-INITIO; MICROCRYSTALLINE PROTEIN; ANTIMICROBIAL PEPTIDE; QUANTUM-CHEMISTRY; ANISOTROPY MEASUREMENTS AB We have obtained the C-13 alpha chemical shift tensors for each amino acid in the protein GB1. We then developed a CST force field and incorporated this into the Xplor-NIH structure determination program. GB1 structures obtained by using CST restraints had improved precision over those obtained in the absence of CST restraints and were also more accurate. When combined with isotropic chemical shifts, distance, and vector angle restraints, the root-mean squared error with respect to existing X-ray structures was better than similar to 1.0 angstrom. These results are of broad general interest since they show that chemical shift tensors can be used in protein structure refinement, improving both structural accuracy and precision, opening up the way to accurate de novo structure determination. C1 [Wylie, Benjamin J.; Oldfield, Eric; Rienstra, Chad M.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Schwieters, Charles D.] NIH, Imaging Sci Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Rienstra, CM (reprint author), Univ Illinois, Dept Chem, 600 S Mathews Ave, Urbana, IL 61801 USA. EM rienstra@scs.uiuc.edu FU National Science Foundation [MCB 0347824]; National Institutes of Health [GM73216, GM73770]; University of Illinois at Urbana-Champaign FX This research was supported by the National Science Foundation (CAREER Award, MCB 0347824 to C.M.R.), the CIT Intramural Research Program of the NIH (C.D.S.), and in part by the National Institutes of Health (GM73216 to E.O. and GM73770 to C.M.R.). We thank the NMR Facility at the School of Chemical Sciences, University of Illinois at Urbana-Champaign, for technical assistance. NR 65 TC 36 Z9 36 U1 1 U2 16 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 JAN 28 PY 2009 VL 131 IS 3 BP 985 EP 992 DI 10.1021/ja804041p PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 427PQ UT WOS:000264791600038 PM 19123862 ER PT J AU Burkhart, BA Ivey, ML Archer, TK AF Burkhart, Barbara A. Ivey, Melissa L. Archer, Trevor K. TI Long-term low level glucocorticoid exposure induces persistent repression in chromatin SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Glucocorticoid resistance; Transcriptional repression; Chromatin; MMTV; SGK ID RECEPTOR-DEPENDENT TRANSCRIPTION; GENE-EXPRESSION; IN-VIVO; NUCLEAR RECEPTORS; MMTV PROMOTER; HISTONE H1; KAPPA-B; RESISTANCE; STRESS; CELLS AB Environmental exposure to low concentration hormones can have permanent epigenetic effects in animals and humans. The consequence of long-term low concentration glucocorticoid exposure was investigated in cell culture using glucocorticoid responsive genes organized in alternative chromatin structures. The MMTV promoter is induced by short-term glucocorticoid exposure on either an integrated (normal chromatin) or transient (unstructured chromatin) promoter. Longer hormone treatment causes a transient refractory repression of only the integrated promoter. Exposure to low concentrations of hormone for several passages persistently represses the integrated MMTV and endogenous glucocorticoid responsive promoters. The glucocorticoid receptor cannot bind to persistently repressed promoters. Induction by androgens is also inhibited on the repressed MMTV promoter. Similarly, osmotic stress induction of the endogenous Sgk gene is repressed. Persistent repression by glucocorticoids targets glucocorticoid responsive genes using a chromatin-dependent mechanism that disrupts binding of both GR-dependent and GR-indepenclent transcription complexes. Published by Elsevier Ireland Ltd. C1 [Burkhart, Barbara A.; Ivey, Melissa L.; Archer, Trevor K.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, 111 Alexander Dr,POB 12233 MD C4-01, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU National Institute of Environmental Health Sciences; NIH: [Z01 ES071006-09] FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH: project number Z01 ES071006-09. NR 50 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 27 PY 2009 VL 298 IS 1-2 BP 66 EP 75 DI 10.1016/j.mce.2008.10.011 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 398KX UT WOS:000262732100009 PM 19007849 ER PT J AU Berezhkovskii, AM Coppey, M Shvartsman, SY AF Berezhkovskii, Alexander M. Coppey, Mathieu Shvartsman, Stanislav Y. TI Signaling gradients in cascades of two-state reaction-diffusion systems SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECEPTOR TYROSINE KINASE; TERMINAL BODY PATTERN; DROSOPHILA-EMBRYO; POSITIONAL INFORMATION; MORPHOGEN GRADIENTS; GENE-EXPRESSION; MITOTIC-CYCLES; NUCLEAR; TORSO; DYNAMICS AB Biological networks frequently use cascades, generally defined as chain-like arrangements of similar modules. Spatially lumped cascades can serve as noise filters, time-delay, or thresholding elements. The operation and functional capabilities of spatially distributed cascades are much less understood. Motivated by studies of pattern formation in the early Drosophila embryo, we analyze cascades of 2-state reaction-diffusion systems. At each stage within such as a cascade, a diffusible particle is reversibly bound by immobile traps and can be annihilated in both mobile and immobile states. When trapped, these particles drive the next stage by converting mobile particles of a different type from a passive to active form. The cascade initiated by injection of mobile particles into the first stage. We derive analytical expressions for the steady-state concentration profiles of mobile and immobile particles and analyze how the output of a cascade is controlled by properties of the constituent stages. C1 [Coppey, Mathieu; Shvartsman, Stanislav Y.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08540 USA. [Coppey, Mathieu; Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem Engn, Princeton, NJ 08540 USA. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Shvartsman, SY (reprint author), Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08540 USA. EM stas@princeton.edu FU National Institutes of Health, [HHSN266200500021C, N01-AI-50021]; Center for Information Technology [P50 GM071508, R01 RM078079] FX We thank Alistair Boettiger for numerous helpful discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Information Technology ( A. M. B.), by Grants P50 GM071508 and R01 RM078079 from the National Institutes of Health ( to S. Y. S.), and by National Institutes of Health contract no. HHSN266200500021C, ADB no. N01-AI-50021 ( S. Y. S. and M. C.). NR 38 TC 16 Z9 16 U1 1 U2 9 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 JAN 27 PY 2009 VL 106 IS 4 BP 1087 EP 1092 DI 10.1073/pnas.0811807106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399XC UT WOS:000262831600025 PM 19147842 ER PT J AU Calado, RT Regal, JA Hills, M Yewdell, WT Dalmazzo, LF Zago, MA Lansdorp, PM Hogge, D Chanock, SJ Estey, EH Falcao, RP Young, NS AF Calado, Rodrigo T. Regal, Joshua A. Hills, Mark Yewdell, William T. Dalmazzo, Leandro F. Zago, Marco A. Lansdorp, Peter M. Hogge, Donna Chanock, Stephen J. Estey, Elihu H. Falcao, Roberto P. Young, Neal S. TI Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE risk factor; telomere; dyskeratosis congenita; cancer ID BRITISH COOPERATIVE GROUP; BONE-MARROW FAILURE; DYSKERATOSIS-CONGENITA; REVERSE-TRANSCRIPTASE; FUNCTIONAL-CHARACTERIZATION; HEMATOLOGIC DISORDERS; GENOME INSTABILITY; PULMONARY-FIBROSIS; APLASTIC-ANEMIA; CANCER AB Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in TERT and TERC genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one TERT gene variant. In the first cohort, 11 patients carried missense TERT gene variants that were not present in controls (P<0.0001); in the second cohort, TERT mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (n = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (n = 1,110; P = 0.0009). Introduction of TERT mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability. C1 [Calado, Rodrigo T.; Regal, Joshua A.; Yewdell, William T.; Young, Neal S.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Chanock, Stephen J.] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Dalmazzo, Leandro F.; Zago, Marco A.; Falcao, Roberto P.] Univ Sao Paulo, Ribeirao Preto Med Sch, Ctr Cell Based Therapy, Dept Internal Med, BR-14048900 Ribeirao Preto, Brazil. [Estey, Elihu H.] Univ Texas MD Anderson Canc Ctr, Leukemia Dept, Houston, TX 77030 USA. [Hills, Mark; Lansdorp, Peter M.; Hogge, Donna] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 4E6, Canada. [Lansdorp, Peter M.; Hogge, Donna] Univ British Columbia, Ctr Canc, Dept Med, Vancouver, BC V6T 1ZA, Canada. RP Calado, RT (reprint author), 10 Ctr Dr,Bldg 10-CRC,Room 3E-5140, Bethesda, MD 20892 USA. EM calador@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011; Celulas tronco, Inct/I-1921-2013 FU National Institutes of Health Intramural Research Program; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico; Canadian Institutes of Health Research [MOP38075, GMH79042] FX This work was supported by the National Institutes of Health Intramural Research Program (R. T. C., S. J. C., and N. S. Y.), Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (L. F. D., M. A. Z., and R. P. F.), and Canadian Institutes of Health Research Grants MOP38075 and GMH79042 (to P. M. L.). NR 36 TC 99 Z9 102 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 JAN 27 PY 2009 VL 106 IS 4 BP 1187 EP 1192 DI 10.1073/pnas.0807057106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399XC UT WOS:000262831600042 PM 19147845 ER PT J AU Chien, AJ Moore, EC Lonsdorf, AS Kulikauskas, RM Rothberg, BG Berger, AJ Major, MB Hwang, ST Rimm, DL Moon, RT AF Chien, Andy J. Moore, Erin C. Lonsdorf, Anke S. Kulikauskas, Rima M. Rothberg, Bonnie Gould Berger, Aaron J. Major, Michael B. Hwang, Sam T. Rimm, David L. Moon, Randall T. TI Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE differentiation; prognosis; metastasis; WNT5A; B16 model; microarray ID CUTANEOUS MALIGNANT-MELANOMA; AMERICAN-JOINT-COMMITTEE; BETA-CATENIN; PROGNOSTIC-SIGNIFICANCE; PROTEIN EXPRESSION; COLORECTAL-CANCER; WILMS-TUMOR; CELL-LINES; STEM-CELLS; EXON 3 AB This study demonstrates that in malignant melanoma, elevated levels of nuclear beta-catenin in both primary tumors and metastases correlate with reduced expression of a marker of proliferation and with improved survival, in contrast to colorectal cancer. The reduction in proliferation observed in vivo is recapitulated in B16 murine melanoma cells and in human melanoma cell lines cultured in vitro with either WNT3A or small-molecule activators of beta-catenin signaling. Consistent with these results, B16 melanoma cells expressing WNT3A also exhibit decreased tumor size and decreased metastasis when implanted into mice. Genome-wide transcriptional profiling reveals that WNT3A up-regulates genes implicated in melanocyte differentiation, several of which are down-regulated with melanoma progression. These findings suggest that WNT3A can mediate transcriptional changes in melanoma cells in a manner reminiscent of the known role of Wnt/beta-catenin signaling in normal melanocyte development, thereby altering melanoma cell fate to one that may be less proliferative and potentially less aggressive. Our results may explain the observed loss of nuclear beta-catenin with melanoma progression in human tumors, which could reflect a dysregulation of cellular differentiation through a loss of homeostatic Wnt/beta-catenin signaling. C1 [Chien, Andy J.; Kulikauskas, Rima M.; Major, Michael B.; Moon, Randall T.] Univ Washington, Sch Med, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. [Chien, Andy J.; Moore, Erin C.; Kulikauskas, Rima M.] Univ Washington, Sch Med, Dept Med, Div Dermatol, Seattle, WA 98195 USA. [Moon, Randall T.] Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA. [Moore, Erin C.; Major, Michael B.; Moon, Randall T.] Natl Canc Ctr, Howard Hughes Med Inst, Bethesda, MD 20815 USA. [Moore, Erin C.; Major, Michael B.; Moon, Randall T.] Natl Canc Ctr, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20815 USA. [Rothberg, Bonnie Gould; Berger, Aaron J.; Rimm, David L.] Yale Univ, Dept Pathol, New Haven, CT 06520 USA. RP Moon, RT (reprint author), Univ Washington, Sch Med, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. EM rtmoon@u.washington.edu RI Moon, Randall/B-1743-2014; OI Moon, Randall/0000-0002-9352-1408; Major, Michael/0000-0002-6753-8513 FU National Institutes of Health-German Research Foundation; Center for Cancer Research; American Skin Association; Dermatology Foundation; National Cancer Institute FX E. M. was supported as a Medical Fellow, M. M. as an Associate, and R. M. as an Investigator by the Howard Hughes Medical Institute. A. L. is funded by a National Institutes of Health-German Research Foundation Research Career Transition Award. Research support was provided in part by intramural research funds from the Center for Cancer Research ( to S. H. and A. L.). A. C. received funding support through a Research Scholar Award from the American Skin Association, a Career Award from the Dermatology Foundation, and a K08 Career Development Award from the National Cancer Institute. We thank Sancy Leachman, Pamela Cassidy, and Brett Milash at the University of Utah for their assistance in facilitating our microarray studies. We also thank the staff of the University of Washington Department of Biostatistics for their consultative guidance in our statistical analysis. NR 53 TC 157 Z9 167 U1 0 U2 5 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 JAN 27 PY 2009 VL 106 IS 4 BP 1193 EP 1198 DI 10.1073/pnas.0811902106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399XC UT WOS:000262831600043 PM 19144919 ER PT J AU Wang, GJ Volkow, ND Telang, F Jayne, M Ma, YM Pradhan, K Zhu, W Wong, CT Thanos, PK Geliebter, A Biegon, A Fowler, JS AF Wang, Gene-Jack Volkow, Nora D. Telang, Frank Jayne, Millard Ma, Yeming Pradhan, Kith Zhu, Wei Wong, Christopher T. Thanos, Panayotis K. Geliebter, Allan Biegon, Anat Fowler, Joanna S. TI Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amygdala; cognitive inhibition; food stimuli; Orbitofrontal cortex ID MEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; NUCLEUS-ACCUMBENS; MENSTRUAL-CYCLE; BASOLATERAL AMYGDALA; NEURAL RESPONSES; DORSAL STRIATUM; EATING BEHAVIOR; REWARD; DOPAMINE AB Although impaired inhibitory control is linked to a broad spectrum of health problems, including obesity, the brain mechanism(s) underlying voluntary control of hunger are not well understood. We assessed the brain circuits involved in voluntary inhibition of hunger during food stimulation in 23 fasted men and women using PET and 2-deoxy-2[ (18)F] fluoro-D-glucose ((18)FDG). In men, but not in women, food stimulation with inhibition significantly decreased activation in amygdala, hippocampus, insula, orbitofrontal cortex, and striatum, which are regions involved in emotional regulation, conditioning, and motivation. The suppressed activation of the orbitofrontal cortex with inhibition in men was associated with decreases in self-reports of hunger, which corroborates the involvement of this region in processing the conscious awareness of the drive to eat. This finding suggests a mechanism by which cognitive inhibition decreases the desire for food and implicates lower ability to suppress hunger in women as a contributing factor to gender differences in obesity. C1 [Wang, Gene-Jack; Wong, Christopher T.; Biegon, Anat; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Wang, Gene-Jack; Fowler, Joanna S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Volkow, Nora D.; Telang, Frank; Jayne, Millard; Ma, Yeming; Thanos, Panayotis K.] NIAAA NIDA, Rockville, MD 20857 USA. [Pradhan, Kith; Zhu, Wei] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. [Geliebter, Allan] St Lukes Roosevelt Hosp, New York, NY 10025 USA. RP Wang, GJ (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM gjwang@bnl.gov FU Department of Energy OBER [DE-ACO2 -98CH10886]; National Institute on Drug Abuse [DA6891, DA6278]; National Institute on Alcohol Abuse and Alcoholism [AA9481, Y1AA3009]; General Clinical Research Center at Stony Brook University Hospital [NIH MO1RR 10710] FX We thank all of the subjects who participated in this study. We also thank K. Torres for Institutional Review Board correspondence and study compliance; D. Schlyer and M. Schueller for Cyclotron operations; D. Alexoff, P. Vaska, and D. Warner for PET operations; C. Shea, Y. Xu, L. Muench, and P. King for radiotracer preparation and analysis; P. Carter and B. Hubbard for patient care and A. Ruggiero for manuscript submission. This work was supported by the Department of Energy OBER (DE-ACO2 -98CH10886), National Institute on Drug Abuse (DA6891 & DA6278), National Institute on Alcohol Abuse and Alcoholism (AA9481 & Y1AA3009), and the General Clinical Research Center at Stony Brook University Hospital (NIH MO1RR 10710). NR 64 TC 109 Z9 111 U1 1 U2 16 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 JAN 27 PY 2009 VL 106 IS 4 BP 1249 EP 1254 DI 10.1073/pnas.0807423106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399XC UT WOS:000262831600053 PM 19164587 ER PT J AU Nagappan, G Zaitsev, E Senatorov, VV Yang, JM Hempstead, BL Lu, B AF Nagappan, Guhan Zaitsev, Eugene Senatorov, Vladimir V., Jr. Yang, Jianmin Hempstead, Barbara L. Lu, Bai TI Control of extracellular cleavage of ProBDNF by high frequency neuronal activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BDNF; hippocampus; LTP; proteases; tPA ID ACTIVITY-DEPENDENT RELEASE; TISSUE-PLASMINOGEN ACTIVATOR; LONG-TERM-POTENTIATION; NERVE GROWTH-FACTOR; NEUROTROPHIC FACTOR; HIPPOCAMPAL-NEURONS; BDNF; PLASTICITY; SECRETION; LTP AB Pro-and mature neurotrophins often elicit opposing biological effects. For example, mature brain-derived neurotrophic factor (mBDNF) is critical for long-term potentiation induced by high-frequency stimulation, whereas proBDNF facilitate long-term depression induced by low-frequency stimulation. Because mBDNF is derived from proBDNF by endoproteolytic cleavage, mechanisms regulating the cleavage of proBDNF may control the direction of BDNF regulation. Using methods that selectively detect proBDNF or mBDNF, we show that low-frequency stimulation induced predominant proBDNF secretion in cultured hippocampal neurons. In contrast, high-frequency stimulation preferentially increased extracellular mBDNF. Inhibition of extracellular, but not intracellular cleavage of proBDNF greatly reduced high-frequency stimulation-induced extracellular mBDNF. Moreover, high-frequency, but not low-frequency stimulation selectively induced the secretion of tissue plasminogen activator, a key protease involved in extracellular proBDNF to mBDNF conversion. Thus, high-frequency neuronal activity controls the ratio of extracellular proBDNF/mBDNF by regulating the secretion of extracellular proteases. Our study demonstrates activity-dependent control of extracellular proteolytic cleavage of a secretory protein, and reveals an important mechanism that controls diametrically opposed functions of BDNF isoforms. C1 [Nagappan, Guhan; Zaitsev, Eugene; Senatorov, Vladimir V., Jr.; Lu, Bai] NICHHD, Sect Neural Dev & Plast, Gene Cognit & Psychosis Program, NIMH,NIH, Bethesda, MD 20892 USA. [Yang, Jianmin; Hempstead, Barbara L.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, Gene Cognit & Psychosis Program, NIMH,NIH, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012 FU Intramural Research Programs of National Institute of Child Health; National Institue of Mental Health FX We thank Drs. Newton Woo and Keri Martinowich for their thoughtful comments and suggestions. The rat tPA-Venus in the pEGFP-N1 vector was kindly provided by Dr. Wolfhard Almers. Microscopy imaging was performed at the Microscopy & Imaging Core (National Institute of Child Health and Development, National Institutes of Health) with the assistance of Dr. Vincent Schram. This work is supported by the Intramural Research Programs of National Institute of Child Health and National Institue of Mental Health. NR 34 TC 115 Z9 119 U1 0 U2 7 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 JAN 27 PY 2009 VL 106 IS 4 BP 1267 EP 1272 DI 10.1073/pnas.0807322106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399XC UT WOS:000262831600056 PM 19147841 ER PT J AU Li, YZ Perry, T Kindy, MS Harvey, BK Tweedie, D Holloway, HW Powers, K Shen, H Egan, JM Sambamurti, K Brossi, A Lahiri, DK Mattson, MP Hoffer, BJ Wang, Y Greig, NH AF Li, Yazhou Perry, TracyAnn Kindy, Mark S. Harvey, Brandon K. Tweedie, David Holloway, Harold W. Powers, Kathleen Shen, Hui Egan, Josephine M. Sambamurti, Kumar Brossi, Arnold Lahiri, Debomoy K. Mattson, Mark P. Hoffer, Barry J. Wang, Yun Greig, Nigel H. TI GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diabetes; exendin-4; neurodegeneration; neuroprotection; stroke ID GLUCAGON-LIKE PEPTIDE-1; NERVE GROWTH-FACTOR; CEREBELLAR GRANULE NEURONS; DIABETES-MELLITUS; CYCLIC-AMP; CEREBRAL-ISCHEMIA; ANIMAL-MODEL; IN-VITRO; APOPTOSIS; DISEASE AB Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved to treat T2DM. GLP-1Rs are coupled to the cAMP second messenger pathway and, along with pancreatic cells, are expressed within the nervous system of rodents and humans, where receptor activation elicits neurotrophic actions. We detected GLP-1R mRNA expression in both cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons. These cells are vulnerable to hypoxia-and 6-hydroxydopamine-induced cell death, respectively. We found that GLP-1 and Ex-4 conferred protection in these cells, but not in cells from Glp1r knockout (-/-) mice. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model. Ex-4 treatment also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and PD. C1 [Li, Yazhou; Perry, TracyAnn; Tweedie, David; Holloway, Harold W.; Mattson, Mark P.; Greig, Nigel H.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Kindy, Mark S.; Sambamurti, Kumar] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Kindy, Mark S.] Neurol Testing Serv, Mt Pleasant, SC 29466 USA. [Harvey, Brandon K.; Powers, Kathleen; Shen, Hui; Wang, Yun] Natl Inst Drug Abuse, Mol Neuropsychiat Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Egan, Josephine M.] NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Brossi, Arnold] Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. [Lahiri, Debomoy K.] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Hoffer, Barry J.] Natl Inst Drug Abuse, Cellular Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Greig, NH (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM greign@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural Research Programs of the National Institute on Aging and the National Institute on Drug Abuse FX This work was supported in part by the Intramural Research Programs of the National Institute on Aging and the National Institute on Drug Abuse. Animal studies were performed in accordance with approved protocols, in compliance with the National Institutes of Health's Guidelines for Animal Experimentation. Daniel J. Drucker, MD, University of Toronto, kindly provided the Glp1r-/- mice. NR 44 TC 199 Z9 212 U1 0 U2 21 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 JAN 27 PY 2009 VL 106 IS 4 BP 1285 EP 1290 DI 10.1073/pnas.0806720106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399XC UT WOS:000262831600059 PM 19164583 ER PT J AU Volfovsky, N Oleksyk, TK Cruz, KC Truelove, AL Stephens, RM Smith, MW AF Volfovsky, Natalia Oleksyk, Taras K. Cruz, Kristine C. Truelove, Ann L. Stephens, Robert M. Smith, Michael W. TI Genome and gene alterations by insertions and deletions in the evolution of human and chimpanzee chromosome 22 SO BMC GENOMICS LA English DT Article ID DNA-SEQUENCES; HAPLOTYPE MAP; DISEASE; POLYMORPHISM; DIVERGENCE; INDELS; DUPLICATIONS; ALIGNMENT; MAJORITY; ELEMENTS AB Background: Understanding structure and function of human genome requires knowledge of genomes of our closest living relatives, the primates. Nucleotide insertions and deletions (indels) play a significant role in differentiation that underlies phenotypic differences between humans and chimpanzees. In this study, we evaluated distribution, evolutionary history, and function of indels found by comparing syntenic regions of the human and chimpanzee genomes. Results: Specifically, we identified 6,279 indels of 10 bp or greater in a similar to 33 Mb alignment between human and chimpanzee chromosome 22. After the exclusion of those in repetitive DNA, 1,429 or 23% of indels still remained. This group was characterized according to the local or genome-wide repetitive nature, size, location relative to genes, and other genomic features. We defined three major classes of these indels, using local structure analysis: (i) those indels found uniquely without additional copies of indel sequence in the surrounding (10 Kb) region, (ii) those with at least one exact copy found nearby, and (iii) those with similar but not identical copies found locally. Among these classes, we encountered a high number of exactly repeated indel sequences, most likely due to recent duplications. Many of these indels (683 of 1,429) were in proximity of known human genes. Coding sequences and splice sites contained significantly fewer of these indels than expected from random expectations, suggesting that selection is a factor in limiting their persistence. A subset of indels from coding regions was experimentally validated and their impacts were predicted based on direct sequencing in several human populations as well as chimpanzees, bonobos, gorillas, and two subspecies of orangutans. Conclusion: Our analysis demonstrates that while indels are distributed essentially randomly in intergenic and intronic genomic regions, they are significantly under-represented in coding sequences. There are substantial differences in representation of indel classes among genomic elements, most likely caused by differences in their evolutionary histories. Using local sequence context, we predicted origins and phylogenetic relationships of gene-impacting indels in primate species. These results suggest that genome plasticity is a major force behind speciation events separating the great ape lineages. C1 [Oleksyk, Taras K.; Cruz, Kristine C.; Truelove, Ann L.; Smith, Michael W.] NCI, Lab Genom Divers, Ft Detrick, MD 21702 USA. [Volfovsky, Natalia; Stephens, Robert M.] NCI, Adv Biochem Comp Ctr, Adv Technol Program, SAIC Frederick, Ft Detrick, MD 21702 USA. [Oleksyk, Taras K.; Truelove, Ann L.; Smith, Michael W.] NCI, Basic Res Program, SAIC Frederick, Ft Detrick, MD 21702 USA. [Oleksyk, Taras K.; Truelove, Ann L.; Smith, Michael W.] Univ Puerto Rico, Dept Biol, Mayaguez, PR 00681 USA. RP Smith, MW (reprint author), NCI, Lab Genom Divers, Ft Detrick, MD 21702 USA. EM natalia@ncifcrf.gov; dna@uprm.edu; cruzkc@gmail.com; anntruelove@gmail.com; bobs@ncifcrf.gov; smithm@ncifcrf.gov RI Smith, Michael/B-5341-2012; Taras, Oleksyk/J-8805-2013 OI Taras, Oleksyk/0000-0002-8148-3918 FU National Cancer Institute; National Institutes of Health [N01-CO-12400] FX We thank the patients and staff of all the participating cohorts in the study. We thank Drs. Cheryl Winkler, Michael Dean, and Mary Carrington for helpful insights in developing the ideas for this manuscript. We are also grateful to Randy Johnson, Kai Zhao, Bailey Kessing, and Michael Malasky for their assistance. We would like to thank Maritta Grau and Allen Kane from SAIC- Frederick Scientific Publications, Graphics and Media for their help with writing and the display items. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. The project included in this manuscript 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. NR 48 TC 6 Z9 7 U1 0 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 JAN 26 PY 2009 VL 10 AR 51 DI 10.1186/1471-2164-10-51 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 430EE UT WOS:000264970800001 PM 19171065 ER PT J AU Taylor-Cousar, JL Zariwala, MA Burch, LH Pace, RG Drumm, ML Calloway, H Fan, HY Weston, BW Wright, FA Knowles, MR AF Taylor-Cousar, Jennifer L. Zariwala, Maimoona A. Burch, Lauranell H. Pace, Rhonda G. Drumm, Mitchell L. Calloway, Hollin Fan, Haiying Weston, Brent W. Wright, Fred A. Knowles, Michael R. CA Gene Modifier Study Grp TI Histo-Blood Group Gene Polymorphisms as Potential Genetic Modifiers of Infection and Cystic Fibrosis Lung Disease Severity SO PLOS ONE LA English DT Article AB Background: The pulmonary phenotype in cystic fibrosis (CF) is variable; thus, environmental and genetic factors likely contribute to clinical heterogeneity. We hypothesized that genetically determined ABO histo-blood group antigen (ABH) differences in glycosylation may lead to differences in microbial binding by airway mucus, and thus predispose to early lung infection and more severe lung disease in a subset of patients with CF. Methods and Principal Findings: Clinical information and DNA was collected on > 800 patients with the Delta F508/Delta F508 genotype. Patients in the most severe and mildest quartiles for lung phenotype were enrolled. Blood samples underwent lymphocyte transformation and DNA extraction using standard methods. PCR and sequencing were performed using standard techniques to identify the 9 SNPs required to determine ABO blood type, and to identify the four SNPs that account for 90-95% of Lewis status in Caucasians. Allele identification of the one nonsynonymous SNP in FUT2 that accounts for > 95% of the incidence of nonsecretor phenotype in Caucasians was completed using an ABI Taqman assay. The overall prevalence of ABO types, and of FUT2 (secretor) and FUT 3 (Lewis) alleles was consistent with that found in the Caucasian population. There was no difference in distribution of ABH type in the severe versus mild patients, or the age of onset of Pseudomonas aeruginosa infection in the severe or mild groups. Multivariate analyses of other clinical phenotypes, including gender, asthma, and meconium ileus demonstrated no differences between groups based on ABH type. Conclusions and Significance: Polymorphisms in the genes encoding ABO blood type, secretor or Lewis genotypes were not shown to associate with severity of CF lung disease, or age of onset of P. aeruginosa infection, nor was there any association with other clinical phenotypes in a group of 808 patients homozygous for the Delta F508 mutation. C1 Univ New Mexico, Hlth Sci Ctr, Div Pulm, Albuquerque, NM 87131 USA. [Zariwala, Maimoona A.; Pace, Rhonda G.; Calloway, Hollin; Knowles, Michael R.] Univ N Carolina, Cystic Fibrosis Pulmonary Res & Treatment Ctr, Chapel Hill, NC USA. [Burch, Lauranell H.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Wright, Fred A.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Fan, Haiying; Weston, Brent W.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Drumm, Mitchell L.] Case Western Reserve Univ, Dept Pediat, Div Pediat Pulmonary, Cleveland, OH 44106 USA. RP Taylor-Cousar, JL (reprint author), Univ New Mexico, Hlth Sci Ctr, Div Pulm, Albuquerque, NM 87131 USA. EM JTCousar@salud.unm.edu FU NIH [HL068890, 1F32HL082207-01]; GlaxoSmithKline Pulmonary Fellowship Award FX This work was supported by NIH HL068890, NIH 1F32HL082207-01, and the GlaxoSmithKline Pulmonary Fellowship Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 19 Z9 20 U1 2 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 JAN 26 PY 2009 VL 4 IS 1 BP CP5 EP U11 AR e4270 DI 10.1371/journal.pone.0004270 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437JE UT WOS:000265482800001 PM 19169360 ER PT J AU Loucks, FA Schroeder, EK Zommer, AE Hilger, S Kelsey, NA Bouchard, RJ Blackstone, C Brewster, JL Linseman, DA AF Loucks, F. Alexandra Schroeder, Emily K. Zommer, Amelia E. Hilger, Shea Kelsey, Natalie A. Bouchard, Ron J. Blackstone, Craig Brewster, Jay L. Linseman, Daniel A. TI Caspases indirectly regulate cleavage of the mitochondrial fusion GTPase OPA1 in neurons undergoing apoptosis SO BRAIN RESEARCH LA English DT Article DE Optic atrophy type 1 (OPA1); Dynamin GTPase; Mitochondrial fusion; Apoptosis; Caspase; Cerebellar granule neuron ID CEREBELLAR GRANULE NEURONS; DYNAMIN-RELATED PROTEIN; DOMINANT OPTIC ATROPHY; CYTOCHROME-C RELEASE; INDUCED CELL-DEATH; PROTEOLYTIC CLEAVAGE; OXIDATIVE STRESS; MAMMALIAN-CELLS; MESSENGER-RNA; NITRIC-OXIDE AB The critical processes of mitochondrial fission and fusion are regulated by members of the dynamin family of GTPases. Imbalances in mitochondrial fission and fusion contribute to neuronal cell death. For example, increased fission mediated by the dynamin-related GTPase, Drp1, or decreased fusion resulting from inactivating mutations in the OPA1 GTPase, causes neuronal apoptosis and/or neurodegeneration. Recent studies indicate that post-translational processing regulates OPA1 function in non-neuronal cells and moreover, aberrant processing of OPA1 is induced during apoptosis. To date, the post-translational processing of OPA1 during neuronal apoptosis has not been examined. Here, we show that cerebellar granule neurons (CGNs) or neuroblastoma cells exposed to pro-apoptotic stressors display a novel N-terminal cleavage of OPA1 which is blocked by either pan-caspase or caspase-8 selective inhibitors. OPA1 cleavage occurs concurrently with mitochondrial fragmentation and cytochrome c release in CGNs deprived of depolarizing potassium (5K condition). Although a caspase-8 selective inhibitor prevents both 5K-induced OPA1 cleavage and mitochondrial fragmentation, recombinant caspase-8 fails to cleave OPA1 in vitro. In marked contrast, either caspase-8 or caspase-3 stimulates OPA1 cleavage in digitonin-permeabilized rat brain mitochondria, suggesting that OPA1 is cleaved by an intermembrane space protease which is regulated by active caspases. Finally, the N-terminal truncation of OPA1 induced during neuronal apoptosis removes an essential residue (K301) within the GTPase domain. These data are the first to demonstrate OPA1 cleavage during neuronal apoptosis and they implicate caspases as indirect regulators of OPA1 processing in degenerating neurons. Published by Elsevier B.V. C1 [Zommer, Amelia E.; Kelsey, Natalie A.; Linseman, Daniel A.] Univ Denver, Dept Biol Sci, Denver, CO 80208 USA. [Zommer, Amelia E.; Kelsey, Natalie A.; Linseman, Daniel A.] Univ Denver, Eleanor Roosevelt Inst, Denver, CO 80208 USA. [Loucks, F. Alexandra; Schroeder, Emily K.; Bouchard, Ron J.; Linseman, Daniel A.] Vet Affairs Med Ctr, Res Serv, Denver, CO USA. [Hilger, Shea; Brewster, Jay L.] Pepperdine Univ, Div Nat Sci, Malibu, CA 90265 USA. [Blackstone, Craig] Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, NIH, Bethesda, MD USA. [Linseman, Daniel A.] Univ Colorado, Hlth Sci Ctr, Dept Med, Div Clin Pharmacol & Toxicol, Denver, CO 80262 USA. RP Linseman, DA (reprint author), Univ Denver, Dept Biol Sci, FW Olin Hall,Rm 102,2190 E Iliff Ave, Denver, CO 80208 USA. EM daniel.linseman@du.edu FU Department of Veterans Affairs; National Institutes of Health FX This study was supported by a Merit Review grant from the Department of Veterans Affairs (to D.A.L.) and an AREA grant from the National Institutes of Health (to J.L.B.). We thank Dr. Klaus Aktories and Dr. Torsten Giesemann for C. difficile toxin B and Dr. Stephen Fisher for SH-SY5Y cells. We acknowledge Shoshona Le, Angela Zimmermann, and Ingrid Anderson for technical assistance. NR 41 TC 11 Z9 12 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 23 PY 2009 VL 1250 BP 63 EP 74 DI 10.1016/j.brainres.2008.10.081 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 407WI UT WOS:000263394600007 PM 19046944 ER PT J AU Macova, M Pavel, J Saavedra, JM AF Macova, Miroslava Pavel, Jaroslav Saavedra, Juan M. TI A peripherally administered, centrally acting angiotensin II AT(2) antagonist selectively increases brain AT(1) receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH SO BRAIN RESEARCH LA English DT Article DE Brain Angiotensin II receptor; Central sympathetic system; Pituitary hormone; Locus coeruleus; Paraventricular nucleus; Inferior olive ID SPONTANEOUSLY HYPERTENSIVE-RATS; GENE-DISRUPTED MICE; MESSENGER-RNA EXPRESSION; TYPE-2 RECEPTOR; BLOOD-PRESSURE; NORMOTENSIVE RATS; ISOLATION STRESS; PASTE STANDARDS; AT1; SUBTYPES AB The physiological actions of brain Angiotensin II AT(2) receptors and their relationship to Angiotensin II AT(1) receptors remain controversial. To further clarify their role, we determined to what extent systemic administration of an AT(2) receptor antagonist affected AT(2) receptor binding within the brain and the expression of AT(1) receptors. For this purpose, we subcutaneously administered the AT(2) receptor antagonist PD123319 (1 mg/kg/day) to adult male rats for two weeks via osmotic minipumps. We also studied the content of pituitary adrenocorticotropic hormone and vasopressin, representative of hypothalamic-pituitary-adrenal axis activation, and the tyrosine hydroxylase gene expression in the locus coeruleus as a measure of central norepinephrine function. We found significant decreases in AT(2) receptor binding in brain areas inside the blood brain barrier, the inferior olive and the locus coeruleus. AT(2) receptor blockade increased AT(1) receptor binding and mRNA expression not only in the subfornical organ and the median eminence, situated outside the blood brain barrier, but also in the hypothalamic paraventricular nucleus, located inside the blood brain barrier. These changes paralleled decreased expression of tyrosine hydroxylase mRNA in the locus coeruleus and decreased pituitary adrenocorticotropic and vasopressin content. Our results demonstrate that sustained peripheral administration of an AT(2) antagonist decreases binding to brain AT(2) receptors, indicating that this drug is a useful tool for the study of their central role. AT(2) receptor activity inhibition up-regulates AT(1) receptor expression in specific brain areas. Blockade of brain AT(2) receptors is compatible with enhanced hypothalamic-pituitary-adrenal axis and decreased central sympathetic system activity. Published by Elsevier B.V. C1 [Macova, Miroslava; Pavel, Jaroslav; Saavedra, Juan M.] NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov FU Division of intramural Research Programs, National institute of Mental Health, Department of Health and Human Services, USA FX This study was supported by the Division of intramural Research Programs, National institute of Mental Health, Department of Health and Human Services, USA. NR 56 TC 20 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 23 PY 2009 VL 1250 BP 130 EP 140 DI 10.1016/j.brainres.2008.11.006 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 407WI UT WOS:000263394600014 PM 19038235 ER PT J AU Forgacs, E Sakamoto, T Cartwright, S Belknap, B Kovacs, M Toth, J Webb, MR Sellers, JR White, HD AF Forgacs, Eva Sakamoto, Takeshi Cartwright, Suzanne Belknap, Betty Kovacs, Mihaly Toth, Judit Webb, Martin R. Sellers, James R. White, Howard D. TI Switch 1 Mutation S217A Converts Myosin V into a Low Duty Ratio Motor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KINETIC MECHANISM; NECK LENGTH; ACTOMYOSIN; PROCESSIVITY; PHOSPHATE; DOMAIN; ACTIN; ADP; NUCLEOTIDE; RESOLUTION AB We have determined the kinetic mechanism and motile properties of the switch 1 mutant S217A of myosin Va. Phosphate dissociation from myosin V-ADP-P(i) (inorganic phosphate) and actomyosin V-ADP-P(i) and the rate of the hydrolysis step ( myosin V-ATP -> myosin V-ADP-P(i)) were all similar to 10-fold slower in the S217A mutant than in wild type (WT) myosin V, resulting in a slower steady-state rate of basal and filamentous actin (actin)-activated ATP hydrolysis. Substrate binding and ADP dissociation kinetics were all similar to or slightly faster in S217A than in WT myosin V and mechanochemical gating of the rates of dissociation of ADP between trail and lead heads is maintained. The reduction in the rate constants of the hydrolysis and phosphate dissociation steps reduces the duty ratio from similar to 0.85 in WT myosin V to similar to 0.25 in S217A and produces a motor in which the average run length on actin at physiological concentrations of ATP is reduced 10-fold. Thus we demonstrate that, by mutational perturbation of the switch 1 structure, myosin V can be converted into a low duty ratio motor that is processive only at low substrate concentrations. C1 [Forgacs, Eva; Cartwright, Suzanne; Belknap, Betty; White, Howard D.] Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23507 USA. [Webb, Martin R.] Natl Inst Med Res, Div Phys Biochem, London NW7 1AA, England. [Sakamoto, Takeshi; Kovacs, Mihaly; Toth, Judit; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Kovacs, Mihaly] Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. [Toth, Judit] Hungarian Acad Sci, Biol Res Ctr, Inst Enzymol, H-1113 Budapest, Hungary. RP White, HD (reprint author), Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23507 USA. EM whitehd@evms.edu RI Kovacs, Mihaly/A-6841-2011 FU National Institutes of Health [EB00209] FX This work was supported, in whole or in part, by National Institutes of Health Grant EB00209 ( to H. D. W.). NR 37 TC 19 Z9 19 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 23 PY 2009 VL 284 IS 4 BP 2138 EP 2149 DI 10.1074/jbc.M805530200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 395TE UT WOS:000262545600023 PM 19008235 ER PT J AU Utreras, E Futatsugi, A Rudrabhatla, P Keller, J Iadarola, MJ Pant, HC Kulkarni, AB AF Utreras, Elias Futatsugi, Akira Rudrabhatla, Parvathi Keller, Jason Iadarola, Michael J. Pant, Harish C. Kulkarni, Ashok B. TI Tumor Necrosis Factor-alpha Regulates Cyclin-dependent Kinase 5 Activity during Pain Signaling through Transcriptional Activation of p35 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NERVE GROWTH-FACTOR; TNF-ALPHA; PC12 CELLS; INFLAMMATORY HYPERALGESIA; NEUROPATHIC PAIN; MESSENGER-RNA; UP-REGULATION; SPINAL-CORD; CDK5; PHOSPHORYLATION AB Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/ threonine kinase. We have previously reported that Cdk5 participates in the regulation of nociceptive signaling, and the expression of Cdk5 and its activator, p35, are up-regulated in nociceptive neurons during peripheral inflammation. The aim of our current study was to identify the proinflammatory molecules that regulate Cdk5/p35 activity in response to inflammation. We constructed a vector that contains the mouse p35 promoter driving luciferase expression. We transiently transfected this vector in PC12 cells to test the effect of several cytokines on p35 transcriptional activity and Cdk5 activity. Our results indicate that tumor necrosis factor-alpha (TNF-alpha) activates p35 promoter activity in a dose- and time-dependent manner and concomitantly up-regulates Cdk5 activity. Because TNF-alpha is known to activate ERK1/2, p38 MAPK, JNK, and NF-kappa B signaling pathways, we examined their involvement in the activation of p35 promoter activity. MEK inhibitor, which inhibits ERK activation, decreased p35 promoter activity, whereas the inhibitors of p38 MAPK, JNK, and NF-kappa B increased p35 promoter activity, indicating that these pathways regulate p35 expression differently. The mRNA and protein levels of Egr-1, a transcription factor, were increased by TNF-alpha treatment, and this increase was dependent on ERK signaling. In a mouse model of inflammation-induced pain in which carrageenan injection into the hind paw causes hypersensitivity to heat stimuli, TNF-alpha mRNA was increased at the site of injection. These findings suggest that TNF-alpha-mediated regulation of Cdk5 activity plays an important role in inflammation-induced pain signaling. C1 [Kulkarni, Ashok B.] NIH, LCDB, NIDCR, Funct Gen Sect, Bethesda, MD 20892 USA. [Keller, Jason; Iadarola, Michael J.] NIH, Neurobiol & Pain Therapeut Sect, NIDCR, Bethesda, MD 20892 USA. [Rudrabhatla, Parvathi; Pant, Harish C.] NIH, Neurochem Lab, NINDS, Bethesda, MD 20892 USA. RP Kulkarni, AB (reprint author), NIH, LCDB, NIDCR, Funct Gen Sect, 30 Convent Dr,Bldg 30,Rm 130,MSC 4395, Bethesda, MD 20892 USA. EM ak40m@nih.gov RI utreras, elias/I-1038-2013 OI utreras, elias/0000-0002-1004-0466 FU National Institutes of Health; Division of Intramural Research of NIDCR; NINDS FX This work was supported, in whole or in part, by the National Institutes of Health, Division of Intramural Research of NIDCR and NINDS. 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 46 TC 47 Z9 47 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 23 PY 2009 VL 284 IS 4 BP 2275 EP 2284 DI 10.1074/jbc.M805052200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 395TE UT WOS:000262545600037 PM 19049962 ER PT J AU Martin, B Brenneman, R Golden, E Walent, T Becker, KG Prabhu, VV Wood, W Ladenheim, B Cadet, JL Maudsley, S AF Martin, Bronwen Brenneman, Randall Golden, Erin Walent, Tom Becker, Kevin G. Prabhu, Vinayakumar V. Wood, William, III Ladenheim, Bruce Cadet, Jean-Lud Maudsley, Stuart TI Growth Factor Signals in Neural Cells COHERENT PATTERNS OF INTERACTION CONTROL MULTIPLE LEVELS OF MOLECULAR AND PHENOTYPIC RESPONSES SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENE SET ENRICHMENT; ALPHA-B-CRYSTALLIN; PHEOCHROMOCYTOMA CELLS; NEURONAL DIFFERENTIATION; TYROSINE KINASES; PC12 CELLS; ACTIVATION; EXPRESSION; SHC; PROTEINS AB Individual neurons express receptors for several different growth factors that influence the survival, growth, neurotransmitter phenotype, and other properties of the cell. Although there has been considerable progress in elucidating the molecular signal transduction pathways and physiological responses of neurons and other cells to individual growth factors, little is known about if and how signals from different growth factors are integrated within a neuron. In this study, we determined the interactive effects of nerve growth factor, insulin-like growth factor 1, and epidermal growth factor on the activation status of downstream kinase cascades and transcription factors, cell survival, and neurotransmitter production in neural cells that express receptors for all three growth factors. We document considerable differences in the quality and quantity of intracellular signaling and eventual phenotypic responses that are dependent on whether cells are exposed to a single or multiple growth factors. Dual stimulations that generated the greatest antagonistic or synergistic actions, compared with a theoretically neutral summation of their two activities, yielded the largest eventual change of neuronal phenotype indicated by the ability of the cell to produce norepinephrine or resist oxidative stress. Combined activation of insulin-like growth factor 1 and epidermal growth factor receptors was particularly notable for antagonistic interactions at some levels of signal transduction and norepinephrine production, but potentiation at other levels of signaling and cytoprotection. Our findings suggest that in true physiological settings where multiple growth factors are present, activation of one receptor type may result in molecular and phenotypic responses that are different from that observed in typical experimental paradigms in which cells are exposed to only a single growth factor at a time. C1 [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Ladenheim, Bruce; Cadet, Jean-Lud] Natl Inst Drug Abuse, Mol Psychiat Branch, Baltimore, MD 21224 USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, Neurosci Lab, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health (Intramural Research Program of the NIA). 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 58 TC 22 Z9 22 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 JAN 23 PY 2009 VL 284 IS 4 BP 2493 EP 2511 DI 10.1074/jbc.M804545200 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 395TE UT WOS:000262545600056 PM 19038969 ER PT J AU Sarafianos, SG Marchand, B Das, K Himmel, DM Parniak, MA Hughes, SH Arnold, E AF Sarafianos, Stefan G. Marchand, Bruno Das, Kalyan Himmel, Daniel M. Parniak, Michael A. Hughes, Stephen H. Arnold, Eddy TI Structure and Function of HIV-1 Reverse Transcriptase: Molecular Mechanisms of Polymerization and Inhibition SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE polymerase structure and mechanism; AIDS; drug resistance; drug design; ribonuclease H ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNASE-H DOMAIN; HIGH-LEVEL RESISTANCE; DEPENDENT PRIMER UNBLOCKING; HIGH-RESOLUTION STRUCTURES; POLYMERASE ACTIVE-SITE; ATP-MEDIATED EXCISION; STRAND DNA-SYNTHESIS; RIBONUCLEASE-H; DRUG-RESISTANCE AB The rapid replication of HIV-1 and the errors made during viral replication cause the virus to evolve rapidly in patients, making the problems of vaccine development and drug therapy particularly challenging. In the absence of an effective vaccine, drugs are the only useful treatment. Anti-HIV drugs work; so far drug therapy has saved more than three million years of life. Unfortunately, HIV-1 develops resistance to all of the available drugs. Although a number of useful anti-HIV drugs have been approved for use in patients, the problems associated with drug toxicity and the development of resistance means that the search for new drugs is an ongoing process. The three viral enzymes, reverse transcriptase (RT), integrase (IN), and protease (PR) are all good drug targets. Two distinct types of RT inhibitors, both of which block the polymerase activity of RT, have been approved to treat HIV-1. infections, nucleoside analogs (NRTIs) and nonnucleosides (NNRTIs), and there are promising leads for compounds that either block the RNase H activity or block the polymerase in other ways. A better understanding of the structure and function(s) of RT and of the mechanism(s) of inhibition can be used to generate better drugs; in particular, drugs that are effective against the current drug-resistant strains of HIV-1. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Das, Kalyan; Himmel, Daniel M.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Das, Kalyan; Himmel, Daniel M.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Biol Chem, Piscataway, NJ 08854 USA. [Sarafianos, Stefan G.; Marchand, Bruno] Univ Missouri, Christopher Bond Life Sci Ctr, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. [Parniak, Michael A.] Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. [Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIH [A1076119, AT079801, A1074389, AI27690, P01 GM 066671]; amfAR Mathilde Kim Fellowship grant; Intramural Research Program of NIH; NCI; Center for Cancer Research; NIGMS; NTH [AI060452, AI73975, AI076119, AI07980] FX S.G.S. acknowledges support by NIH (grants A1076119, AT079801, and A1074389). Support for B.M. comes from an amfAR Mathilde Kim Fellowship grant. S.H.H. was supported by the Intramural Research Program of NIH, NCI, Center for Cancer Research, and NIGMS. M.A.R was supported by NTH grants AI060452, AI73975, AI076119, AI07980. E.A. is grateful for support from NIH (grants AI27690 MERIT Award and P01 GM 066671). NR 164 TC 204 Z9 209 U1 4 U2 50 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 JAN 23 PY 2009 VL 385 IS 3 BP 693 EP 713 DI 10.1016/j.jmb.2008.10.071 PG 21 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 402HG UT WOS:000263004200001 PM 19022262 ER PT J AU Kelly-Hope, LA McKenzie, FE AF Kelly-Hope, Louise A. McKenzie, F. Ellis TI The multiplicity of malaria transmission: a review of entomological inoculation rate measurements and methods across sub-Saharan Africa SO MALARIA JOURNAL LA English DT Review ID LINKED-IMMUNOSORBENT-ASSAY; PLASMODIUM-FALCIPARUM TRANSMISSION; SAMPLING ANOPHELINE MOSQUITOS; HUMAN LANDING CATCH; CONTROL LIGHT TRAP; WESTERN KENYA; AFROTROPICAL ANOPHELES; SPOROZOITE DETECTION; HOLOENDEMIC AREA; FIELD-EVALUATION AB Plasmodium falciparum malaria is a serious tropical disease that causes more than one million deaths each year, most of them in Africa. It is transmitted by a range of Anopheles mosquitoes and the risk of disease varies greatly across the continent. The "entomological inoculation rate" is the commonly-used measure of the intensity of malaria transmission, yet the methods used are currently not standardized, nor do they take the ecological, demographic, and socioeconomic differences across populations into account. To better understand the multiplicity of malaria transmission, this study examines the distribution of transmission intensity across sub-Saharan Africa, reviews the range of methods used, and explores ecological parameters in selected locations. It builds on an extensive geo-referenced database and uses geographical information systems to highlight transmission patterns, knowledge gaps, trends and changes in methodologies over time, and key differences between land use, population density, climate, and the main mosquito species. The aim is to improve the methods of measuring malaria transmission, to help develop the way forward so that we can better assess the impact of the large-scale intervention programmes, and rapid demographic and environmental change taking place across Africa. C1 [Kelly-Hope, Louise A.] Univ Liverpool, Liverpool Sch Trop Med, Vector Grp, Liverpool L3 5QA, Merseyside, England. [Kelly-Hope, Louise A.; McKenzie, F. Ellis] Natl Inst Hlth, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies, Bethesda, MD USA. RP Kelly-Hope, LA (reprint author), Univ Liverpool, Liverpool Sch Trop Med, Vector Grp, Liverpool L3 5QA, Merseyside, England. EM Kelly-Hope@liverpool.ac.uk; mckenzel@mail.nih.gov NR 88 TC 80 Z9 81 U1 1 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JAN 23 PY 2009 VL 8 AR 19 DI 10.1186/1475-2875-8-19 PG 16 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 424NQ UT WOS:000264573800001 PM 19166589 ER PT J AU Mitchell, K Yang, HYT Berk, JD Tran, JH Iadarola, MJ AF Mitchell, K. Yang, H. -Y. T. Berk, J. D. Tran, J. H. Iadarola, M. J. TI MONOCYTE CHEMOATTRACTANT PROTEIN-1 IN THE CHOROID PLEXUS: A POTENTIAL LINK BETWEEN VASCULAR PRO-INFLAMMATORY MEDIATORS AND THE CNS DURING PERIPHERAL TISSUE INFLAMMATION SO NEUROSCIENCE LA English DT Article DE BBB; BCSFB; ccl2; cox-2; cytokines; glial cells ID BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; RAT-BRAIN; SPINAL-CORD; MICROGLIAL ACTIVATION; CEREBROSPINAL-FLUID; PROSTAGLANDIN E-2; FREUNDS-ADJUVANT; GLIAL ACTIVATION AB During peripheral tissue inflammation, inflammatory processes in the CNS can be initiated by blood-borne pro-inflammatory mediators. The choroid plexus, the site of cerebrospinal fluid (CSF) production, is a highly specialized interface between the vascular system and CNS, and thus, this structure may be an important element in communication between the vascular compartment and the CNS during peripheral tissue inflammation. We investigated the potential participation of the choroid plexus in this process during peripheral tissue inflammation by examining expression of the small inducible cytokine A2 (SCYA2) gene which codes for monocyte chemoattractant protein-1 (MCP-1). MCPA protein was previously reported to be induced in a variety of cells during peripheral tissue inflammation. In the basal state, SCYA2 is highly expressed in the choroid plexus as compared with other rat CNS tissues. During hind paw inflammation, SCYA2 expression was significantly elevated in choroid plexus, whereas it remained unchanged in a variety of brain regions. The SCYA2-expressing cells were strongly associated with the choroid plexus as vascular depletion of blood cells by whole-body saline flush did not significantly alter SCYA2 expression in the choroid plexus. In situ hybridization suggested that the SCYA2-expressing cells were localized to the choroid plexus stroma. To elucidate potential molecular mechanisms of SCYA2 increase, we examined genes in the nuclear factor-kappa B (NF-kappa B) signaling cascade including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1 beta) and inhibitor of kappa B alpha (I kappa B alpha) in choroid tissue. Given that we also detected increased levels of MCPA protein by ELISA, we sought to identify potential downstream targets of MCPA and observed altered expression levels of mRNAs encoding tight junction proteins TJP2 and claudin 5. Finally, we detected a substantial up-regulation of the transcript encoding endothelial leukocyte adhesion molecule 1 (E-selectin), a molecule which could participate in leukocyte recruitment to the choroid plexus along with MCP-1. Together, these results suggest that profound changes occur in the choroid plexus during peripheral tissue inflammation, likely initiated by blood-borne inflammatory mediators, which may modify events in CNS. Published by Elsevier Ltd on behalf of IBRO. C1 [Mitchell, K.; Yang, H. -Y. T.; Berk, J. D.; Tran, J. H.; Iadarola, M. J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Iadarola, MJ (reprint author), Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, NIH, Dept Hlth & Human Serv, Bldg 49,Room 1C20,49 Convent Dr,MSC 4410, Bethesda, MD 20892 USA. EM miadarola@dir.nidcr.nih.gov FU Intramural Research Program; NIDCR; NIH; DHHS FX This research was supported by the Intramural Research Program, NIDCR, NIH, DHHS. NR 46 TC 25 Z9 26 U1 0 U2 3 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 JAN 23 PY 2009 VL 158 IS 2 BP 885 EP 895 DI 10.1016/j.neuroscience.2008.10.047 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 401RP UT WOS:000262959900051 PM 19032979 ER PT J AU Sabado, RL Kavanagh, DG Kaufmann, DE Fru, K Babcock, E Rosenberg, E Walker, B Lifson, J Bhardwaj, N Larsson, M AF Sabado, Rachel Lubong Kavanagh, Daniel G. Kaufmann, Daniel E. Fru, Karlhans Babcock, Ethan Rosenberg, Eric Walker, Bruce Lifson, Jeffrey Bhardwaj, Nina Larsson, Marie TI In Vitro Priming Recapitulates In Vivo HIV-1 Specific T Cell Responses, Revealing Rapid Loss of Virus Reactive CD4(+) T Cells in Acute HIV-1 Infection SO PLOS ONE LA English DT Article AB Background: The requirements for priming of HIV-specific T cell responses initially seen in infected individuals remain to be defined. Activation of T cell responses in lymph nodes requires cell-cell contact between T cells and DCs, which can give concurrent activation of T cells and HIV transmission. Methodology: The study aim was to establish whether DCs pulsed with HIV-1 could prime HIV-specific T cell responses and to characterize these responses. Both infectious and aldrithiol-2 inactivated noninfectious HIV-1 were compared to establish efficiencies in priming and the type of responses elicited. Findings: Our findings show that both infectious and inactivated HIV-1 pulsed DCs can prime HIV-specific responses from naive T cells. Responses included several CD4(+) and CD8(+) T cell epitopes shown to be recognized in vivo by acutely and chronically infected individuals and some CD4(+) T cell epitopes not identified previously. Follow up studies of acute and recent HIV infected samples revealed that these latter epitopes are among the earliest recognized in vivo, but the responses are lost rapidly, presumably through activation-induced general CD4(+) T cell depletion which renders the newly activated HIV-specific CD4(+) T cells prime targets for elimination. Conclusion: Our studies highlight the ability of DCs to efficiently prime naive T cells and induce a broad repertoire of HIV-specific responses and also provide valuable insights to the pathogenesis of HIV-1 infection in vivo. C1 [Babcock, Ethan; Bhardwaj, Nina] NYU, Sch Med, New York, NY 10003 USA. [Kavanagh, Daniel G.; Kaufmann, Daniel E.; Rosenberg, Eric; Walker, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, PARC, Charlestown, MA USA. [Lifson, Jeffrey] NCI, NIH, SAIC Fredrick Inc, Frederick, MD USA. [Fru, Karlhans; Larsson, Marie] Linkoping Univ, Dept Clin & Expt Med, S-58183 Linkoping, Sweden. RP Sabado, RL (reprint author), NYU, Sch Med, New York, NY 10003 USA. EM marla@imk.liu.se FU The Swedish Research Council; The Swedish, Physicians against AIDS research Foundation; The Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University hospital research Fund; C ALF; The Swedish Society of Medicine; Emerald Foundation; Burroughs Wellcome; Elizabeth Glaser Pediatric AIDS Foundation; Bill and Melinda Gates Foundation; Center for HIV/AIDS Vaccine Initiative (CHAVI); NIH [AI52731, AI55274, AI61684, AI57127, AI44628]; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX All below funders have provided funding for performing this study. This work has been supported by grants through: ML: AI52731, The Swedish Research Council, The Swedish, Physicians against AIDS research Foundation, The Swedish International Development Cooperation Agency; SIDA SARC, VINNMER for Vinnova, Linkoping University hospital research Fund, C ALF, and The Swedish Society of Medicine. NB: Emerald Foundation, Burroughs Wellcome, Elizabeth Glaser Pediatric AIDS Foundation, Bill and Melinda Gates Foundation and the Center for HIV/AIDS Vaccine Initiative (CHAVI) and NIH grants AI52731, AI55274, AI61684, AI57127, and AI44628. JL: 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 of 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 63 TC 24 Z9 24 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 JAN 23 PY 2009 VL 4 IS 1 AR e4256 DI 10.1371/journal.pone.0004256 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437JD UT WOS:000265482400004 ER PT J AU Yong, ASM Keyvanfar, K Hensel, N Eniafe, R Savani, BN Berg, M Lundqvist, A Adams, S Sloand, EM Goldman, JM Childs, R Barrett, AJ AF Yong, Agnes S. M. Keyvanfar, Keyvan Hensel, Nancy Eniafe, Rhoda Savani, Bipin N. Berg, Maria Lundqvist, Andreas Adams, Sharon Sloand, Elaine M. Goldman, John M. Childs, Richard Barrett, A. John TI Primitive quiescent CD34(+) cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; COMPLETE CYTOGENETIC REMISSION; DONOR LYMPHOCYTE INFUSIONS; APOPTOSIS-INDUCING LIGAND; T-CELLS; CHRONIC-PHASE; PROGENITOR-CELLS; STEM-CELLS; PROTEASOME INHIBITION; TUMOR-CYTOTOXICITY AB Primitive quiescent CD34(+) chronic myeloid leukemia (CML) cells are more biologically resistant to tyrosine kinase inhibitors than their cycling counterparts; however, graft-versus-leukemia (GVL) effects after allogeneic stem cell transplantation (SCT) probably eliminate even these quiescent cells in long-term surviving CML transplant recipients. We studied the progeny of CD34(+) cells from CML patients before SCT, which were cultured 4 days in serum-free media with hematopoietic growth factors. BCR-ABL expression was similar in both cycling and quiescent noncycling CD34(+) populations. Quiescent CD34(+) cells from CML patients were less susceptible than their cycling CD34(+) and CD34(-) counterparts to lysis by natural killer (NK) cells from their HLA-identical sibling donors. Compared with cycling populations, quiescent CD34(+) CML cells had higher surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. Bortezomib upregulated TRAIL receptor expression on quiescent CD34(+) CML cells, and further enhanced their susceptibility to cytotoxicity by in vitro expanded donor NK cells. These results suggest that donor-derived NK cell-mediated GVL effects may be improved by sensitizing residual quiescent CML cells to NK-cell cytotoxicity after SCT. Such treatment, as an adjunct to donor lymphocyte infusions and pharmacologic therapy, may reduce the risk of relapse in CML patients who require treatment by SCT. (Blood. 2009;113:875-882) C1 [Yong, Agnes S. M.; Keyvanfar, Keyvan; Hensel, Nancy; Eniafe, Rhoda; Savani, Bipin N.; Berg, Maria; Lundqvist, Andreas; Adams, Sharon; Sloand, Elaine M.; Goldman, John M.; Childs, Richard; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Yong, ASM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Room 3-5140,10 Ctr Dr,MSC 12, Bethesda, MD 20892 USA. EM yonga@nhlbi.nih.gov OI Lundqvist, Andreas/0000-0002-9709-2970 FU National Institutes of Health FX The authors thank Dr Heather Jorgensen and Prof Tessa Holyoake from the Section of Experimental Hematology, University of Glasgow, United Kingdom, for technical advice on quiescent CML CD34+ cell cultures, and Dr Giuseppe Sconocchia from the National Research Council Institute for Organ Transplantation and Immunocitology, Rome, Italy, for advice on NK-cell cultures. The authors are grateful to Dr Colin Wu from the Office of Biostatistics Research at the National Heart, Lung, and Blood Institute (NHLBI) for providing formal statistical review.; This research was supported by the Intramural Research Program of the National Institutes of Health at the NHLBI. NR 45 TC 37 Z9 37 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 JAN 22 PY 2009 VL 113 IS 4 BP 875 EP 882 DI 10.1182/blood-2008-05-158253 PG 8 WC Hematology SC Hematology GA 397EW UT WOS:000262646200016 PM 18922853 ER PT J AU Johnson, AD O'Donnell, CJ AF Johnson, Andrew D. O'Donnell, Christopher J. TI An Open Access Database of Genome-wide Association Results SO BMC MEDICAL GENETICS LA English DT Article ID CANDIDATE GENES; SUSCEPTIBILITY; DISEASE; POLYMORPHISMS; GENETICS; HAPMAP; OAS-1; LOCI; SNPS; TOOL AB Background: The number of genome-wide association studies (GWAS) is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results. Methods: We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS. Results: Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e. g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e. g., APOE, LPL). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (SLC16A7, CSMD1, OAS1), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 x 10(-14)), a finding which was not perturbed by a sensitivity analysis. Conclusion: We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting. C1 [Johnson, Andrew D.; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP O'Donnell, CJ (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. EM johnsonad2@nhlbi.nih.gov; odonnellc@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU NIH/NHLBI [N01-HC-25195] FX We would like to acknowledge the many thousands of international, anonymous participants of the GWAS included here for their contribution to human genetics. We thank Wolfgang Lieb, MD and Raghava Velagaleti, MD for their assistance as QC reviewers of the dataset. ADJ was supported by an intramural NHLBI IRTA fellowship award. This project was supported in part by the NHLBI's Framingham Heart Study (NIH/NHLBI Contract N01-HC-25195). We thank Teri Manolio, MD PhD for her comments on the manuscript. NR 33 TC 173 Z9 180 U1 2 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JAN 22 PY 2009 VL 10 AR 6 DI 10.1186/1471-2350-10-6 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 418MS UT WOS:000264152900002 PM 19161620 ER PT J AU Hickman, HD Bennink, JR Yewdell, JW AF Hickman, Heather D. Bennink, Jack R. Yewdell, Jonathan W. TI Caught in the Act: Intravital Multiphoton Microscopy of Host-Pathogen Interactions SO CELL HOST & MICROBE LA English DT Article ID GREEN FLUORESCENT PROTEIN; CD8(+) T-CELLS; CONDITIONAL MACROPHAGE ABLATION; INTERACTIONS IN-VIVO; DENDRITIC CELLS; LYMPH-NODES; REAL-TIME; INFECTION; GENE; DIFFERENTIATION AB Intravital multiphoton microscopy provides a unique opportunity to discover and characterize biological phenomena in the natural context of living organisms. Here we provide an overview of multiphoton microscopy with particular attention to its application for studying host-pathogen interactions. C1 [Hickman, Heather D.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hickman, HD (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM hhickman@mail.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS [Z01 AI001053-01] NR 49 TC 18 Z9 19 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JAN 22 PY 2009 VL 5 IS 1 BP 13 EP 21 DI 10.1016/j.chom.2008.12.007 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 400RG UT WOS:000262885700005 PM 19154984 ER PT J AU Balasubramanian, R Raghavan, B Begaye, A Sackett, DL Fecik, RA AF Balasubramanian, Ranganathan Raghavan, Bhooma Begaye, Adrian Sackett, Dan L. Fecik, Robert A. TI Total Synthesis and Biological Evaluation of Tubulysin U, Tubulysin V, and Their Analogues SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POTENTIAL ANTICANCER; MYXOBACTERIA; POLYMERIZATION; TUBULIN AB A stercoselective total synthesis of the cytotoxic natural products tubulysin U, tubulysin V, and its unnatural epimer epitubulysin V, is reported. Simplified analogues containing N,N-dimethyl-D-alanine as a replacement for the N-terminal N-Me-pipecolinic acid residue of the tubulysins are also disclosed. Biological evaluation of these natural products and analogues provided key information with regard to structural and stereochemical requirements for antiproliferative activity and tubulin polymerization inhibition. C1 [Balasubramanian, Ranganathan; Raghavan, Bhooma; Fecik, Robert A.] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. [Begaye, Adrian; Sackett, Dan L.] NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Fecik, RA (reprint author), Univ Minnesota, Dept Med Chem, 308 Harvard St SE,8-101 Weaver Densford Hall, Minneapolis, MN 55455 USA. EM fecik001@umn.edu FU American Cancer Society [RSG-05-105-01-CDD]; National Institute of Child Health and Human Development, NIH; University of Minnesota Medical School, NSF [BIR-961577]; Minnesota Medical Foundation FX This work was generously supported by the American Cancer Society, Grant RSG-05-105-01-CDD (to R.A.F.) and was supported in part by intramural funds from the National Institute of Child Health and Human Development, NIH. Funding for NMR instrumentation in the Department of Biochemistry, Molecular Biology, and Biophysics was provided by the University of Minnesota Medical School, NSF (Grant BIR-961577), and the Minnesota Medical Foundation. NR 20 TC 28 Z9 28 U1 0 U2 13 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 JAN 22 PY 2009 VL 52 IS 2 BP 238 EP 240 DI 10.1021/jm8013579 PG 3 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 395KD UT WOS:000262522100003 PM 19102699 ER PT J AU Leopold, DA AF Leopold, David A. TI NEUROSCIENCE Pre-emptive blood flow SO NATURE LA English DT Editorial Material ID NEURAL BASIS; FMRI; SIGNALS C1 [Leopold, David A.] NIH, Neuropsychol Lab, Unit Cognit Neurophysiol & Imaging, Bethesda, MD 20892 USA. RP Leopold, DA (reprint author), NIH, Neuropsychol Lab, Unit Cognit Neurophysiol & Imaging, Bldg 10, Bethesda, MD 20892 USA. EM leopoldd@mail.nih.gov OI Leopold, David/0000-0002-1345-6360 FU Intramural NIH HHS [Z01 MH002896-01, Z01 MH002899-01, Z01 MH002838-04] NR 9 TC 13 Z9 13 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 22 PY 2009 VL 457 IS 7228 BP 387 EP 388 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 395JA UT WOS:000262519200025 PM 19158777 ER PT J AU Carim-Todd, L Bath, KG Fulgenzi, G Yanpallewar, S Jing, DQ Barrick, CA Becker, J Buckley, H Dorsey, SG Lee, FS Tessarollo, L AF Carim-Todd, Laura Bath, Kevin G. Fulgenzi, Gianluca Yanpallewar, Sudhirkumar Jing, Deqiang Barrick, Colleen A. Becker, Jodi Buckley, Hannah Dorsey, Susan G. Lee, Francis S. Tessarollo, Lino TI Endogenous Truncated TrkB.T1 Receptor Regulates Neuronal Complexity and TrkB Kinase Receptor Function In Vivo SO JOURNAL OF NEUROSCIENCE LA English DT Article DE TrkB.T1; BDNF; mouse; anxiety; neurites; amygdala ID NEUROTROPHIC FACTOR; NERVOUS-SYSTEM; FULL-LENGTH; CONDITIONAL DELETION; SIGNAL-TRANSDUCTION; HUMAN-MEMORY; CELL-DEATH; RAT TRKC; BDNF; HIPPOCAMPAL AB Pathological or in vitro overexpression of the truncated TrkB (TrkB.T1) receptor inhibits signaling through the full-length TrkB (TrkB.FL) tyrosine kinase receptor. However, to date, the role of endogenous TrkB.T1 is still unknown. By studying mice lacking the truncated TrkB.T1 isoform but retaining normal spatiotemporal expression of TrkB.FL, we have analyzed TrkB.T1-specific physiological functions and its effect on endogenous TrkB kinase signaling in vivo. We found that TrkB.T1-deficient mice develop normally but show increased anxiety in association with morphological abnormalities in the length and complexity of neurites of neurons in the basolateral amygdala. However, no behavioral abnormalities were detected in hippocampal-dependent memory tasks, which correlated with lack of any obvious hippocampal morphological deficits or alterations in basal synaptic transmission and long-term potentiation. In vivo reduction of TrkB signaling by removal of one BDNF allele could be partially rescued by TrkB.T1 deletion, which was revealed by an amelioration of the enhanced aggression and weight gain associated with BDNF haploinsufficiency. Our results suggest that, at the physiological level, TrkB.T1 receptors are important regulators of TrkB.FL signaling in vivo. Moreover, TrkB.T1 selectively affects dendrite complexity of certain neuronal populations. C1 [Carim-Todd, Laura; Fulgenzi, Gianluca; Yanpallewar, Sudhirkumar; Barrick, Colleen A.; Becker, Jodi; Buckley, Hannah; Dorsey, Susan G.; Tessarollo, Lino] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Bath, Kevin G.; Jing, Deqiang; Lee, Francis S.] Cornell Univ, Weill Cornell Med Coll, Dept Psychiat, New York, NY 10021 USA. [Fulgenzi, Gianluca] Univ Marche, Dept Mol Pathol, I-60020 Ancona, Italy. [Dorsey, Susan G.] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. RP Tessarollo, L (reprint author), NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, 7th St,Bldg 560,Room 32-31D,POB B, Frederick, MD 21702 USA. EM tessarol@mail.nih.gov OI Fulgenzi, Gianluca/0000-0003-2646-7728 FU National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research [MH060478, NS052819] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and NIH Grants MH060478 (K. G. B.) and NS052819 (F. S. L.). NR 53 TC 61 Z9 62 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 JAN 21 PY 2009 VL 29 IS 3 BP 678 EP 685 DI 10.1523/JNEUROSCI.5060-08.2009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 395TH UT WOS:000262545900010 PM 19158294 ER PT J AU Kong, LL Wang, XY Choe, DW Polley, M Burnett, BG Bosch-Marce, M Griffin, JW Rich, MM Sumner, CJ AF Kong, Lingling Wang, Xueyong Choe, Dong W. Polley, Michelle Burnett, Barrington G. Bosch-Marce, Marta Griffin, John W. Rich, Mark M. Sumner, Charlotte J. TI Impaired Synaptic Vesicle Release and Immaturity of Neuromuscular Junctions in Spinal Muscular Atrophy Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE spinal muscular atrophy; motor neuron; neuromuscular junction; synapse; synaptic vesicle; acetylcholine receptor ID MOTOR-NEURON DISEASE; TO-EPSILON-SWITCH; MOUSE MODEL; ACETYLCHOLINE-RECEPTOR; AXONAL DEGENERATION; TRANSMITTER RELEASE; DETERMINING GENE; SKELETAL-MUSCLE; IN-VIVO; SMN AB The motor neuron disease spinal muscular atrophy (SMA) causes profound muscle weakness that most often leads to early death. At autopsy, SMA is characterized by loss of motor neurons and muscle atrophy, but the initial cellular events that precipitate motor unit dysfunction and loss remain poorly characterized. Here, we examined the function and corresponding structure of neuromuscular junction (NMJ) synapses in a mouse model of severe SMA (hSMN2/delta7SMN/mSmn(-/-)). Surprisingly, most SMA NMJs remained innervated even late in the disease course; however they showed abnormal synaptic transmission. There was a two-fold reduction in the amplitudes of the evoked endplate currents (EPCs), but normal spontaneous miniature EPC (MEPC) amplitudes. These features in combination indicate reduced quantal content. SMA NMJs also demonstrated increased facilitation suggesting a reduced probability of vesicle release. By electron microscopy, we found a decreased density of synaptic vesicles that is likely to contribute to the reduced release probability. In addition to presynaptic defects, there were postsynaptic abnormalities. EPC and MEPC decay time constants were prolonged because of a slowed switch from the fetal acetylcholine receptor (AChR) gamma-subunit to the adult epsilon-subunit. There was also reduced size of AChR clusters and small myofibers, which expressed an immature pattern of myosin heavy chains. Together these results indicate that impaired synaptic vesicle release at NMJs in severe SMA is likely to contribute to failed postnatal maturation of motor units and muscle weakness. C1 [Kong, Lingling; Choe, Dong W.; Polley, Michelle; Bosch-Marce, Marta; Griffin, John W.; Sumner, Charlotte J.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Wang, Xueyong; Rich, Mark M.] Wright State Univ, Dept Neurol Neurosci Cell Biol & Physiol, Dayton, OH 45435 USA. [Burnett, Barrington G.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Sumner, CJ (reprint author), Johns Hopkins Univ, Dept Neurol, 600 N Wolfe St,Meyer 5-119B, Baltimore, MD 21287 USA. EM csumner1@jhmi.edu FU Robert Packard Center; National Institute of Neurological Disorders and Stroke (NINDS) [K22-NS0048199-01, P01NS057228]; Families of Spinal Muscular Atrophy Grant; Howard Hughes Medical Institute Physician Scientist Award FX L. K. was supported by funding from the Robert Packard Center for ALS Research. C.J.S. was supported by a National Institute of Neurological Disorders and Stroke (NINDS) Career Transition Award (K22-NS0048199-01), Families of Spinal Muscular Atrophy Grant, and Howard Hughes Medical Institute Physician Scientist Award. M. M. R. was supported by NINDS Grant P01NS057228. B. G. B. was supported by an NINDS Competitive Fellowship Award. We thank Carol Rubright for EM support and Norihiro Yumoto for providing the AChR gamma antibody. NR 50 TC 194 Z9 195 U1 1 U2 15 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 JAN 21 PY 2009 VL 29 IS 3 BP 842 EP 851 DI 10.1523/JNEUROSCI.4434-08.2009 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 395TH UT WOS:000262545900024 PM 19158308 ER PT J AU Zhu, BP Li, DD Zhou, QF Shi, J Shung, KK AF Zhu, B. P. Li, D. D. Zhou, Q. F. Shi, J. Shung, K. K. TI Piezoelectric PZT thick films on LaNiO3 buffered stainless steel foils for flexible device applications SO JOURNAL OF PHYSICS D-APPLIED PHYSICS LA English DT Article ID PULSED-LASER DEPOSITION; DIELECTRIC-PROPERTIES; ELECTRICAL-PROPERTIES; AEROSOL DEPOSITION; METAL FOILS AB In this paper, we report on 4.5 mu m piezoelectric Pb(Zr0.52Ti0.48)O-3 (PZT) thick films deposited on flexible stainless steel (SS) foils with LaNiO3 (LNO) buffer layers using a ceramic powder/sol-gel solution modified composite method. The polycrystalline thick films show a hysteresis loop at an applied electric field of 900 kV cm(-1) with remanent polarization and coercive electric field values of 27 mu C cm(-2) and 85 kV cm(-1), respectively. At 1 kHz, the dielectric constant is 653 and the dielectric loss is 0.052. The leakage current density of the film is lower than 1.55 x 10(-5) A cm(-2) over the range of 0 to +/-150V. The conduction current shows ohmic behaviour at a low electric field and space-charge-limited current characteristics at a high electric field. C1 [Zhu, B. P.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Zhu, B. P.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Zhu, B. P.; Shi, J.] Wuhan Univ, Dept Phys, Wuhan 430072, Peoples R China. [Zhu, B. P.; Shi, J.] Wuhan Univ, Key Lab Acoust & Photon Mat & Devices, Minist Educ, Wuhan 430072, Peoples R China. [Li, D. D.] Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, Shanghai 200240, Peoples R China. RP Zhou, QF (reprint author), Univ So Calif, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu RI Li, Dongdong/A-2703-2011 OI Li, Dongdong/0000-0003-3219-181X FU NIH [P41-EB2182]; Chinese Scholarship Council, China FX The authors acknowledge the support of the NIH grant P41-EB2182. B P Zhu is supported by the Chinese Scholarship Council, China. NR 20 TC 5 Z9 5 U1 0 U2 10 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0022-3727 J9 J PHYS D APPL PHYS JI J. Phys. D-Appl. Phys. PD JAN 21 PY 2009 VL 42 IS 2 AR 025504 DI 10.1088/0022-3727/42/2/025504 PG 4 WC Physics, Applied SC Physics GA 385WB UT WOS:000261843200035 ER PT J AU Greene, MH Mai, PL AF Greene, Mark H. Mai, Phuong L. TI What Have We Learned from Risk-Reducing Salpingo-oophorectomy? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PROPHYLACTIC OOPHORECTOMY; PERCEIVED AMBIGUITY; MUTATION CARRIERS; CANCER PREVENTION; OVARIAN-CANCER; RECOMMENDATIONS; PERCEPTIONS; CARCINOMA; BRCA1 C1 [Greene, Mark H.; Mai, Phuong L.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Greene, MH (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room EPS 7032, Rockville, MD 20852 USA. EM greenem@mail.nih.gov NR 10 TC 2 Z9 2 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 JAN 21 PY 2009 VL 101 IS 2 BP 70 EP 71 DI 10.1093/jnci/djn476 PG 2 WC Oncology SC Oncology GA 398GU UT WOS:000262721400001 PM 19141782 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, Ramachandran S. Levy, Daniel TI Single Versus Combined Blood Pressure Components and Risk for Cardiovascular Disease The Framingham Heart Study SO CIRCULATION LA English DT Article DE blood pressure; cardiovascular diseases; hypertension; mean arterial pressure; pulse pressure ID PULSE PRESSURE; MYOCARDIAL-INFARCTION; HYPERTENSIVE PATIENTS; MORTALITY; ASSOCIATION; PREDICTOR; PULSATILE; INDEXES; HEALTH; ADULTS AB Background-The utility of single versus combined blood pressure (BP) components in predicting cardiovascular disease (CVD) events is not established. We compared systolic BP (SBP) and diastolic BP (DBP) versus pulse pressure (PP) and mean arterial pressure (MAP) combined and each of these 4 BP components alone in predicting CVD events. Methods and Results-In participants in the original (n=4760) and offspring (n=4897) Framingham Heart Study who were free of CVD events and BP-lowering therapy, 1439 CVD events occurred over serial 4-year intervals from 1952 to 2001. In pooled logistic regression with the use of BP categories, combining SBP with DBP and PP with MAP improved model fit compared with individual BP components (P<0.05 to P<0.0001). Significant interactions were noted between SBP and DBP (P=0.02) and between PP and MAP (P=0.01) in their respective multivariable models. Models with continuous variables for SBP+DBP and PP+MAP proved identical in predicting CVD events (Akaike Information Criteria = 10 625 for both). Addition of a quadratic DBP(2) term to DBP and SBP further improved fit (P=0.0016). Conclusions-Combining PP with MAP and SBP with DBP produced models that were superior to single BP components for predicting CVD, and the extent of CVD risk varied with the level of each BP component. The combination of PP+MAP (unlike SBP+DBP) has a monotonic relation with risk and may provide greater insight into hemodynamics of altered arterial stiffness versus impaired peripheral resistance but is not superior to SBP+DBP in predicting CVD events. (Circulation. 2009;119:243-250.) C1 [Franklin, Stanley S.; Lopez, Victor A.; Wong, Nathan D.] Univ Calif Irvine, Dept Med, Heart Dis Prevent Program, Irvine, CA 92697 USA. [Larson, Martin G.; Vasan, Ramachandran S.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Med Ctr, Div Cardiol, Boston, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Franklin, SS (reprint author), Univ Calif Irvine, Dept Med, Heart Dis Prevent Program, C240 Med Sci, Irvine, CA 92697 USA. EM ssfranklinmd@earthlink.net OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health/National Heart, Lung, and Blood Institute [N01-HC-25195, 2K24HL04334] FX The Framingham Heart study is supported by National Institutes of Health/National Heart, Lung, and Blood Institute contract N01-HC-25195. Dr Vasan was supported in part by National Institutes of Health/National Heart, Lung, and Blood Institute contract 2K24HL04334. NR 36 TC 114 Z9 126 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 20 PY 2009 VL 119 IS 2 BP 243 EP U69 DI 10.1161/CIRCULATIONAHA.108.797936 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 396XL UT WOS:000262625300009 PM 19118251 ER PT J AU Garg, PK Liu, K Tian, L Guralnik, JM Ferrucci, L Criqui, MH Tan, J McDermott, MM AF Garg, Parveen K. Liu, Kiang Tian, Lu Guralnik, Jack M. Ferrucci, Luigi Criqui, Michael H. Tan, Jin McDermott, Mary M. TI Physical Activity During Daily Life and Functional Decline in Peripheral Arterial Disease SO CIRCULATION LA English DT Article DE claudication; exercise; peripheral vascular disease; risk factors ID ANKLE BRACHIAL INDEX; LOWER-EXTREMITY FUNCTION; CHRONIC HEART-FAILURE; INTERMITTENT CLAUDICATION; CALTRAC ACCELEROMETER; EXERCISE CAPACITY; OCCLUSIVE DISEASE; LONGITUDINAL DATA; 6-MINUTE WALK; LEG SYMPTOMS AB Background-Few modifiable behaviors have been identified that are associated with slower rates of functional decline in persons with lower-extremity peripheral arterial disease. We determined whether higher levels of physical activity during daily life are associated with less functional decline in persons with peripheral arterial disease. Methods and Results-The study population included 203 peripheral arterial disease participants who underwent vertical accelerometer-measured physical activity continuously over 7 days and were followed up annually for up to 4 years (mean, 33.6 months). Outcomes were average annual changes in 6-minute walk performance, usual-paced and fast-paced 4-m walking velocity, and the short performance physical battery. Analyses were adjusted for age, sex, race, comorbidities, body mass index, ankle brachial index, smoking, and walking exercise frequency. Higher baseline physical activity levels measured by a vertical accelerometer were associated with significantly less average annual decline in 6-minute walk performance (P for trend=0.010), fast-paced 4-m walking velocity (P for trend=0.002), and the short performance physical battery (P for trend=0.001). Compared with the lowest baseline quartile, those in the highest baseline quartile of physical activity had less annual decline in 6-minute walk performance (-50.82 versus -107.0 ft/y; P=0.019), fast-paced 4-m walking speed (-0.0034 versus -0.111 m . s(-1) . y (-)1; P = 0.002), and the short performance physical battery (-0.074 versus -0.829; P=0.005). Conclusions-Higher physical activity levels during daily life are associated with less functional decline among people with peripheral arterial disease. These findings may be particularly important for the large number of peripheral arterial disease persons without access to supervised walking exercise programs. (Circulation. 2009;119:251-260.) C1 [Garg, Parveen K.; Liu, Kiang; Tian, Lu; Tan, Jin; McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Lab Clin Epidemiol, Bethesda, MD 20892 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU Intramural NIH HHS [ZIA AG001056-02] NR 48 TC 59 Z9 64 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 JAN 20 PY 2009 VL 119 IS 2 BP 251 EP 260 DI 10.1161/CIRCULATIONAHA.108.791491 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 396XL UT WOS:000262625300010 PM 19118256 ER PT J AU Mavrakis, M Rikhy, R Lippincott-Schwartz, J AF Mavrakis, Manos Rikhy, Richa Lippincott-Schwartz, Jennifer TI Plasma Membrane Polarity and Compartmentalization Are Established before Cellularization in the Fly Embryo SO DEVELOPMENTAL CELL LA English DT Article ID DROSOPHILA EMBRYO; ACTIN POLYMERIZATION; EPITHELIAL POLARITY; MORPHOGEN GRADIENT; TOLL GENE; PROTEIN; NUCLEAR; CELLS; EMBRYOGENESIS; LOCALIZATION AB Patterning in the Drosophila embryo requires local activation and dynamics of proteins in the plasma membrane (PM). We used in vivo fluorescence imaging to characterize the organization and diffusional properties of the PM in the early embryonic syncytium. Before cellularization, the PM is polarized into discrete domains having epithelial-like characteristics. One domain resides above individual nuclei and has apical-like characteristics, while the other domain is lateral to nuclei and contains markers associated with basolateral membranes and junctions. Pulse-chase photoconversion experiments show that molecules can diffuse within each domain but do not exchange between PM regions above adjacent nuclei. Drug-induced F-actin depolymerization disrupted both the apicobasal-like polarity and the diffusion barriers within the syncytial PM. These events correlated with perturbations in the spatial pattern of dorsoventral Toll signaling. We propose that epithelial-like properties and an intact F-actin network compartmentalize the PM and shape morphogen gradients in the syncytial embryo. C1 NICHHD, NIH, Cell Biol & Metab Program, Bethesda, MD 20892 USA. RP Mavrakis, M (reprint author), Univ Aix Marseille 2, CNRS, UMR6216, Inst Dev Biol Marseille Luminy, Parc Sci Luminy BP 907, F-13009 Marseille, France. EM mavrakis@ibdml.univ-mrs.fr; jlippin@helix.nih.gov RI Rikhy, Richa/J-4481-2012; OI Rikhy, Richa/0000-0002-4262-0238 FU Intramural Research Program of the NIH; National Institute of Child Health and Human Development FX We thank the members of the Lippincott-Schwartz and Mary Lilly labs for their supporl throughout this work, as well as Yannick Azou. Bernhard Hampoelz, and Ldfc Le Goff for their valuable comments and helpful discussions. We are especially grateful to Mary Lilly for providing us with the facility for Drosophila work. This work was supported by the Intramural Research Program of the NIH, National Institute of Child Health and Human Development. NR 43 TC 42 Z9 43 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD JAN 20 PY 2009 VL 16 IS 1 BP 93 EP 104 DI 10.1016/j.devcel.2008.11.003 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 398UR UT WOS:000262757500013 PM 19154721 ER PT J AU Tsukasaki, K Hermine, O Bazarbachi, A Ratner, L Ramos, JC Harrington, W O'Mahony, D Janik, JE Bittencourt, AL Taylor, GP Yamaguchi, K Utsunomiya, A Tobinai, K Watanabe, T AF Tsukasaki, Kunihiro Hermine, Olivier Bazarbachi, Ali Ratner, Lee Ramos, Juan Carlos Harrington, William, Jr. O'Mahony, Deirdre Janik, John E. Bittencourt, Achilea L. Taylor, Graham P. Yamaguchi, Kazunari Utsunomiya, Atae Tobinai, Kensei Watanabe, Toshiki TI Definition, Prognostic Factors, Treatment, and Response Criteria of Adult T-Cell Leukemia-Lymphoma: A Proposal From an International Consensus Meeting SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-of-Hematology CY DEC 08-11, 2007 CL Atlanta, GA SP Amer Soc Hematol ID I-TRANSFORMED-CELLS; INTERFERON-ALPHA; CLINICAL-SIGNIFICANCE; WORLDWIDE METAANALYSIS; ARSENIC TRIOXIDE; LEUKEMIA/LYMPHOMA; ZIDOVUDINE; COMBINATION; INVOLVEMENT; EXPRESSION AB Adult T-cell leukemia-lymphoma ( ATL) is a distinct peripheral T-lymphocytic malignancy associated with a retrovirus designated human T-cell lymphotropic virus type I (HTLV-1). The diversity in clinical features and prognosis of patients with this disease has led to its subclassification into the following four categories: acute, lymphoma, chronic, and smoldering types. The chronic and smoldering subtypes are considered indolent and are usually managed with watchful waiting until disease progression, analogous to the management of some patients with chronic lymphoid leukemia (CLL) or other indolent histology lymphomas. Patients with aggressive ATL generally have a poor prognosis because of multidrug resistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications as a result of a profound T-cell immunodeficiency. Under the sponsorship of the 13th International Conference on Human Retrovirology: HTLV, a group of ATL researchers joined to form a consensus statement based on established data to define prognostic factors, clinical subclassifications, and treatment strategies. A set of response criteria specific for ATL reflecting a combination of those for lymphoma and CLL was proposed. Clinical subclassification is useful but is limited because of the diverse prognosis among each subtype. Molecular abnormalities within the host genome, such as tumor suppressor genes, may account for these diversities. A treatment strategy based on the clinical subclassification and prognostic factors is suggested, including watchful waiting approach, chemotherapy, antiviral therapy, allogeneic hematopoietic stem-cell transplantation (alloHSCT), and targeted therapies. C1 [Tsukasaki, Kunihiro] Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Med & Hematol, Mol Med Unit,Atom Bomb Dis Inst, Nagasaki 8528523, Japan. Univ Paris 05, Necker Hosp, Paris, France. CNRS, UMR 8147, Paris, France. Amer Univ Beirut, Dept Internal Med, Beirut, Lebanon. Washington Univ, St Louis, MO USA. Natl Canc Inst, Bethesda, MD USA. Univ Fed Bahia, BR-41170290 Salvador, BA, Brazil. Univ London Imperial Coll Sci Technol & Med, London, England. Univ Tokyo, Tokyo, Japan. Natl Inst Infect Dis, Tokyo, Japan. Natl Canc Ctr, Tokyo, Japan. Imamura Bunin Hosp, Kagoshima, Japan. RP Tsukasaki, K (reprint author), Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Med & Hematol, Mol Med Unit,Atom Bomb Dis Inst, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. EM tsukasak@net.nagasaki-u.ac.jp FU Intramural NIH HHS NR 61 TC 204 Z9 208 U1 0 U2 12 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 JAN 20 PY 2009 VL 27 IS 3 BP 453 EP 459 DI 10.1200/JCO.2008.18.2428 PG 7 WC Oncology SC Oncology GA 395CE UT WOS:000262499100022 PM 19064971 ER PT J AU Wang, H Iguchi, N Rong, Q Zhou, ML Ogunkorode, M Inoue, N Pribitkin, EA Bachnianov, AA Margolskee, RF Pfeifer, K Huang, LQ AF Wang, Hong Iguchi, Naoko Rong, Qi Zhou, Minliang Ogunkorode, Martina Inoue, Niasashi Pribitkin, Edmund A. Bachnianov, Alexander A. Margolskee, Robert F. Pfeifer, Karl Huang, Liquan TI Expression of the Voltage-Gated Potassium Channel KCNQ1 in Mammalian Taste Bud Cells and the Effect of Its Null-Mutation on Taste Preferences SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE cell turnover; human biopsy; co-expression; gene knockout ID PUTATIVE PHEROMONE RECEPTORS; SWEET TASTE; ACTION-POTENTIALS; UMAMI TASTE; K+ CHANNELS; TARGETED DISRUPTION; SIGNALING PATHWAYS; DEPENDENT CURRENTS; CATION CHANNEL; T1R FAMILY AB Vertebrate taste buds undergo continual cell turnover. To understand how the gustatory progenitor cells in the stratified lingual epithelium migrate and differentiate into different types of mature taste cells, we sought to identify genes that were selectively expressed in taste cells at different maturation stages. Here we report the expression of the voltage-gated potassium channel KCNQ1 in mammalian taste buds of mouse, rat, and human. Immunohistochemistry and nuclear staining showed that nearly all rodent and human taste cells express this channel. Double immunostaining with antibodies against type II and III taste cell markers validated the presence of KCNQ1 in these two types of cells. Co-localization studies with cytokeratin 14 indicated that KCNQ1 is also expressed in type IV basal precursor cells. Null mutation of the kcnq1 gene in mouse, however, did not alter the gross structure of taste buds or the expression of taste signaling molecules. Behavioral assays showed that the mutant mice display reduced preference to some umami substances, but not to any other taste compounds tested. Gustatory nerve recordings, however, were unable to detect any significant change in the integrated nerve responses of the mutant mice to umami stimuli. These results suggest that although it is expressed in nearly all taste bud cells, the function of KCNQ1 is not required for gross taste bud development or peripheral taste transduction pathways, and the reduced preference of kcnq1-null mice in the behavioral assays may be attributable to the deficiency in the central nervous system or other organs. J. Comp. Neurol. 512:384-398, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Wang, Hong; Iguchi, Naoko; Zhou, Minliang; Ogunkorode, Martina; Bachnianov, Alexander A.; Huang, Liquan] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Rong, Qi; Pfeifer, Karl] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. [Inoue, Niasashi] Tokyo Univ Pharm & Life Sci, Dept Life Sci, Tokyo, Japan. [Pribitkin, Edmund A.] Thomas Jefferson Univ, Dept Otolaryngol Head & Neck Surg, Philadelphia, PA 19107 USA. [Margolskee, Robert F.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. RP Huang, LQ (reprint author), Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. EM Lhuang@monell.org OI Bachmanov, Alexander/0000-0002-2861-3322; Pfeifer, Karl/0000-0002-0254-682X FU National Institutes of Health [R01 DC007487, R03 DC007974, R01 DC00882, R01 DC003155]; National Science Foundation [DBJ-0216310] FX Grant Sponsor: National Institutes of Health; Grant numbers: R01 DC007487 (to L.H.), R03 DC007974 (to H.W.), R01 DC00882 (toA.A.B.), R01 DC003155 (to R.F.M.); Grant sponsor: National Science Foundation; Grant number: DBJ-0216310 (to N. Rawson). NR 84 TC 17 Z9 17 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 20 PY 2009 VL 512 IS 3 BP 384 EP 398 DI 10.1002/cne.21899 PG 15 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 383XP UT WOS:000261708000007 PM 19006182 ER PT J AU Hook-Barnard, IG Hinton, DM AF Hook-Barnard, India G. Hinton, Deborah M. TI The promoter spacer influences transcription initiation via sigma(70) region 1.1 of Escherichia coli RNA polymerase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OPEN COMPLEX-FORMATION; LAC UV5 PROMOTER; P-R PROMOTER; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; CLOSED COMPLEXES; STRUCTURAL BASIS; DNA-SEQUENCE; A-TRACTS AB Transcription initiation is a dynamic process in which RNA polymerase (RNAP) and promoter DNA act as partners, changing in response to one another, to produce a polymerase/promoter open complex (RPo) competent for transcription. In Escherichia coli RNAP, region 1.1, the N-terminal 100 residues of sigma(70), is thought to occupy the channel that will hold the DNA downstream of the transcription start site; thus, region 1.1 must move from this channel as RPo is formed. Previous work has also shown that region 1.1 can modulate RPo formation depending on the promoter. For some promoters region 1.1 stimulates the formation of open complexes; at the P-minor promoter, region 1.1 inhibits this formation. We demonstrate here that the AT-rich P-minor spacer sequence, rather than promoter recognition elements or downstream DNA, determines the effect of region 1.1 on promoter activity. Using a P-minor derivative that contains good sigma 70-dependent DNA elements, we find that the presence of a more GC-rich spacer or a spacer with the complement of the P-minor sequence results in a promoter that is no longer inhibited by region 1.1. Furthermore, the presence of the P-minor spacer, the GC-rich spacer, or the complement spacer results in different mobilities of promoter DNA during gel electrophoresis, suggesting that the spacer regions impart differing conformations or curvatures to the DNA. We speculate that the spacer can influence the trajectory or flexibility of DNA as it enters the RNAP channel and that region 1.1 acts as a "gatekeeper'' to monitor channel entry. C1 [Hook-Barnard, India G.; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hinton, DM (reprint author), NIDDK, Gene Express & Regulat Sect, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM dhinton@helix.nih.gov FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank R. Bonocora, T. James, K. Baxter, L. Knipling, L. Shern, S. Adhya, and R. Martin for helpful discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 59 TC 19 Z9 20 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 JAN 20 PY 2009 VL 106 IS 3 BP 737 EP 742 DI 10.1073/pnas.0808133106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399OR UT WOS:000262809700014 PM 19139410 ER PT J AU Bukreyev, A Marzi, A Feldmann, F Zhang, LQ Yang, LJ Ward, JM Dorward, DW Pickles, RJ Murphy, BR Feldmann, H Collins, PL AF Bukreyev, Alexander Marzi, Andrea Feldmann, Friederike Zhang, Liqun Yang, Lijuan Ward, Jerrold M. Dorward, David W. Pickles, Raymond J. Murphy, Brian R. Feldmann, Heinz Collins, Peter L. TI Chimeric human parainfluenza virus bearing the Ebola virus glycoprotein as the sole surface protein is immunogenic and highly protective against Ebola virus challenge SO VIROLOGY LA English DT Article DE Ebola virus; Vaccine; Antibody; Vector ID POLARIZED EPITHELIAL-CELLS; VACCINIA VIRUS; RHESUS-MONKEYS; MARBURG VIRUS; HEMAGGLUTININ-NEURAMINIDASE; NEUTRALIZING ANTIBODIES; NUCLEOTIDE-SEQUENCE; ADENOVIRUS VECTORS; ANTI-AD5 IMMUNITY; NONHUMAN-PRIMATES AB We generated a new live-attenuated vaccine against Ebola virus (EBOV) based on a chimeric virus HPIV3/Delta F-HN/EboGP that contains the EBOV glycoprotein (GP) as the sole transmembrane envelope protein combined with the internal proteins of human parainfluenza virus type 3 (HPIV3). Electron microscopy analysis of the virus particles showed that they have an envelope and surface spikes resembling those of EBOV and a particle size and shape resembling those of HPIV3. When HPIV3/Delta F-HN/EboGP was inoculated via apical surface of an in vitro model of human ciliated airway epithelium, the virus was released from the apical surface; when applied to basolateral surface, the virus infected basolateral cells but did not spread through the tissue. Following intranasal (IN) inoculation of guinea pigs, scattered infected cells were detected in the lungs by immunohistochemistry, but infectious HPIV3/Delta F-HN/EboGP could not be recovered from the lungs, blood, or other tissues. Despite the attenuation, the virus was highly immunogenic, and a single IN dose completely protected the animals against a highly lethal intraperitoneal challenge of guinea pig-adapted EBOV. Published by Elsevier Inc. C1 [Bukreyev, Alexander; Yang, Lijuan; Ward, Jerrold M.; Murphy, Brian R.; Collins, Peter L.] NIAID, NIH, Bethesda, MD 20892 USA. [Marzi, Andrea; Feldmann, Friederike; Feldmann, Heinz] Canadian Sci Ctr Human & Anim Hlth, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB, Canada. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3T 2N2, Canada. [Zhang, Liqun; Pickles, Raymond J.] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC USA. [Dorward, David W.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Bukreyev, A (reprint author), NIAID, NIH, Bldg 50,Room 6505,50 S Dr MSC 8007, Bethesda, MD 20892 USA. EM abukreyev@nih.gov FU NIAID Intramural Program; Public Health Agency of Canada; National Institutes of Health (NIH) [NIH R01 HL77844-1] FX This project was funded as a part of the NIAID Intramural Program, Public Health Agency of Canada, and the National Institutes of Health (NIH) grant NIH R01 HL77844-1. NR 44 TC 35 Z9 38 U1 1 U2 11 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 JAN 20 PY 2009 VL 383 IS 2 BP 348 EP 361 DI 10.1016/j.virol.2008.09.030 PG 14 WC Virology SC Virology GA 396QH UT WOS:000262605700020 PM 19010509 ER PT J AU Lewis, GS Cohen, TL Seisler, AR Kirby, KA Sheehan, FT Piazza, SJ AF Lewis, Gregory S. Cohen, Tamara L. Seisler, Andrea R. Kirby, Kevin A. Sheehan, Frances T. Piazza, Stephen J. TI In vivo tests of an improved method for functional location of the subtalar joint axis SO JOURNAL OF BIOMECHANICS LA English DT Article ID DUAL EULER ANGLES; STANCE PHASE; TALOCALCANEAL JOINT; COORDINATE SYSTEM; LOWER-EXTREMITY; MOTION; ANKLE; OPTIMIZATION; KINEMATICS; COMPLEX C1 [Piazza, Stephen J.] Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. [Cohen, Tamara L.] Marquette Univ, Dept Biomed Engn, Milwaukee, WI 53201 USA. [Lewis, Gregory S.; Piazza, Stephen J.] Penn State Univ, Dept Mech & Nucl Engn, University Pk, PA 16802 USA. [Seisler, Andrea R.; Sheehan, Frances T.] NIH, Bethesda, MD 20892 USA. [Kirby, Kevin A.] Calif Sch Podiatr Med, Oakland, CA 94609 USA. [Piazza, Stephen J.] Penn State Univ, Dept Orthopaed & Rehabil, Hershey, PA 17033 USA. RP Piazza, SJ (reprint author), Penn State Univ, Dept Kinesiol, 29 Recreat Bldg, University Pk, PA 16802 USA. EM sjp12@psu.edu RI sheehan, frances/B-6962-2009; Piazza, Stephen/A-7731-2009 OI Piazza, Stephen/0000-0002-5026-7569 NR 42 TC 5 Z9 5 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD JAN 19 PY 2009 VL 42 IS 2 BP 146 EP 151 DI 10.1016/j.jbiomech.2008.10.010 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 405BN UT WOS:000263197200008 PM 19010472 ER PT J AU Veiseh, O Gunn, JW Kievit, FM Sun, C Fang, C Lee, JSH Zhang, MQ AF Veiseh, Omid Gunn, Jonathan W. Kievit, Forrest M. Sun, Conroy Fang, Chen Lee, Jerry S. H. Zhang, Miqin TI Inhibition of Tumor-Cell Invasion with Chlorotoxin-Bound Superparamagnetic Nanoparticles SO SMALL LA English DT Article DE antitumor agents; biological materials; cells; imaging; peptides ID PRIMARY BRAIN-TUMORS; MATRIX METALLOPROTEINASE-2; MOLECULAR-MECHANISMS; CANCER-THERAPY; GLIOMA; MIGRATION; DIAGNOSIS AB Nanoparticles have been investigated as drug delivery vehicles, contrast agents, and multifunctional devices for patient care. Current nanoparticle-based therapeutic strategies for cancer treatment are mainly based on delivery of chemotherapeutic agents to induce apoptosis or DNA/siRNA to regulate oncogene expression. Here, a nanoparticle system that demonstrates an alternative approach to the treatment of cancers through the inhibition of cell invasion, while serving as a magnetic resonance and optical imaging contrast agent, is presented. The nanoparticle comprises an iron oxide nanoparticle core conjugated with an amine-functionalized poly (ethylene glycol) silane and a small peptide, chlorotoxin (CTX), which enables the tumor cell-specific binding of the nanoparticle. It is shown that the nanoparticle exhibits substantially enhanced cellular uptake and an invasion inhibition rate of similar to 98% compared to unbound CTX (similar to 45%). Significantly, the investigation from flow cytometry analysis, transmission electron microscopy, and fluorescent imaging reveals that the CTX-enabled nanoparticles deactivated the membrane-bound matrix metalloproteinase 2 (MMP-2) and induced increased internalization of lipid rafts that contain surface-expressed MMP-2 and volume-regulating ion channels through receptor-mediated endocytosis, leading to enhanced prohibitory effects. Since upregulation and activity of MMP-2 have been observed in tumors of neuroectodermal origin, and in cancers of the breast, colon, skin, lung, prostate, ovaries, and a host of others, this nanoparticle system can be potentially used for non-invasive diagnosis and treatment of a variety of cancer types. C1 [Veiseh, Omid; Gunn, Jonathan W.; Kievit, Forrest M.; Sun, Conroy; Fang, Chen; Zhang, Miqin] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA. [Lee, Jerry S. H.] NCI, NIH, Bethesda, MD 20892 USA. [Lee, Jerry S. H.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. RP Zhang, MQ (reprint author), Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA. EM mzhang@u.washington.edu RI Lee, Jerry/K-4553-2014; Zhang, Miqin/F-5537-2010; Lee, Jerry/A-3189-2008; Veiseh, Omid/A-9972-2012; Sun, Conroy/B-5611-2013 OI Zhang, Miqin/0000-0001-8974-1494; Kievit, Forrest/0000-0002-9847-783X; Lee, Jerry/0000-0003-1515-0952; Sun, Conroy/0000-0001-5193-6907 FU NIH [NO 5R01CA9408, NIBIB R01EB006043, NO 5R01CA112350, T32GM065098]; JWG; NCI; NSF IGERT; Ford Motor Company FX This work is supported by NIH grants (NO 5R01CA9408, NIBIB R01EB006043, and NO 5R01CA112350). We would like to acknowledge NIH training grant (T32GM065098) for support of JWG, and NCI/NSF IGERT and Ford Motor Company fellowships for support of OV and CS, respectively. We would also like to acknowledge the lab assistance of Ms. Ni Mu and the use of resources at the Diagnostic Imaging Sciences Center (DISC), and Keck microscopy imaging facilities at the University of Washington. NR 30 TC 96 Z9 104 U1 7 U2 53 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1613-6810 J9 SMALL JI Small PD JAN 19 PY 2009 VL 5 IS 2 BP 256 EP 264 DI 10.1002/smll.200800646 PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 403NG UT WOS:000263088700016 PM 19089837 ER PT J AU Looze, C Yui, D Leung, L Ingham, M Kaler, M Yao, XL Wu, WW Shen, RF Daniels, MP Levine, SJ AF Looze, Christopher Yui, David Leung, Lester Ingham, Matthew Kaler, Maryann Yao, Xianglan Wu, Wells W. Shen, Rong-Fong Daniels, Mathew P. Levine, Stewart J. TI Proteomic profiling of human plasma exosomes identifies PPAR gamma as an exosome-associated protein SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Exosome; Plasma; Peroxisome proliferator-activated receptor-gamma; Lipoprotein ID VESICLES AB Exosomes are nanovesicles that are released from cells as a mechanism of cell-free intercellular communication. Only a limited number of proteins have been identified from the plasma exosome proteome. Here, we developed a multi-step fractionation scheme incorporating gel exclusion chromatography, rate zonal centrifugation through continuous sucrose gradients, and high-speed centrifugation to purify exosomes from human plasma. Exosome-associated proteins were separated by SDS-PAGE and 66 proteins were identified by LC-MS/MS, which included both cellular and extracellular proteins. Furthermore, we identified and characterized peroxisome proliferator-activated receptor-gamma (PPAR gamma), a nuclear receptor that regulates adipocyte differentiation and proliferation, as well as immune and inflammatory cell functions, as a novel component of plasma-derived exosomes. Given the important role of exosomes as intercellular messengers, the discovery of PPAR gamma as a component of human plasma exosomes identifies a potential new pathway for the paracrine transfer of nuclear receptors. Published by Elsevier Inc. C1 [Looze, Christopher; Yui, David; Leung, Lester; Ingham, Matthew; Kaler, Maryann; Yao, Xianglan; Levine, Stewart J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Wu, Wells W.; Shen, Rong-Fong] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Daniels, Mathew P.] NHLBI, Electron Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nblbi.nih.gov FU Division of Intramural Research,; NHLBI; NIH FX This work was funded by the Division of Intramural Research, NHLBI, NIH. We are grateful to Patricia S. Connelly of the NHLBI Electron Microscopy Core Facility for technical assistance. NR 9 TC 60 Z9 60 U1 5 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 16 PY 2009 VL 378 IS 3 BP 433 EP 438 DI 10.1016/j.bbrc.2008.11.050 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 393AL UT WOS:000262343200022 PM 19028452 ER PT J AU Kortum, RL Samelson, LE AF Kortum, Robert L. Samelson, Lawrence E. TI Priming the Pump: Adhesion Enhances T Cell Antigen Receptor-Induced Signaling SO IMMUNITY LA English DT Editorial Material ID PROTEIN-KINASE; ACTIVATION; THRESHOLD AB In this issue of Immunity, Conche et al. (2009) define an antigen-independent signaling pathway that is dependent on cyclic adenosine monophosphate and extracellular signal-regulated kinase and T cells for subsequent T cell antigen receptor signaling. C1 [Kortum, Robert L.; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. EM samelson@helix.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JAN 16 PY 2009 VL 30 IS 1 BP 3 EP 5 DI 10.1016/j.immuni.2008.12.007 PG 3 WC Immunology SC Immunology GA 398ZJ UT WOS:000262769900002 PM 19144310 ER PT J AU Tolar, P Hanna, J Krueger, PD Pierce, SK AF Tolar, Pavel Hanna, Joseph Krueger, Peter D. Pierce, Susan K. TI The Constant Region of the Membrane Immunoglobulin Mediates B Cell-Receptor Clustering and Signaling in Response to Membrane Antigens SO IMMUNITY LA English DT Article ID RESONANCE ENERGY-TRANSFER; LIVING CELLS; LYMPH-NODE; SUBCAPSULAR SINUS; STRUCTURAL BASIS; BOUND ANTIGEN; T-CELLS; MICROCLUSTERS; ACTIVATION; LIGAND AB B cells are activated in vivo after the B cell receptors (BCRs) bind to antigens captured on the surfaces of antigen-presenting cells. Antigen binding results in BCR microclustering and signaling; however, the molecular nature of the signaling-active BCR clusters is not well understood. Using single-molecule imaging techniques, we provide evidence that within microclusters, the binding of monovalent membrane antigens results in the assembly of immobile signaling-active BCR oligomers. The oligomerization depends on interactions between the membrane-proximal C mu 4 domains of the membrane immunoglobulin that are both necessary and sufficient for assembly. Antigen-bound BCRs that lacked the C mu 4 domain failed to cluster and signal, and conversely, C mu 4 domains alone clustered spontaneously and activated B cells. These results support a unique mechanism for the initiation of BCR signaling in which antigen binding induces a conformational change in the Fc portion of the BCR, revealing an interface that promotes BCR clustering. C1 [Tolar, Pavel; Hanna, Joseph; Krueger, Peter D.; Pierce, Susan K.] NIAID, Immunogenet Lab, Natl Inst Hlth, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, Natl Inst Hlth, Rockville, MD 20852 USA. EM spierce@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank M. Davis and J. Huppa for advice on bilayer preparation, T. Meckel for advice on single-molecule data analysis, C.-Y. Huang for advice on statistical analysis, and J. Brzostowski for help with imaging and comments on the manuscript. This work has been supported by the Intramural Research program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 46 TC 105 Z9 107 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JAN 16 PY 2009 VL 30 IS 1 BP 44 EP 55 DI 10.1016/j.immuni.2008.11.007 PG 12 WC Immunology SC Immunology GA 398ZJ UT WOS:000262769900009 PM 19135393 ER PT J AU Wei, G Wei, L Zhu, JF Zang, CZ Hu-Li, J Yao, ZJ Cui, KR Kanno, Y Roh, TY Watford, WT Schones, DE Peng, WQ Sun, HW Paul, WE O'Shea, JJ Zhao, KJ AF Wei, Gang Wei, Lai Zhu, Jinfang Zang, Chongzhi Hu-Li, Jane Yao, Zhengju Cui, Kairong Kanno, Yuka Roh, Tae-Young Watford, Wendy T. Schones, Dustin E. Peng, Weiqun Sun, Hong-wei Paul, William E. O'Shea, John J. Zhao, Keji TI Global Mapping of H3K4me3 and H3K27me3 Reveals Specificity and Plasticity in Lineage Fate Determination of Differentiating CD4(+) T Cells SO IMMUNITY LA English DT Article ID EMBRYONIC STEM-CELLS; HUMAN GENOME; GENE-EXPRESSION; TGF-BETA; TRANSCRIPTION FACTORS; FOXP3 EXPRESSION; HELPER TYPE-1; T(H)17 CELLS; TH17 CELLS; TH2 CELLS AB Multipotential naive CD4(+) T cells differentiate into distinct lineages including T helper 1 (Th1), Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4(+) T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naive, Th1, Th2, Th17, iTreg, and natural Treg (nTreg) cells. We found that although modifications of signature-cytokine genes (Ifng, II4, and II17) partially conform to the expectation of lineage commitment, genes encoding transcription factors like Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and interferon-gamma induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4(+) T helper cell differentiation. C1 [Wei, Lai; Yao, Zhengju; Kanno, Yuka; Watford, Wendy T.; O'Shea, John J.] NIH, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Wei, Gang; Cui, Kairong; Roh, Tae-Young; Schones, Dustin E.; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Sun, Hong-wei] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Zang, Chongzhi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP O'Shea, JJ (reprint author), NIH, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov; zhaok@nhlbi.nih.gov RI Wei, Gang/A-3291-2011; Zhu, Jinfang/B-7574-2012; Zang, Chongzhi/D-1445-2011; Kanno, Yuka/B-5802-2013; Wei, Lai/D-1088-2014; OI Kanno, Yuka/0000-0001-5668-9319 FU National Institute of Allergy and Infectious Diseases (NIAID); NHLBI; NIAMS FX We thank W. Leonard for critical reading of the manuscript and J. Simone for technical help with cell sorting. The gene-expression analysis with the Affymetrix microarrays was performed by the Gene Expression Gore Facilities of National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). This research was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases (NIAID), NHLBI, and NIAMS. NR 59 TC 591 Z9 606 U1 1 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JAN 16 PY 2009 VL 30 IS 1 BP 155 EP 167 DI 10.1016/j.immuni.2008.12.009 PG 13 WC Immunology SC Immunology GA 398ZJ UT WOS:000262769900018 PM 19144320 ER PT J AU Volodin, AA Bocharova, TN Smirnova, EA Camerini-Otero, RD AF Volodin, Alexander A. Bocharova, Tatiana N. Smirnova, Elena A. Camerini-Otero, R. Daniel TI Reversibility, Equilibration, and Fidelity of Strand Exchange Reaction between Short Oligonucleotides Promoted by RecA Protein from Escherichia coli and Human Rad51 and Dmc1 Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HOMOLOGOUS GENETIC-RECOMBINATION; ATP HYDROLYSIS; DUPLEX DNA; HETERODUPLEX PRODUCT; HOP2-MND1 COMPLEX; SYNAPTIC COMPLEX; ENERGY-TRANSFER; BINDING; FILAMENT; RECOGNITION AB We demonstrate the reversibility of RecA-promoted strand exchange reaction between short oligonucleotides in the presence of adenosine 5'-O-(thiotriphosphate). The reverse reaction proceeds without the dissociation of RecA from DNA. The reaction reaches equilibrium and its yield depends on the homology between the reaction substrates. We estimate the tolerance of the RecA-promoted strand exchange to individual base substitutions for a comprehensive set of possible base combinations in a selected position along oligonucleotide substrates for strand exchange and find, in agreement with previously reported estimations, that this tolerance is higher than in the case of free DNA. It is demonstrated that the short oligonucleotide-based approach can be applied to the human recombinases Rad51 and Dmc1 when strand exchange is performed in the presence of calcium ions and ATP. Remarkably, despite the commonly held belief that the eukaryotic recombinases have an inherently lower strand exchange activity, in our system their efficiencies in strand exchange are comparable with that of RecA. Under our experimental conditions, the human recombinases exhibit a significantly higher tolerance to interruptions of homology due to point base substitutions than RecA. Finding conditions where a chemical reaction is reversible and reaches equilibrium is critically important for its thermodynamically correct description. We believe that the experimental system described here will substantially facilitate further studies on different aspects of the mechanisms of homologous recombination. C1 [Volodin, Alexander A.; Bocharova, Tatiana N.; Smirnova, Elena A.] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. [Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), Bldg 5,Rm 205A,5 Mem Dr,MSC0538, Bethesda, MD 20892 USA. EM camerini@ncifcrf.gov RI Volodin, Alexander/B-9656-2012 FU National Institutes of Health FX This work was authored, in whole or in part, by National Institutes of Health staff. 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 65 TC 9 Z9 9 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 JAN 16 PY 2009 VL 284 IS 3 BP 1495 EP 1504 DI 10.1074/jbc.M800612200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 392VK UT WOS:000262330100017 PM 19004837 ER PT J AU Nakayama, M Hisatsune, J Yamasaki, E Isomoto, H Kurazono, H Hatakeyama, M Azuma, T Yamaoka, Y Yahiro, K Moss, J Hirayama, T AF Nakayama, Masaaki Hisatsune, Junzo Yamasaki, Eiki Isomoto, Hajime Kurazono, Hisao Hatakeyama, Masanori Azuma, Takeshi Yamaoka, Yoshio Yahiro, Kinnosuke Moss, Joel Hirayama, Toshiya TI Helicobacter pylori VacA-induced Inhibition of GSK3 through the PI3K/Akt Signaling Pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; GASTRIC EPITHELIAL-CELLS; BETA-CATENIN SIGNAL; AZ-521 CELLS; VACUOLATING TOXIN; WNT PATHWAY; ACTIVATION; PROTEIN; INDUCTION; CYTOTOXIN AB Helicobacter pylori VacA toxin contributes to the pathogenesis and severity of gastric injury. We found that incubation of AZ-521 cells with VacA resulted in phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3 beta (GSK3 beta) through a PI3K-dependent pathway. Following phosphorylation and inhibition of GSK3 beta,beta-catenin was released from a GSK3 beta/beta-catenin complex, with subsequent nuclear translocation. Methyl-beta-cyclodextrin (MCD) and phosphatidylinositol-specific phospholipase C (PIPLC), but not 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and bafilomycin A1, inhibited VacA-induced phosphorylation of Akt, indicating that it does not require VacA internalization and is independent of vacuolation. VacA treatment of AZ-521 cells transfected with TOPtkLuciferase reporter plasmid or control FOPtkLucifease reporter plasmid resulted in activation of TOPtkLuciferase, but not FOPtkLucifease. In addition, VacA transactivated the beta-catenin-dependent cyclin D1 promoter in a luciferase reporter assay. Infection of AZ-521 cells by a vacA mutant strain of H. pylori failed to induce phosphorylation of Akt and GSK3 beta, or release of beta-catenin from a GSK3 beta/beta-catenin complex. Taken together, these results support the conclusion that VacA activates the PI3K/Akt signaling pathway, resulting in phosphorylation and inhibition of GSK3 beta, and subsequent translocation of beta-catenin to the nucleus, consistent with effects of VacA on beta-catenin-regulated transcriptional activity. These data introduce the possibility that Wnt-dependent signaling might play a role in the pathogenesis of H. pylori infection, including the development of gastric cancer. C1 [Nakayama, Masaaki; Hisatsune, Junzo; Hirayama, Toshiya] Nagasaki Univ, Dept Bacteriol, Inst Trop Med, Nagasaki 8528523, Japan. [Yamasaki, Eiki; Kurazono, Hisao] Obihiro Univ Agr & Vet Med, Dept Appl Vet Med & Publ Hlth, Obihiro, Hokkaido 0808555, Japan. [Isomoto, Hajime] Nagasaki Univ, Dept Endoscopy, Sch Med, Nagasaki 8528523, Japan. [Hatakeyama, Masanori] Hokkaido Univ, Div Mol Oncol, Inst Med Genet, Sapporo, Hokkaido 0600815, Japan. [Azuma, Takeshi] Kobe Univ, Sch Med, Dept Gastroenterol, Kobe, Hyogo 6500017, Japan. [Yamaoka, Yoshio] Michael E DeBakey Vet Affairs Med Ctr, Dept Med Gastroenterol, Houston, TX 77030 USA. [Yamaoka, Yoshio] Baylor Coll Med, Houston, TX 77030 USA. [Yahiro, Kinnosuke; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Hirayama, T (reprint author), Nagasaki Univ, Dept Bacteriol, Inst Trop Med, Nagasaki 8528523, Japan. EM hirayama@net.nagasaki-u.ac.jp FU Intramural Research Program of the NHLBI; National Institutes of Health; Ministry of Education, Culture, Sports, Science and Technology of Japan FX This work was supported, in whole or in part, by the Intramural Research Program of the NHLBI, National Institutes of Health (to J. M.). This work was also supported by Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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 56 Z9 59 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 16 PY 2009 VL 284 IS 3 BP 1612 EP 1619 DI 10.1074/jbc.M806981200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 392VK UT WOS:000262330100029 PM 18996844 ER PT J AU Jian, XY Brown, P Schuck, P Gruschus, JM Balbo, A Hinshaw, JE Randazzo, PA AF Jian, Xiaoying Brown, Patrick Schuck, Peter Gruschus, James M. Balbo, Andrea Hinshaw, Jenny E. Randazzo, Paul A. TI Autoinhibition of Arf GTPase-activating Protein Activity by the BAR Domain in ASAP1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOLIPASE A2 ACTIVITY; MEMBRANE CURVATURE; RECYCLING ENDOSOME; ACTIN CYTOSKELETON; PH DOMAINS; GAPS; BINDING; FAMILY; ULTRACENTRIFUGATION; RECOGNITION AB ASAP1 is an Arf GTPase-activating protein (GAP) that functions on membrane surfaces to catalyze the hydrolysis of GTP bound to Arf. ASAP1 contains a tandem of BAR, pleckstrin homology (PH), and Arf GAP domains and contributes to the formation of invadopodia and podosomes. The PH domain interacts with the catalytic domain influencing both the catalytic and Michaelis constants. Tandem BAR-PH domains have been found to fold into a functional unit. The results of sedimentation velocity studies were consistent with predictions from homology models in which the BAR and PH domains of ASAP1 fold together. We set out to test the hypothesis that the BAR domain of ASAP1 affects GAP activity by interacting with the PH and/or Arf GAP domains. Recombinant proteins composed of the BAR, PH, Arf GAP, and Ankyrin repeat domains (called BAR-PZA) and the PH, Arf GAP, and Ankyrin repeat domains (PZA) were compared. Catalytic power for the two proteins was determined using large unilamellar vesicles as a reaction surface. The catalytic power of PZA was greater than that of BAR-PZA. The effect of the BAR domain was dependent on the N-terminal loop of the BAR domain and was not the consequence of differential membrane association or changes in large unilamellar vesicle curvature. The K(m) for BAR-PZA was greater and the k(cat) was smaller than for PZA determined by saturation kinetics. Analysis of single turnover kinetics revealed a transition state intermediate that was affected by the BAR domain. We conclude that BAR domains can affect enzymatic activity through intraprotein interactions. C1 [Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Brown, Patrick; Schuck, Peter; Balbo, Andrea] NIDDK, Sect Dynam Macromol Assembly, NIH, Bethesda, MD 20892 USA. [Gruschus, James M.] NIDDK, NHLBI, NIH, Bethesda, MD 20892 USA. [Hinshaw, Jenny E.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37,Rm 2042, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU NCI; NIBIB; National Institutes of Health; Department of Health and Human Services FX This work was supported, in whole or in part, by the intramural program at NCI and by the NIBIB, National Institutes of Health, Department of Health and Human Services. 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 42 TC 35 Z9 35 U1 1 U2 15 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 JAN 16 PY 2009 VL 284 IS 3 BP 1652 EP 1663 DI 10.1074/jbc.M804218200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 392VK UT WOS:000262330100034 PM 19017632 ER PT J AU Lin, HY Fridy, PC Ribeiro, AA Choi, JH Barma, DK Vogel, G Falck, JR Shears, SB York, JD Mayr, GW AF Lin, Hongying Fridy, Peter C. Ribeiro, Anthony A. Choi, Jae H. Barma, Deb K. Vogel, Guenter Falck, J. R. Shears, Stephen B. York, John D. Mayr, Georg W. TI Structural Analysis and Detection of Biological Inositol Pyrophosphates Reveal That the Family of VIP/Diphosphoinositol Pentakisphosphate Kinases Are 1/3-Kinases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DIPHOSPHOINOSITOL POLYPHOSPHATE PHOSPHOHYDROLASE; HEXAKISPHOSPHATE KINASE; DICTYOSTELIUM; TETRAKISPHOSPHATE; PHOSPHATES; IDENTIFICATION; PURIFICATION; METABOLISM; CELLS; POLYSPHONDYLIUM AB We have characterized the positional specificity of the mammalian and yeast VIP/diphosphoinositol pentakisphosphate kinase (PPIP5K) family of inositol phosphate kinases. We deployed a microscale metal dye detection protocol coupled to a high performance liquid chromatography system that was calibrated with synthetic and biologically synthesized standards of inositol pyrophosphates. In addition, we have directly analyzed the structures of biological inositol pyrophosphates using two-dimensional (1)H-(1)H and (1)H-(31)P nuclear magnetic resonance spectroscopy. Using these tools, we have determined that the mammalian and yeast VIP/PPIP5K family phosphorylates the 1/3-position of the inositol ring in vitro and in vivo. For example, the VIP/PPIP5K enzymes convert inositol hexakisphosphate to 1/3-diphosphoinositol pentakisphosphate. The latter compound has not previously been identified in any organism. We have also unequivocally determined that 1/3,5-(PP)(2)-IP(4) is the isomeric structure of the bis-diphosphoinositol tetrakisphosphate that is synthesized by yeasts and mammals, through a collaboration between the inositol hexakisphosphate kinase and VIP/PPIP5K enzymes. These data uncover phylogenetic variability within the crown taxa in the structures of inositol pyrophosphates. For example, in the Dictyostelids, the major bis-diphosphoinositol tetrakisphosphate is 5,6-(PP)(2)-IP(4) (Laussmann, T., Eujen, R., Weisshuhn, C. M., Thiel, U., Falck, J. R., and Vogel, G. (1996) Biochem. J. 315, 715-725). Our study brings us closer to the goal of understanding the structure/function relationships that control specificity in the synthesis and biological actions of inositol pyrophosphates. C1 [Lin, Hongying; Mayr, Georg W.] Univ Klinikum Hamburg Eppendorf, Inst Biochem & Mol Biol Zellulare Signaltransdukt, D-20246 Hamburg, Germany. [Fridy, Peter C.; York, John D.] Duke Univ, Med Ctr, Howard Hughes Med Inst, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Ribeiro, Anthony A.] Duke Univ, Med Ctr, NMR Ctr, Durham, NC 27710 USA. [Ribeiro, Anthony A.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Ribeiro, Anthony A.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Choi, Jae H.; Shears, Stephen B.] NIEHS, Inositide Signaling Grp, Lab Signal Transduct, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Barma, Deb K.; Falck, J. R.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Vogel, Guenter] Berg Univ Wuppertal, Fachbereich Math & Nat Wissensch Biochem, D-42097 Wuppertal, Germany. RP Mayr, GW (reprint author), Univ Klinikum Hamburg Eppendorf, Inst Biochem & Mol Biol Zellulare Signaltransdukt, Martinistr 52, D-20246 Hamburg, Germany. EM mayr@uke.uni-hamburg.de OI Fridy, Peter/0000-0002-8208-9154; Falck, John/0000-0002-9219-7845 FU National Institutes of Health (NIH) Intramural Research Program of the NIEHS; NIH [R01 HL-55672, R01 A1057588]; Howard Hughes Medical Institute; Deutsche Forschungsgemeinschaft [MA 989/2-3]; National Science Foundation; NIH; North Carolina Biotechnology Center; Duke University; [NCI P30CA- 14236] FX This work was supported, in whole or in part, by the National Institutes of Health (NIH) Intramural Research Program of the NIEHS ( to S. B. S.) and NIH Grants R01 HL-55672 ( to J. D. Y.), R01 A1057588 ( to A. A. R.), and NCI P30CA- 14236 ( to A. A. R.). This research was also supported by the Howard Hughes Medical Institute ( to J. D. Y.) and Deutsche Forschungsgemeinschaft Grant MA 989/2-3 ( to G. W. M.). Instrumentation in the Duke NMR Center is funded by the National Science Foundation, the NIH, the North Carolina Biotechnology Center, and Duke University. 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 38 TC 62 Z9 64 U1 1 U2 9 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 JAN 16 PY 2009 VL 284 IS 3 BP 1863 EP 1872 DI 10.1074/jbc.M805686200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 392VK UT WOS:000262330100057 PM 18981179 ER PT J AU Lu, WB Ma, H Sheng, ZH Mochida, S AF Lu, Wenbo Ma, Huan Sheng, Zu-Hang Mochida, Sumiko TI Dynamin and Activity Regulate Synaptic Vesicle Recycling in Sympathetic Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; FROG NEUROMUSCULAR JUNCTION; HIPPOCAMPAL SYNAPSES; TRANSMITTER RELEASE; DROSOPHILA MUTANT; GANGLION NEURONS; NERVE-TERMINALS; MEMBRANE; AMPHIPHYSIN; CHANNELS AB Neurotransmission in central neuronal synapses is supported by the recycling of synaptic vesicles via endocytosis at different time scales during and after transmitter release. Here, we examine the kinetics and molecular determinants of different modes of synaptic vesicle recycling at a peripheral neuronal synapse formed between superior cervical ganglion neurons in culture, via acute disruption of endocytosis with Dynasore, an inhibitor of dynamin activation, or a dynamin peptide (P4) that perturbs linkage of dynamin to clathrin coats through amphiphysin. When paired action potentials are generated to produce excitatory postsynaptic potential responses, the second response was reduced after application of Dynasore but not P4. In addition, graded reduction in synaptic transmission during a train of action potentials was accelerated by Dynasore but enhanced by P4. After full depletion of releasable vesicles, P4 delayed the recovery of synaptic transmission while Dynasore limited recovery to 10%. In control neurons, synaptic transmission is stable for more than 1 h under low frequency presynaptic stimulation (0.2 Hz), but was reduced gradually by P4 and rapidly but incompletely blocked by Dynasore at a much lower stimulation frequency. These results suggest two essential modes of dynamin-mediated synaptic vesicle recycling, one activity-dependent and the other activity-independent. Our findings extend the current understanding of synaptic vesicle recycling to sympathetic nerve terminals and provide evidence for a physiological and molecular heterogeneity in endocytosis, a key cellular process for efficient replenishment of the vesicle pool, and thus for synaptic plasticity. C1 [Mochida, Sumiko] Tokyo Med Univ, Dept Physiol, Shinjuku Ku, Tokyo 1608402, Japan. [Lu, Wenbo; Ma, Huan; Mochida, Sumiko] Shanghai Jiao Tong Univ, Dept Neurobiol, Sch Med, Shanghai 200025, Peoples R China. [Sheng, Zu-Hang] NINDS, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. RP Mochida, S (reprint author), Tokyo Med Univ, Dept Physiol, Shinjuku Ku, 1-1 Shinjuku 6 Chome, Tokyo 1608402, Japan. EM mochida@tokyo-med.ac.jp RI Ma, Huan/A-1379-2012 NR 46 TC 19 Z9 21 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 16 PY 2009 VL 284 IS 3 BP 1930 EP 1937 DI 10.1074/jbc.M803691200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 392VK UT WOS:000262330100063 PM 19010787 ER PT J AU Maul, RW Gearhart, PJ AF Maul, Robert W. Gearhart, Patricia J. TI Women, autoimmunity, and cancer: a dangerous liaison between estrogen and activation-induced deaminase? SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INDUCED CYTIDINE DEAMINASE; B-CELLS; EXPRESSION; AID; MICRORNA-155; NUCLEUS AB Why women are more susceptible to autoimmune diseases is not completely clear, but new data suggest that the hormone estrogen may play an important role. A new study now shows that estrogen activates the expression of activation-induced deaminase (AID), a protein that drives antibody diversification by deaminating cytosine in DNA to uracil. If estrogen increases the level of AID, increased mutations could transform benign antibodies into anti-self pariahs. AID might also contribute to cancer-particularly in breast tissue, which is highly responsive to estrogen-by introducing mutations and strand breaks into the genome. C1 [Maul, Robert W.; Gearhart, Patricia J.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM gearhartp@grc.nia.nih.gov OI Maul, Robert/0000-0002-6958-8514 NR 19 TC 10 Z9 11 U1 0 U2 1 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 JAN 16 PY 2009 VL 206 IS 1 BP 11 EP 13 DI 10.1084/jem.20080086 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VK UT WOS:000266008300003 PM 19139165 ER PT J AU Takatori, H Kanno, Y Watford, WT Tato, CM Weiss, G Ivanov, II Littman, DR O'Shea, JJ AF Takatori, Hiroaki Kanno, Yuka Watford, Wendy T. Tato, Cristina M. Weiss, Greta Ivanov, Ivaylo I. Littman, Dan R. O'Shea, John J. TI Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID T-HELPER-CELLS; AUTOIMMUNE INFLAMMATION; TH17 CELLS; CD4(+)CD3(-) CELLS; DIFFERENTIATION; EXPRESSION; CYTOKINE; RECEPTOR; DRIVES; INTERLEUKIN-12 AB The interleukin (IL) 17 family of cytokines has emerged to be critical for host defense as well as the pathogenesis of autoimmune and autoinflammatory disorders, and serves to link adaptive and innate responses. Recent studies have identified a new subset of T cells that selectively produce IL-17 (Th17 cells; Bettelli, E., T. Korn, and V. K. Kuchroo. 2007. Curr. Opin. Immunol. 19:652-657; Kolls, J.K., and A. Linden. 2004. Immunity. 21: 467 476), but the regulation of IL-17 production by innate immune cells is less well understood. We report that in vitro stimulation with IL-23 induced IL-17 production by recombination activating gene (Rag) 2(-/-) splenocytes but not Rag2(-/-) common gamma chain(-/-) splenocytes. We found that a major source of IL-17 was CD4(+)CD3(-)NK1.1(-)CD11b(-)Gr1(-)CD 11c(-)B220(-) cells, a phenotype that corresponds to lymphoid tissue inducer-like cells (LTi-like cells), which constitutively expressed the IL-23 receptor, aryl hydrocarbon receptor, and CCR6. In vivo challenge with the yeast cell wall product zymosan rapidly induced IL-17 production in these cells. Genetic deletion of signal transducer and activator of transcription 3 reduced but did not abrogate IL-17 production in LTi-like cells. Thus, it appears that splenic LTi-like cells are a rapid source of IL-17 and IL-22, which might contribute to dynamic organization of secondary lymphoid organ structure or host defense. C1 [Takatori, Hiroaki; Kanno, Yuka; Watford, Wendy T.; Tato, Cristina M.; O'Shea, John J.] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Weiss, Greta] Univ Penn, NIH, Grad Program, Bethesda, MD 20892 USA. [Ivanov, Ivaylo I.; Littman, Dan R.] NYU, Sch Med, Howard Hughes Med Inst, Skirball Inst Biomol Med, New York, NY 10016 USA. RP Takatori, H (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. EM takatorih@mail.nih.gov RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 FU Intramural NIH HHS NR 30 TC 392 Z9 397 U1 1 U2 27 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 JAN 16 PY 2009 VL 206 IS 1 BP 35 EP 41 DI 10.1084/jem.20072713 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VK UT WOS:000266008300006 PM 19114665 ER PT J AU Dienz, O Eaton, SM Bond, JP Neveu, W Moquin, D Noubade, R Briso, EM Charland, C Leonard, WJ Ciliberto, G Teuscher, C Haynes, L Rincon, M AF Dienz, Oliver Eaton, Sheri M. Bond, Jeffrey P. Neveu, Wendy Moquin, David Noubade, Rajkumar Briso, Eva M. Charland, Colette Leonard, Warren J. Ciliberto, Gennaro Teuscher, Cory Haynes, Laura Rincon, Mercedes TI The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4(+) T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID FOLLICULAR-HELPER-CELLS; TRANSGENIC MICE; B-CELLS; TH1 CELLS; DIFFERENTIATION; INTERLEUKIN-6; GENERATION; CYTOKINE; RECEPTOR; ANTIGEN AB Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4(+) T cells upon T cell receptor stimulation. IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity. C1 [Dienz, Oliver; Neveu, Wendy; Moquin, David; Noubade, Rajkumar; Briso, Eva M.; Charland, Colette; Teuscher, Cory; Rincon, Mercedes] Univ Vermont, Dept Med, Immunobiol Program, Burlington, VT 05405 USA. [Dienz, Oliver; Neveu, Wendy; Moquin, David; Noubade, Rajkumar; Briso, Eva M.; Charland, Colette; Teuscher, Cory; Rincon, Mercedes] Univ Vermont, Dept Microbiol & Mol Genet Bioinformat, Burlington, VT 05405 USA. [Eaton, Sheri M.; Haynes, Laura] Trudeau Inst Inc, Saranac Lake, NY 12983 USA. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Ciliberto, Gennaro] Ist Ric Biol Mol P Angeletti, I-00040 Rome, Italy. RP Rincon, M (reprint author), Univ Vermont, Dept Med, Immunobiol Program, Burlington, VT 05405 USA. EM mrincon@uvm.edu OI Ciliberto, Gennaro/0000-0003-2851-8605 FU NCRR NIH HHS [P20 RR016462, P20 RR021905, P20 RR16462]; NIAID NIH HHS [P01AI045666, P01 AI045666] NR 42 TC 149 Z9 159 U1 1 U2 6 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 JAN 16 PY 2009 VL 206 IS 1 BP 69 EP 78 DI 10.1084/jem.20081571 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VK UT WOS:000266008300010 PM 19139170 ER PT J AU Acker, MG Shin, BS Nanda, JS Saini, AK Dever, TE Lorsch, JR AF Acker, Michael G. Shin, Byung-Sik Nanda, Jagpreet S. Saini, Adesh K. Dever, Thomas E. Lorsch, Jon R. TI Kinetic Analysis of Late Steps of Eukaryotic Translation Initiation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE eukaryotic translation initiation; protein synthesis; eIF1A; eIF5B; subunit joining ID START CODON SELECTION; 40S RIBOSOMAL-SUBUNIT; PROTEIN-SYNTHESIS; IN-VIVO; SACCHAROMYCES-CEREVISIAE; PREINITIATION COMPLEX; RABBIT RETICULOCYTES; LIGHT-SCATTERING; SITE SELECTION; GTP HYDROLYSIS AB Little is known about the molecular mechanics of the late events of translation initiation in eukaryotes. We present a kinetic dissection of the transition from a preinitiation complex after start codon recognition to the final 80S initiation complex. The resulting framework reveals that eukaryotic initiation factor (eIF)5B actually accelerates the rate of ribosomal subunit Joining, and this acceleration is influenced by the conformation of the GTPase active site of the factor mediated by the bound nucleotide. eIF1A accelerates joining through its C-terminal interaction with eIF5B, and eIF1A release from the initiating ribosome, which occurs only after subunit joining, is accelerated by GTP hydrolysis by eIF5B. Following subunit joining, GTP hydrolysis by eIF5B alters the conformation of the final initiation complex and clears a path to promote rapid release of eIF1A. Our data, coupled with previous work, indicate that eIF1A is present on the ribosome throughout the entire initiation process and plays key roles at every stage. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Acker, Michael G.; Nanda, Jagpreet S.; Lorsch, Jon R.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. [Shin, Byung-Sik; Saini, Adesh K.; Dever, Thomas E.] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. EM jlorsch@jhmi.edu RI Nanda, Jagpreet/F-9833-2011; OI Dever, Thomas/0000-0001-7120-9678; Lorsch, Jon/0000-0002-4521-4999 FU National Institutes of Health [GM62128]; American Cancer Society [RSG-03-156-01]; National Institutes of Health; National Institute of Child Health and Human Development FX We thank members of our labs and Alan Hinnebusch for comments on the manuscript. Work on eIF1A was funded by National Institutes of Health grant GM62128 to J.R.L., and work on eIF5B was funded by American Cancer Society grant RSG-03-156-01 to J.R.L. This work was also supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development (to T.E.D.). NR 56 TC 35 Z9 36 U1 0 U2 0 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 JAN 16 PY 2009 VL 385 IS 2 BP 491 EP 506 DI 10.1016/j.jmb.2008.10.029 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401CV UT WOS:000262916900013 PM 18976658 ER PT J AU Plaza, A Bifulco, G Keffer, JL Lloyd, JR Baker, HL Bewley, CA AF Plaza, Alberto Bifulco, Giuseppe Keffer, Jessica L. Lloyd, John R. Baker, Heather L. Bewley, Carole A. TI Celebesides A-C and Theopapuamides B-D, Depsipeptides from an Indonesian Sponge That Inhibit HIV-1 Entry SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID BIOACTIVE MARINE METABOLITES; TETRAMIC ACID GLYCOSIDES; HETERONUCLEAR COUPLING-CONSTANTS; CONSTITUENT AMINO-ACIDS; THEONELLA-SWINHOEI; SILIQUARIASPONGIA-JAPONICA; RELATIVE CONFIGURATION; ABSOLUTE-CONFIGURATION; ORGANIC-COMPOUNDS; PRACTICAL ASPECTS AB Six new depsipeptides belonging to two different structural classes, termed celebesides A-C and theopapuamides B-D, have been isolated from the marine sponge Siliquariaspongia mirabilis. Their structures were determined using extensive 2D NMR and ESI-MS/MS techniques. Celebesides are unusual cyclic depsipeptides that comprise a polyketide moiety and five amino acid residues, including an uncommon 3-carbamoyl threonine, and a phosphoserine residue in celebesides A and B. Theopapuamides B-D are undecapeptides with an N-terminal fatty acid moiety containing two previously unreported amino acids, 3-acetamido-2-aminopropanoic acid and 4-amino-2,3-dihydroxy-5-methylhexanoic acid. The relative configuration of the polyketide moiety in celebesides was resolved by J-based analysis and quantum mechanical calculations, the results of which were self-consistent. Celebeside A neutralized HIV-1 in a single-round infectivity assay with an IC(50) value of 1.9 +/- 0.4 mu g/mL while the nonphosphorylated analog celebeside C was inactive at concentrations as high as 50 mu g/mL. Theopapuamides A-C showed cytotoxicity against human colon carcinoma (HCT-116) cells with IC(50) values between 2.1 and 4.0 mu g/mL and exhibited strong antifungal activity against wildtype and amphotericin B-resistant strains of Candida albicans at loads of 1-5 mu g/disk. C1 [Plaza, Alberto; Keffer, Jessica L.; Lloyd, John R.; Baker, Heather L.; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Bifulco, Giuseppe] Univ Salerno, Dipartimento Sci Farmaceut, I-84084 Salerno, Italy. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov RI Bifulco, Giuseppe/A-5413-2011; OI Bifulco, Giuseppe/0000-0002-1788-5170; Keffer, Jessica/0000-0002-0302-3588 FU NIH Intramural Research Program; Intramural AIDS Targeted Antiviral Program; Office of the Director, NIH FX We thank the Coral Reef Research Foundation, D. Newman, and the country of Indonesia for making possible sample acquisition; M. Kelly and the National Cancer Institute for sponge taxonomy; L. Bell, CRRF, for helpful discussions; and the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH, for reagents and cell lines used in the HIV-1 neutralization assays. This work was supported in part by the NIH Intramural Research Program (NLDDK) and the Intramural AIDS Targeted Antiviral Program, Office of the Director, NIH (C.A.B.). NR 39 TC 47 Z9 49 U1 0 U2 10 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 JAN 16 PY 2009 VL 74 IS 2 BP 504 EP 512 DI 10.1021/jo802232u PG 9 WC Chemistry, Organic SC Chemistry GA 392YS UT WOS:000262338700003 PM 19072692 ER PT J AU Hayakawa, J Washington, K Uchida, N Phang, O Kang, EM Hsieh, MM Tisdale, JF AF Hayakawa, Jun Washington, Kareem Uchida, Naoya Phang, Oswald Kang, Elizabeth M. Hsieh, Matthew M. Tisdale, John F. TI Long-Term Vector Integration Site Analysis Following Retroviral Mediated Gene Transfer to Hematopoietic Stem Cells for the Treatment of HIV Infection SO PLOS ONE LA English DT Article AB We previously reported the efficacy of nonmyeloablative allogeneic transplantation in 2 HIV positive recipients, one of whom received retrovirus transduced hematopoietic stem cells to confer resistance to HIV. Here we report an assessment of retroviral integration sites (RISs) recovered out to 3 years post-transplantation. We identified 213 unique RISs from the patient's peripheral blood samples by linear amplification-mediated PCR (LAM-PCR). While vector integration patterns were similar to that previously reported, only 3.76% of RISs were common among early (up to 3 months) and late samples (beyond 1 year). Additionally, common integration sites were enriched among late samples (14.9% vs. 36.8%, respectively). Three RISs were found near or within known oncogenes, but 2 were limited to early timepoints. Interestingly, an integration site near the MDS1 gene was detected in long-term follow-up samples; however, the overall contribution of MDS1 integrated clone remained stably low during follow-up. C1 [Hayakawa, Jun; Washington, Kareem; Uchida, Naoya; Phang, Oswald; Kang, Elizabeth M.; Hsieh, Matthew M.; Tisdale, John F.] NIDDK, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hayakawa, Jun; Washington, Kareem; Uchida, Naoya; Phang, Oswald; Kang, Elizabeth M.; Hsieh, Matthew M.; Tisdale, John F.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Hayakawa, J (reprint author), NIDDK, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU intramural research program of the National Institute of Diabetes, Digestive, and Kidney Diseases; National Heart, Lung, and Blood Institute of the National Institutes of Health FX This work was supported by the intramural research program of the National Institute of Diabetes, Digestive, and Kidney Diseases and the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funders had no role in data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 8 Z9 8 U1 0 U2 0 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 JAN 16 PY 2009 VL 4 IS 1 AR e4211 DI 10.1371/journal.pone.0004211 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437IH UT WOS:000265479900005 PM 19148292 ER PT J AU Loomba, R Lutchman, G Kleiner, DE Ricks, M Feld, JJ Borg, BB Modi, A Nagabhyru, P Sumner, AE Liang, TJ Hoofnagle, JH AF Loomba, R. Lutchman, G. Kleiner, D. E. Ricks, M. Feld, J. J. Borg, B. B. Modi, A. Nagabhyru, P. Sumner, A. E. Liang, T. J. Hoofnagle, J. H. TI Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID FATTY LIVER-DISEASE; INSULIN-RESISTANCE; NATURAL-HISTORY; OBESE; PLACEBO; LEPTIN; DIET AB Non-alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH. To assess the effects of metformin on insulin sensitivity, body composition, serum alanine aminotransferase (ALT) levels and liver histology in patients with NASH. Patients underwent liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint was a three-point improvement in the histological NASH activity index. Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty per cent achieved a histological response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both, P < 0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histological improvement. Metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH, probably by its effects in causing weight loss. C1 [Loomba, R.; Lutchman, G.; Feld, J. J.; Borg, B. B.; Modi, A.; Nagabhyru, P.; Liang, T. J.; Hoofnagle, J. H.] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, D. E.] NIDDK, Pathol Lab, Natl Canc Inst, Bethesda, MD 20892 USA. [Ricks, M.; Sumner, A. E.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDK, Liver Dis Res Branch, NIH, Bldg 10,Room 9A27,31 Ctr Dr, Bethesda, MD 20892 USA. EM hoofnaglej@extra.niddk.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU National Institute of Diabetes and Digestive and Kidney Diseases FX Declaration of personal interests: None. All authors had access to the data. Analysis was conducted by the first (RL) and the senior author (JHH). The authors thank Drs Edward Doo, Marc Ghany, Theo Heller and Yaron Rotman, and Mrs Yoon Park of the Liver Diseases Branch, NIDDK for the help in managing patients; Ms Francine Thomas, Radiology Department, Clinical Center, NIH for providing help in MRI and CT measurements; Dr Barbara Frempong, Clinical Endocrinology Branch, NIDDK, NIH for conducting FSIGT; Dr Gloria Lena Vega, Clinical Nutrition Center, University of Texas Medical Center, Dallas, Texas, for providing measurements of fasting free fatty acid levels; Ms Blakeley Denkinger and Nancy Sebring, Nutrition Service, Clinical Center, NIH for providing nutritional counseling to the patients. Declaration of funding interests: This study was funded in full by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 25 TC 82 Z9 85 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JAN 15 PY 2009 VL 29 IS 2 BP 172 EP 182 DI 10.1111/j.1365-2036.2008.03869.x PG 11 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 384ZE UT WOS:000261781900003 PM 18945255 ER PT J AU Purdue, MP Hashibe, M Berthiller, J La Vecchia, C Dal Maso, L Herrero, R Franceschi, S Castellsague, X Wei, QY Sturgis, EM Morgenstern, H Zhang, ZF Levi, F Talamini, R Smith, E Muscat, J Lazarus, P Schwartz, SM Chen, C Neto, JE Wunsch, V Zaridze, D Koifman, S Curado, MP Benhamou, S Matos, E Szeszenia-Dabrowska, N Olshan, AF Lence, J Menezes, A Daudt, AW Mates, IN Pilarska, A Fabianova, E Rudnai, P Winn, D Ferro, G Brennan, P Boffetta, P Hayes, RB AF Purdue, Mark P. Hashibe, Mia Berthiller, Julien La Vecchia, Carlo Dal Maso, Luigino Herrero, Rolando Franceschi, Silvia Castellsague, Xavier Wei, Qingyi Sturgis, Erich M. Morgenstern, Hal Zhang, Zuo-Feng Levi, Fabio Talamini, Renato Smith, Elaine Muscat, Joshua Lazarus, Philip Schwartz, Stephen M. Chen, Chu Eluf Neto, Jose Wuensch-Filho, Victor Zaridze, David Koifman, Sergio Curado, Maria Paula Benhamou, Simone Matos, Elena Szeszenia-Dabrowska, Neonilia Olshan, Andrew F. Lence, Juan Menezes, Ana Daudt, Alexander W. Mates, Ioan Nicolae Pilarska, Agnieszka Fabianova, Eleonora Rudnai, Peter Winn, Debbie Ferro, Gilles Brennan, Paul Boffetta, Paolo Hayes, Richard B. TI Type of Alcoholic Beverage and Risk of Head and Neck Cancer-025EFA Pooled Analysis Within the INHANCE Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article ID UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMAS; ORAL-CAVITY; PHARYNGEAL CANCER; PUERTO-RICO; TOBACCO; DRINKING; SMOKING; WINE; CONSUMPTION AB The authors pooled data from 15 case-control studies of head and neck cancer (9,107 cases, 14,219 controls) to investigate the independent associations with consumption of beer, wine, and liquor. In particular, they calculated associations with different measures of beverage consumption separately for subjects who drank beer only (858 cases, 986 controls), for liquor-only drinkers (499 cases, 527 controls), and for wine-only drinkers (1,021 cases, 2,460 controls), with alcohol never drinkers (1,124 cases, 3,487 controls) used as a common reference group. The authors observed similar associations with ethanol-standardized consumption frequency for beer-only drinkers (odds ratios (ORs) = 1.6, 1.9, 2.2, and 5.4 for <= 5, 6-15, 16-30, and > 30 drinks per week, respectively; P(trend) < 0.0001) and liquor-only drinkers (ORs = 1.6, 1.5, 2.3, and 3.6; P < 0.0001). Among wine-only drinkers, the odds ratios for moderate levels of consumption frequency approached the null, whereas those for higher consumption levels were comparable to those of drinkers of other beverage types (ORs = 1.1, 1.2, 1.9, and 6.3; P < 0.0001). Study findings suggest that the relative risks of head and neck cancer for beer and liquor are comparable. The authors observed weaker associations with moderate wine consumption, although they cannot rule out confounding from diet and other lifestyle factors as an explanation for this finding. Given the presence of heterogeneity in study-specific results, their findings should be interpreted with caution. C1 [Purdue, Mark P.; Winn, Debbie; Hayes, Richard B.] NCI, Rockville, MD 20852 USA. [Hashibe, Mia; Berthiller, Julien; Franceschi, Silvia; Curado, Maria Paula; Ferro, Gilles; Brennan, Paul; Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon, France. [La Vecchia, Carlo] Ist Ric Farmacol Mario Negri, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Milan, Italy. [Dal Maso, Luigino; Talamini, Renato] Aviano Canc Ctr, I-33081 Aviano, Italy. [Herrero, Rolando] Inst Invest Epidemiol, San Jose, Costa Rica. [Castellsague, Xavier] Inst Catala Oncol, Barcelona, Spain. [Wei, Qingyi; Sturgis, Erich M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Levi, Fabio] Inst Univ Med Sociale & Prevent, CH-1005 Lausanne, Switzerland. [Smith, Elaine] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. [Muscat, Joshua; Lazarus, Philip] Penn State Coll Med, Hershey, PA USA. [Schwartz, Stephen M.; Chen, Chu] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Eluf Neto, Jose; Wuensch-Filho, Victor] Univ Sao Paulo, Sao Paulo, Brazil. [Zaridze, David] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Koifman, Sergio] Escola Nacl Suade Publ, Rio De Janeiro, Brazil. [Benhamou, Simone] INSERM, U794, Evry, France. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Lodz, Poland. [Olshan, Andrew F.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Lence, Juan] Inst Oncol & Radiobiol, Havana, Cuba. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Mates, Ioan Nicolae] Univ Carol Davila, Fac Med, Bucharest, Romania. [Pilarska, Agnieszka] Med Acad, Maxillofacial Surg Clin 2, Warsaw, Poland. [Fabianova, Eleonora] Specialized State Hlth Inst, Banska Bystrica, Slovakia. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. RP Purdue, MP (reprint author), NCI, 6120 Execut Blvd,EPS 8111, Rockville, MD 20852 USA. EM purduem@mail.nih.gov RI Wunsch Filho, Victor/C-4475-2012; Inca, Inct/K-2204-2013; Zaridze, David/K-5605-2013; Epidemiologicas, Centro de pesquisas /D-4561-2013; Eluf-Neto, Jose/B-2522-2009; Menezes, Ana/G-7266-2012; Szeszenia-Dabrowska, Neonila/F-7190-2010; Castellsague Pique, Xavier/N-5795-2014; Purdue, Mark/C-9228-2016; Benhamou, Simone/K-6554-2015; Curado, Maria Paula/M-6200-2013; Mates, Ioan Nicolae/E-9255-2017 OI Eluf-Neto, Jose/0000-0001-7504-2115; Castellsague Pique, Xavier/0000-0002-0802-3595; Purdue, Mark/0000-0003-1177-3108; Curado, Maria Paula/0000-0001-8172-2483; FU Cancer Research, Switzerland [AKT 617]; Fund for Clinical Research Against Cancer; Gustave-Roussy Institute, Villejuif, France [88D28]; Swiss Research Against Cancer/Oncosuisse [KFS-700, OCS-1633]; World Cancer Research Fund; European Commission's [IC15-CT98-0332]; National Institutes of Health (NIH) [R01CA048896, R01DE012609]; NIH NIDCR [R01DE11979]; NIDCR [R01DE13110]; NIH FIRCA; Veterans Affairs Merit Review Funds; NIH [R01CA61188, P01CA068384, K07CA104231, P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, R21ES011667, R01ES11740, R01CA100264]; National Institute of Environmental Health Sciences [P30ES010126]; UCLA Jonsson Comprehensive Cancer Center; National Cancer Institute; Fondo para la Investigacion Cientifica y Tecnologica (Argentina); Institut Municipal d'Invesigacio Medica (Barcelona); Fundacxao de Amparo a Pesquisa no Estado de Sao Paulo [01/01768-2]; European Commission [IC18-CT97-0222]; International Agency for Research on Cancer (IARC); Fondo de Investigaciones Sanitarias of the Spanish government [FIS 97/0024, FIS 97/0662, BAE 01/5013]; International Union Against Cancer; Yamagiwa-Yoshida Memorial International Cancer Study; Associazione Italiana per la Ricerca sul Cancro FX The individual studies were funded by the following sources: 1) Milan study (Italian Association for Research on Cancer (AIRC)); 2) Aviano and Italy multicenter studies (AIRC, Italian League Against Cancer, and Italian Ministry of Research); 3) French study (Swiss Cancer League, Switzerland (KFS1069-09-2000); League Against Cancer of Fribourg, Switzerland (FOR381.88); Cancer Research, Switzerland (AKT 617); and Fund for Clinical Research Against Cancer, Gustave-Roussy Institute, Villejuif, France (88D28)); 4) Swiss study (Swiss League Against Cancer and the Swiss Research Against Cancer/Oncosuisse (KFS-700 and OCS- 1633)); 5) Central Europe study (World Cancer Research Fund and the European Commission's INCOCOPERNICUS Program (contract no. IC15-CT98-0332)); 6) Seattle study (National Institutes of Health (NIH) (R01CA048896 and R01DE012609)); 7) Iowa study (NIH NIDCR R01DE11979, NIDCR R01DE13110, NIH FIRCA TW01500, and Veterans Affairs Merit Review Funds); 8) North Carolina study (NIH grant R01CA61188 and in part by a grant from the National Institute of Environmental Health Sciences (P30ES010126)); 9) Tampa study (NIH P01CA068384 and K07CA104231); 10) Los Angeles study (NIH grants P50CA90388, R01DA11386, R03CA77954, T32CA09142, U01CA96134, and R21ES011667, as well as the Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center); 11) Houston study (NIH R01ES11740 and R01CA100264); 12) Puerto Rico study (funded by the Intramural Research Program of the US National Institutes of Health (National Cancer Institute)); 13) Latin America study (Fondo para la Investigacion Cientifica y Tecnologica (Argentina), Institut Municipal d'Invesigacio Medica (Barcelona), Fundacxao de Amparo a Pesquisa no Estado de Sao Paulo (no. 01/01768-2), and European Commission (IC18-CT97-0222)); and 14) International Agency for Research on Cancer (IARC) Multicenter Study (Fondo de Investigaciones Sanitarias of the Spanish government (FIS 97/0024, FIS 97/0662, and BAE 01/5013), International Union Against Cancer, and Yamagiwa-Yoshida Memorial International Cancer Study grant). Conflict of interest: none declared. NR 45 TC 44 Z9 45 U1 1 U2 9 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 JAN 15 PY 2009 VL 169 IS 2 BP 132 EP 142 DI 10.1093/aje/kwn306 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 395IQ UT WOS:000262518200002 PM 19064644 ER PT J AU Wang, R Zhang, YW Lan, Q Holford, TR Leaderer, B Zahm, SH Boyle, P Dosemeci, M Rothman, N Zhu, Y Qin, Q Zheng, TZ AF Wang, Rong Zhang, Yawei Lan, Qing Holford, Theodore R. Leaderer, Brian Zahm, Shelia Hoar Boyle, Peter Dosemeci, Mustafa Rothman, Nathaniel Zhu, Yong Qin, Qin Zheng, Tongzhang TI Occupational Exposure to Solvents and Risk of Non-Hodgkin Lymphoma in Connecticut Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article ID UNITED-STATES; ORGANIC-SOLVENTS; NONDIFFERENTIAL MISCLASSIFICATION; BENZENE EXPOSURE; WORKERS; MORTALITY; FORMALDEHYDE; CANCER; COHORT; MEN AB A population-based case-control study involving 601 incident cases of non-Hodgkin lymphoma (NHL) and 717 controls was conducted in 1996-2000 among Connecticut women to examine associations with exposure to organic solvents. A job-exposure matrix was used to assess occupational exposures. Increased risk of NHL was associated with occupational exposure to chlorinated solvents (odds ratio (OR) = 1.4, 95% confidence interval (CI): 1.1, 1.8) and carbon tetrachloride (OR = 2.3, 95% CI: 1.3, 4.0). Those ever exposed to any organic solvent in work settings had a borderline increased risk of NHL (OR = 1.3, 95% CI: 1.0, 1.6); moreover, a significantly increased risk was observed for those with average probability of exposure to any organic solvent at medium-high level (OR = 1.5, 95% CI: 1.1, 1.9). A borderline increased risk was also found for ever exposure to formaldehyde (OR = 1.3, 95% CI: 1.0, 1.7) in work settings. Risk of NHL increased with increasing average intensity (P = 0.01), average probability (P < 0.01), cumulative intensity (P = 0.01), and cumulative probability (P < 0.01) level of organic solvent and with average probability level (P = 0.02) and cumulative intensity level of chlorinated solvent (P = 0.02). Analyses by NHL subtype showed a risk pattern for diffuse large B-cell lymphoma similar to that for overall NHL, with stronger evidence of an association with benzene exposure. Results suggest an increased risk of NHL associated with occupational exposure to organic solvents for women. C1 [Wang, Rong; Zhang, Yawei; Leaderer, Brian; Zhu, Yong; Zheng, Tongzhang] Yale Univ, Sch Publ Hlth, Div Environm Hlth Sci, New Haven, CT 06520 USA. [Lan, Qing; Zahm, Shelia Hoar; Dosemeci, Mustafa; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Holford, Theodore R.] Yale Univ, Sch Publ Hlth, Div Biostat, New Haven, CT USA. [Boyle, Peter] Int Agcy Res Canc, F-69372 Lyon, France. [Qin, Qin] Univ S Maine, Maine Ctr Toxicol & Environm Hlth, Portland, ME USA. RP Zheng, TZ (reprint author), Yale Univ, Sch Publ Hlth, Div Environm Hlth Sci, 60 Coll St,LEPH 427,POB 208034, New Haven, CT 06520 USA. EM tongzhang.zheng@yale.edu RI Wang, Rong/H-3112-2011; Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Wang, Rong/0000-0002-2169-4174; Boyle, Peter/0000-0001-6251-0610; FU National Cancer Institute [CA62006]; National Institutes of Health [5 D43 TW007864] FX Author affiliations: Division of Environmental Health Sciences, Yale University School of Public Health, New Haven, Connecticut (Rong Wang, Yawei Zhang, Brian Leaderer, Yong Zhu, Tongzhang Zheng); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (Qing Lan, Shelia Hoar Zahm, Mustafa Dosemeci, Nathaniel Rothman); Division of Biostatistics, Yale University School of Public Health, New Haven, Connecticut (Theodore R. Holford); International Agency for Research on Cancer, Lyon, France (Peter Boyle); and Maine Center for Toxicology and Environmental Health, University of South Maine, Portland, Maine (Qin Qin).; This study was supported by grant CA62006 from the National Cancer Institute. Preparation of the manuscript for publication was partially supported by National Institutes of Health grant 5 D43 TW007864.; Certain data used in this study were obtained from the Connecticut Tumor Registry located in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. The authors thank the institutions that allowed access to diagnostic materials and pathology reports, including the following Connecticut hospitals: Charlotte Hungerford Hospital, Danbury Hospital, Greenwich Hospital, Griffin Hospital, Hartford Hospital, Johnson Memorial Hospital, Middlesex Hospital, Lawrence and Memorial Hospital, New Britain General Hospital, Bradley Memorial Hospital, Norwalk Hospital, St. Francis Hospital and Medical Center, St. Mary's Hospital, Hospital of St. Raphael, St. Vincent's Medical Center, Stamford Hospital, William W. Backus Hospital, Waterbury Hospital, Yale-New Haven Hospital, Manchester Memorial Hospital, Rockville General Hospital, Bridgeport Hospital, Windham Hospital, Sharon Hospital, Milford Hospital, New Milford Hospital, Bristol Hospital, MidState Medical Center, and Day-Kimball Hospital. Conflict of interest: none declared. Conflict of interest: none declared. NR 60 TC 34 Z9 35 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2009 VL 169 IS 2 BP 176 EP 185 DI 10.1093/aje/kwn300 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 395IQ UT WOS:000262518200008 PM 19056833 ER PT J AU Khoury, MJ Wacholder, S AF Khoury, Muin J. Wacholder, Sholom TI Invited Commentary: From Genome-Wide Association Studies to Gene-Environment-Wide Interaction Studies-025EFChallenges and Opportunities SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID HUMAN-DISEASES; EPIDEMIOLOGY; GENOTYPE; MEDICINE; BIOLOGY; CANCER; RISK AB The recent success of genome-wide association studies in finding susceptibility genes for many common diseases presents tremendous opportunities for epidemiologic studies of environmental risk factors. Analysis of gene-environment interactions, included in only a small fraction of epidemiologic studies until now, will begin to accelerate as investigators integrate analyses of genome-wide variation and environmental factors. Nevertheless, considerable methodological challenges are involved in the design and analysis of gene-environment interaction studies. The authors review these issues in the context of evolving methods for assessing interactions and discuss how the current agnostic approach to interrogating the human genome for genetic risk factors could be extended into a similar approach to gene-environment-wide interaction studies of disease occurrence in human populations. C1 [Khoury, Muin J.] Ctr Dis Control & Prevent, Natl Off Publ Hlth Genom, Atlanta, GA 30341 USA. [Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Natl Off Publ Hlth Genom, 4770 Buford Highway,MS K-89, Atlanta, GA 30341 USA. EM muk1@cdc.gov FU Intramural NIH HHS NR 32 TC 98 Z9 102 U1 0 U2 8 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 JAN 15 PY 2009 VL 169 IS 2 BP 227 EP 230 DI 10.1093/aje/kwn351 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 395IQ UT WOS:000262518200014 PM 19022826 ER PT J AU Chatterjee, N Wacholder, S AF Chatterjee, Nilanjan Wacholder, Sholom TI Invited Commentary: Efficient Testing of Gene-Environment Interaction SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID DESIGNS AB Gene-environment-wide interaction studies of disease occurrence in human populations may be able to exploit the same agnostic approach to interrogating the human genome used by genome-wide association studies. The authors discuss 2 methods for taking advantage of possible independence between a single nucleotide polymorphism they call G (a genetic factor) and an environmental factor they call E while maintaining nominal type I error in studying G-E interaction when information on many genes is available. The first method is a simple 2-step procedure for testing the null hypothesis of no multiplicative interaction against the alternative hypothesis of a multiplicative interaction between an E and at least one of the markers genotyped in a genome-wide association study. The added power for the method derives from a clever work-around of a multiple testing procedure. The second is an empirical-Bayes-style shrinkage estimation framework for G-E interaction and the associated tests that can gain efficiency and power when the G-E independence assumption is met for most G's in the underlying population and yet, unlike the case-only method, is resistant to increased type I error when the underlying assumption of independence is violated. The development of new approaches to testing for interaction is an example of methodological progress leading to practical advantages. C1 [Chatterjee, Nilanjan; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Chatterjee, N (reprint author), 6120 Execut Blvd,EPS 8020, Rockville, MD 20852 USA. EM chattern@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL091172-01] NR 10 TC 14 Z9 14 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 JAN 15 PY 2009 VL 169 IS 2 BP 231 EP 233 DI 10.1093/aje/kwn352 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 395IQ UT WOS:000262518200015 PM 19022825 ER PT J AU Cho, HY Imani, F Miller-DeGraff, L Walters, D Melendi, GA Yamamoto, M Polack, FP Kleeberger, SR AF Cho, Hye-Youn Imani, Farhad Miller-DeGraff, Laura Walters, Dianne Melendi, Guillermina A. Yamamoto, Masayuki Polack, Fernando P. Kleeberger, Steven R. TI Antiviral Activity of Nrf2 in a Murine Model of Respiratory Syncytial Virus Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE airway; oxidative stress; antioxidant response element; inflammation; sulforaphane ID TRANSCRIPTION FACTOR NRF2; BROCCOLI SPROUT EXTRACTS; SMOKE-INDUCED EMPHYSEMA; MUCOUS CELL METAPLASIA; NRF2-DEFICIENT MICE; QUANTITATIVE HISTOCHEMISTRY; ENHANCES SUSCEPTIBILITY; INTERFERON-GAMMA; GENE-EXPRESSION; ENZYME GENES AB Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of significant lower respiratory illness in infants and young children, but its pathogenesis is not fully understood. The transcription factor Nrf2 protects lungs from oxidative injury and inflammation via antioxidant response element (ARE)-mediated gene induction. Objectives: The current study was designed to determine the role of Nrf2-mediated cytoprotective mechanisms in murine airway RSV disease. Methods: Nrf2-deficient (Nrf 2(-/-)) and wild-type (Nrf 2(+/+)) mice were intranasally instilled with RSV or vehicle. In a separate study, Nrf 2(+/+) and Nrf2(-/-) mice were treated orally with sulforaphane (an Nrf 2-ARE inducer) or phosphate-buffered saline before RSV infection. Measurements and Main Results: RSV-induced bronchopulmonary inflammation, epithelial injury, and mucus cell metaplasia as well as nasal epithelial injury were significantly greater in Nrf2(-/-) mice than in Nrf2(+/+) mice. Compared with Nrf2(+/+) mice, significantly attenuated viral clearance and IFN-gamma, body weight loss, heightened protein/lipid oxidation, and AP-1/NF-kappa B activity along with suppressed antioxidant induction was found in Nrf2(-/-) mice in response to RSV. Sulforaphane pretreatment significantly limited lung RSV replication and virus-induced inflammation in Nrf2(+/+) but not in Nrf2(-/-) mice. Conclusions: The results of this study support an association of oxidant stress with RSV pathogenesis and a key role for the Nrf 2-ARE pathway in host defense against RSV. C1 [Cho, Hye-Youn; Imani, Farhad; Miller-DeGraff, Laura; Walters, Dianne; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Melendi, Guillermina A.; Polack, Fernando P.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Melendi, Guillermina A.; Polack, Fernando P.] INFANT Fdn, Buenos Aires, DF, Argentina. [Yamamoto, Masayuki] Tohoku Univ, Grad Sch Med, Sendai, Miyagi 980, Japan. RP Cho, HY (reprint author), NIEHS, Lab Resp Biol, NIH, Bldg 101,MD D-201,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cho2@niehs.nih.gov RI Yamamoto, Masayuki/A-4873-2010; OI Walters, Dianne/0000-0003-3888-2646 FU Intramural Research program of the National Institute of Environmental Health Sciences; National Institutes of Health, Department of Health and Human Services FX Supported by the Intramural Research program of the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services. NR 63 TC 71 Z9 72 U1 1 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 15 PY 2009 VL 179 IS 2 BP 138 EP 150 DI 10.1164/rccm.200804-535OC PG 13 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 394PC UT WOS:000262458000011 PM 18931336 ER PT J AU Fan, MQ Bell, AR Bell, DR Clode, S Fernandes, A Foster, PMD Fry, JR Jiang, T Loizou, G MacNicoll, A Miller, BG Rose, M Shaikh-Omar, O Tran, L White, S AF Fan, Ming Qi Bell, Alex R. Bell, David R. Clode, Sally Fernandes, Alwyn Foster, Paul M. D. Fry, Jeffrey R. Jiang, Tao Loizou, George MacNicoll, Alan Miller, Brian G. Rose, Martin Shaikh-Omar, Osama Tran, Lang White, Shaun TI Recombinant expression of aryl hydrocarbon receptor for quantitative ligand-binding analysis SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Dioxin; PCB; Ligand binding; Aryl hydrocarbon receptor; Species difference ID AH-RECEPTOR; DIOXIN RECEPTOR; NUCLEAR TRANSLOCATOR; MICE LACKING; IN-VIVO; 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN; PROTEIN; HSP90; INDUCTION; AFFINITY AB Recombinant expression of the aryl hydrocarbon receptor (AhR) yields small amounts of ligand-binding-competent AhR. Therefore. Spodoptera frugiperda (Sf9) cells and baculovirus have been evaluated for high-level and functional expression of AhR. Rat and human AhR were expressed as soluble protein in significant amounts. Expression of ligand-binding-competent AhR was sensitive to the protein concentration of Sf9 extract, and coexpression of the chaperone p23 failed to affect the yield Of functional ligand-binding AhR. The expression system yielded high levels of functional protein. with the ligand-binding capacity (B(max)) typically 20-fold higher than that obtained with rat liver cytosol. Quantitative estimates of the ligand-binding affinity Of human and rat AhR were obtained; the K(d) for recombinant rat AhR was indistinguishable from that of native rat AhR, thereby validating the expression system as a faithful model for native AhR. The human AhR bound TCDD with significantly lower affinity than the rat AhR. These findings demonstrate high-level expression of ligand-binding-competent AhR, and sufficient AhR for quantitative analysis of ligand binding. (C) 2008 Elsevier Inc. All rights reserved. C1 [Fan, Ming Qi; Bell, David R.; Jiang, Tao; Shaikh-Omar, Osama] Univ Nottingham, Sch Biol, Nottingham NG7 2RD, England. [Miller, Brian G.; Tran, Lang] Inst Occupat Med, Edinburgh EH14 4AP, Midlothian, Scotland. [Loizou, George] Hlth & Safety Lab, Buxton SK17 9JN, Derby, England. [Fernandes, Alwyn; MacNicoll, Alan; Rose, Martin; White, Shaun] Cent Sci Lab, York YO41 1LZ, N Yorkshire, England. [Bell, Alex R.] AstraZeneca Plc, Alderley Pk, Macclesfield SK10 4TJ, Cheshire, England. [Clode, Sally] Covance Labs Ltd, Harrogate HG3 1PY, N Yorkshire, England. [Foster, Paul M. D.] NIEHS, Res Triangle Pk, NC 27709 USA. [Fry, Jeffrey R.] Univ Nottingham, Queens Med Ctr, Sch Med, Sch Biomed Sci, Nottingham NG7 2UH, England. RP Bell, DR (reprint author), Univ Nottingham, Sch Biol, Univ Pk, Nottingham NG7 2RD, England. EM david.bell@nottingham.ac.uk OI Rose, Martin/0000-0001-7071-180X FU UK Food Standards Agencyx [T01034] FX This work was funded by a contract (T01034) from the UK Food Standards Agency. The authors thank Declan Brady for expert technical assistance, and John Fenlon for help in preparing the AhR antibody. We acknowledge the Food Standards Agency and its expert reviewers (Professors G. Gibson, A.G. Renwick, and Dr. A.G. Smith) for helpful comments and guidance, and Lesa Aylward for helpful comments on the manuscript. We thank Susan Moran and Christopher Bradfield for the gift of the human AhR cDNA, and David Toft for baculovirus containing p23. NR 36 TC 12 Z9 12 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JAN 15 PY 2009 VL 384 IS 2 BP 279 EP 287 DI 10.1016/j.ab.2008.10.003 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 384VQ UT WOS:000261772700011 PM 18938125 ER PT J AU Cismasiu, VB Duque, J Paskaleva, E Califano, D Ghanta, S Young, HA Avram, D AF Cismasiu, Valeriu B. Duque, Javier Paskaleva, Elena Califano, Danielle Ghanta, Sailaja Young, Howard A. Avram, Dorina TI BCL11B enhances TCR/CD28-triggered NF-kappa B activation through up-regulation of Cot kinase gene expression in T-lymphocytes SO BIOCHEMICAL JOURNAL LA English DT Article DE BCL11B; cancer Osaka thyroid oncogene (Cot) kinase; C-terminal binding protein-interacting protein 2 (CTIP2); nuclear factor kappa B (NF-kappa B); T-cell receptor (TCR) signalling ID TRANSCRIPTION FACTOR; PROMOTER ACTIVATION; INTERLEUKIN-2 GENE; RESPONSE ELEMENT; NUCLEAR-FACTOR; IL-2 PROMOTER; CELL-LINES; ALPHA-GENE; C-REL; CD28 AB BCL11B is a Transcriptional regulator with all important role in T-cell development and leukaemogenesis. We demonstrated recently that BCL11B controls expression from the IL (interleukin)-2 promoter through direct binding to file USI (upstream site 1). fit the present study, we provide evidence that BCL11B also participates in the activation of IL-2 gene expression by enhancing NF-kappa B (nuclear factor kappa B) activity in the context of TCR (T-cell receptor)/CD28-triggered T-cell activation. Enhanced NF-kappa B activation is not a consequence of BCL11B binding to file NF-kappa B response elements or association with the NF-kappa B-DNA complexes, but rather the result of higher translocation of NF-kappa B to the nucleus Caused by enhanced degradation Of I kappa B (inhibitor of NF-kappa B). The enhanced I kappa B degradation in cells with increased levels of BCL11B wits specific for T-cells activated through the TCR, but not for cells activated through TNF alpha (tumour necrosis factor alpha) or UV light, and was caused by increased activity of I kappa B kinase, as indicated by its increase in phosphorylation. As BCL11B is a transcription factor, we investigated whether the expression of genes upstream of I kappa B kinase in the TCR/CD28 signalling pathway was affected by increased BCL11B expression, and found that Cot (cancer Osaka thyroid oncogene) kinase mRNA levels were elevated. Cot kinase is known to promote enhanced I kappa B kinase activity, which results in the phosphorylation and degradation Of I kappa B and activation of NF-kappa B. The implied involvement of Cot kinase in BCL11B-mediated NF-kappa B activation in response to TCR activation is supported by the fact that a Cot kinase dominant-negative mutant or Cot kinase siRNA (small interfering RNA) knockdown blocked BCL11B mediated NF-kappa B activation. In support Of Our observations, in the present study we report that BCL11B enhances the expression of several other NF-kappa B Target genes, in addition to IL-2. fit addition, we provide evidence that BCL11B associates with intron 2 of the Cot kinase gene to regulate its expression. C1 [Cismasiu, Valeriu B.; Duque, Javier; Paskaleva, Elena; Califano, Danielle; Ghanta, Sailaja; Avram, Dorina] Albany Med Coll, Ctr Cell Biol & Canc Res, Albany, NY 12208 USA. [Young, Howard A.] NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Avram, D (reprint author), Albany Med Coll, Ctr Cell Biol & Canc Res, 47 New Scotland Ave,MC-165, Albany, NY 12208 USA. EM avramd@mail.amc.edu RI Cismasiu, Valeriu Bogdan/F-1512-2011 FU National Institutes of Health/National Institute of Allergy and Infectious Diseases [R01AI078273]; American Cancer Society [ACS-RSG-04-265-01-MGO] FX This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases [grant number R01AI078273]; and by the American Cancer Society [grant number ACS-RSG-04-265-01-MGO] awarded to D.A. NR 43 TC 22 Z9 22 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JAN 15 PY 2009 VL 417 BP 457 EP 466 DI 10.1042/BJ20080925 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401DG UT WOS:000262918200006 PM 18831712 ER PT J AU Elizondo, G Medina-Diaz, IM Cruz, R Gonzalez, FJ Vega, L AF Elizondo, Guillermo Medina-Diaz, Irma M. Cruz, Raymundo Gonzalez, Frank J. Vega, Libia TI Retinoic acid modulates retinaldehyde dehydrogenase 1 gene expression through the induction of GADD153-C/EBP beta interaction SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Raldh1; Retinoic acid; RAR alpha; C/EBP beta; GADD153 ID ARYL-HYDROCARBON RECEPTOR; HUMAN ALDEHYDE DEHYDROGENASE; BINDING PROTEIN BETA; ALCOHOL-DEHYDROGENASE; NULL MICE; METABOLISM; MOUSE; IDENTIFICATION; ANTAGONISM; ALDH1 AB Mammalian class I aldehyde dehydrogenase (ALDH) plays an important role in the biosynthesis of the hormone retinoic acid (RA), which modulates gene expression and cell differentiation. RA has been shown to mediate control of human ALDH1 gene expression through modulation of the retinoic acid receptor alpha (RAR alpha) and the CCAAT/enhancer binding protein beta (C/EBP beta). The positive activation of these transcription factors on the ALDH1 promoter is inhibited by RA through a decrease of C/EBP beta binding to the ALDH1 CCAAT box response element. However, the mechanism of this effect remains unknown. Here we report that the RAR alpha/retinoid X receptor beta (RXR beta) complex binds to the mouse retinaldehyde dehydrogenase 1 (Raldh1) promoter at a non-consensus RA response element (RARE) with similar affinity to that of the consensus RARE. We found that C/EBP beta binds to a Raldh1 CCAAT box located at -82/-58bp, adjacent to the RARE. Treatment with RA increases GADD153 and GADD153-C/EBP beta interaction resulting in a decreased cellular availability of C/EBP beta for binding to the Raldh1 CCAAT box. These data support a model in which high RA levels inhibit Raldh1 gene expression by sequestering C/EBP beta through its interaction to GADD153. (C) 2008 Elsevier Inc. All rights reserved. C1 [Elizondo, Guillermo] CINVESTAV, Dept Cell Biol, Mexico City 07360, DF, Mexico. [Medina-Diaz, Irma M.] Autonomous Univ Nayarit, Lab Environm & Toxicol Anal, Nayarit, Mexico. [Cruz, Raymundo; Vega, Libia] CINVESTAV, Toxicol Sect, Mexico City 07360, DF, Mexico. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Elizondo, G (reprint author), CINVESTAV, Dept Cell Biol, Av IPN 2508, Mexico City 07360, DF, Mexico. EM gazuela@cinvestav.mx RI Vega, Libia/C-3391-2013 OI Vega, Libia/0000-0002-4993-5267 FU Intramural NIH HHS [Z01 BC005561-21] NR 44 TC 20 Z9 20 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JAN 15 PY 2009 VL 77 IS 2 BP 248 EP 257 DI 10.1016/j.bcp.2008.10.011 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 394ZW UT WOS:000262492700012 PM 18992716 ER PT J AU Pugalenthi, G Tang, K Suganthan, PN Chakrabarti, S AF Pugalenthi, Ganesan Tang, Ke Suganthan, P. N. Chakrabarti, Saikat TI Identification of structurally conserved residues of proteins in absence of structural homologs using neural network ensemble SO BIOINFORMATICS LA English DT Article ID SEQUENCE; SUPERFAMILIES; DATABASE; MOTIFS; REGIONS; ALIGNMENTS; ALGORITHM; FAMILIES; SERVER; TOOLS AB Motivation: So far various bioinformatics and machine learning techniques applied for identification of sequence and functionally conserved residues in proteins. Although few computational methods are available for the prediction of structurally conserved residues from protein structure, almost all methods require homologous structural information and structure-based alignments, which still prove to be a bottleneck in protein structure comparison studies. In this work, we developed a neural network approach for identification of structurally important residues from a single protein structure without using homologous structural information and structural alignment. Results: A neural network ensemble ( NNE) method that utilizes negative correlation learning ( NCL) approach was developed for identification of structurally conserved residues ( SCRs) in proteins using features that represent amino acid conservation and composition, physico-chemical properties and structural properties. The NCL-NNE method was applied to 6042 SCRs that have been extracted from 496 protein domains. This method obtained high prediction sensitivity ( 92.8%) and quality ( Matthew's correlation coefficient is 0.852) in identification of SCRs. Further benchmarking using 60 protein domains containing 1657 SCRs that were not part of the training and testing datasets shows that the NCL-NNE can correctly predict SCRs with similar to 90% sensitivity. These results suggest the usefulness of NCL-NNE for facilitating the identification of SCRs utilizing information derived from a single protein structure. Therefore, this method could be extremely effective in large-scale benchmarking studies where reliable structural homologs and alignments are limited. C1 [Pugalenthi, Ganesan; Suganthan, P. N.] Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore 639798, Singapore. [Tang, Ke] Univ Sci & Technol China, Dept Comp Sci & Technol, Hefei 230026, Anhui, Peoples R China. [Chakrabarti, Saikat] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Suganthan, PN (reprint author), Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore 639798, Singapore. RI Suganthan, .Ponnuthurai /A-5023-2011; Tang, Ke/E-5656-2015 OI Suganthan, .Ponnuthurai /0000-0003-0901-5105; FU Agency for Science, Technology and Research; National Natural Science Foundation of China [60802036]; National Institutes of Health/DHHS FX Funding: A*Star (Agency for Science, Technology and Research to G. P. and P. N. S.); National Natural Science Foundation of China grant ( No. 60802036 to K. T.); Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS ( to S. C.). NR 31 TC 10 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JAN 15 PY 2009 VL 25 IS 2 BP 204 EP 210 DI 10.1093/bioinformatics/btn618 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 395IR UT WOS:000262518300008 PM 19038986 ER PT J AU Tarter, RE Kirisci, L Gavaler, JS Reynolds, M Kirillova, G Clark, DB Wu, JL Moss, HB Vanyukov, M AF Tarter, Ralph E. Kirisci, Levent Gavaler, Judith S. Reynolds, Maureen Kirillova, Galina Clark, Duncan B. Wu, Jionglin Moss, Howard B. Vanyukov, Michael TI Prospective Study of the Association Between Abandoned Dwellings and Testosterone Level on the Development of Behaviors Leading to Cannabis Use Disorder in Boys SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cannabis; etiology; hormones; marijuana; neighborhood; substance abuse ID SUBSTANCE USE DISORDERS; USE SCREENING INVENTORY; EARLY ADOLESCENCE; DRUG-USE; PSYCHOLOGICAL DISTRESS; CONTEXTUAL FACTORS; SEXUAL-MATURATION; NEIGHBORHOOD; PERSONALITY; AGGRESSION AB Background: The role of testosterone in the development of behaviors presaging cannabis use and subsequently cannabis use disorder was investigated in a prospective study of 208 boys. It was theorized that adverse neighborhood correlates with testosterone level that in turn potentiates behaviors predisposing to cannabis consumption and subsequently diagnosis of cannabis use disorder. Methods: Proportion of boarded-up dwellings in the 1990 census tract and testosterone level were recorded at baseline (ages 10-12), followed by assessments of assaultiveness and testosterone level (ages 12-14), social dominance/norm-violating behavior(SDNVB) (age 16), cannabis use (age 19), and cannabis use disorder (age 22). Results: Percent of vacant dwellings correlates with testosterone level that in turn predicts assaultive behavior sequentially leading to SDNVB, cannabis use, and cannabis use disorder. Externalizing behaviors and cannabis use disorder are not directly predicted by neighborhood quality. Conclusions: Elevated testosterone level intermediates the association between neighborhood adversity and aggressive socially deviant behaviors presaging cannabis use and cannabis use disorder. C1 [Tarter, Ralph E.; Kirisci, Levent; Gavaler, Judith S.; Reynolds, Maureen; Kirillova, Galina; Clark, Duncan B.; Vanyukov, Michael] Univ Pittsburgh, Sch Pharm, Ctr Educ & Drug Abuse Res, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Wu, Jionglin] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Moss, Howard B.] NIAAA, Bethesda, MD USA. RP Tarter, RE (reprint author), Univ Pittsburgh, Sch Pharm, Ctr Educ & Drug Abuse Res, Dept Pharmaceut Sci, 711 Salk Hall, Pittsburgh, PA 15261 USA. EM tarter@pitt.edu FU National Institute on Drug Abuse [DA05605, K02-DA018701, K02-DA017822] FX This study was supported by Grants DA05605, K02-DA018701, and K02-DA017822 from the National Institute on Drug Abuse. NR 49 TC 17 Z9 17 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2009 VL 65 IS 2 BP 116 EP 121 DI 10.1016/j.biopsych.2008.08.032 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 391KB UT WOS:000262231100004 PM 18930183 ER PT J AU Shippenberg, TS Chefer, VI Thompson, AC AF Shippenberg, Toni S. Chefer, Vladimir I. Thompson, Alexis C. TI Delta-Opioid Receptor Antagonists Prevent Sensitization to the Conditioned Rewarding Effects of Morphine SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Conditioned place preference; delta opioid receptor; morphine; naltrindole; naltriben; sensitization ID PLACE PREFERENCE; KNOCKOUT MICE; DELTA(1)-OPIOID RECEPTOR; MEDIATED ANTINOCICEPTION; NALTRINDOLE; KAPPA; MU; DEPENDENCE; TOLERANCE; SUBTYPES AB Background: Functional interactions between mu- and delta-opioid receptors (MOPr and DOPr, respectively) are implicated in morphine tolerance and dependence.The contribution of DOPr to the conditioned rewarding effects of morphine and the enhanced conditioned response that occurs after repeated morphine administration is unknown.This issue was addressed with the conditioned place preference procedure (CPP). Methods: Rats received home cage injections of saline or morphine (5.0 mg/kg/day X 5 days) before conditioning. For sensitization studies, DOPr antagonists (DOPr1/2: naltrindole, DOPr2: naltriben, D0Pr1: 7-benzylidenenaltrexone) were administered before morphine injections. Conditioning sessions (2 morphine; 2 saline) commenced 3 days later, To assess the influence of acute DOPr blockade on the conditioning of morphine reward in naive animals, 3 morphine and 3 saline conditioning sessions were employed. Antagonists were administered before morphine conditioning sessions. Results: Morphine was ineffective as a conditioning stimulus after two conditioning sessions in naive rats. However, doses >= 3.0 mg/kg produced significant CPP in morphine pre-exposed rats, confirming that sensitization develops to the conditioned rewarding effects of morphine. In animals that received morphine pre-exposure with naltrindole or naltriben but not 7-benzylidenenaltrexone, sensitization was prevented. No attenuation of morphine CPP was observed in animals that received DOPr antagonists acutely, before conditioning sessions. Conclusions: These data indicate a critical role of DOPr systems in mediating sensitization to the conditioned rewarding effects of morphine. The efficacy of naltrindole and naltriben in preventing the enhanced response to morphine suggest the specific involvement of DOPr2 in the sensitization process. C1 [Shippenberg, Toni S.; Chefer, Vladimir I.] NIDA, Integrat Neurosci Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Thompson, Alexis C.] SUNY Buffalo, Res Inst Addict, Buffalo, NY 14260 USA. RP Shippenberg, TS (reprint author), NIDA, Integrat Neurosci Sect, Intramural Res Program, NIH,US Dept Hlth & Human Serv, 333 Cassell Dr, Baltimore, MD 21224 USA. EM tshippen@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 44 TC 41 Z9 41 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2009 VL 65 IS 2 BP 169 EP 174 DI 10.1016/j.biopsych.2008.09.009 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 391KB UT WOS:000262231100012 PM 18950747 ER PT J AU Phelps, LE Brutsche, N Moral, JR Luckenbaugh, DA Manji, HK Zarate, CA AF Phelps, Laura E. Brutsche, Nancy Moral, Jazmin R. Luckenbaugh, David A. Manji, Husseini K. Zarate, Carlos A., Jr. TI Family History of Alcohol Dependence and Initial Antidepressant Response to an N-methyl-D-aspartate Antagonist SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alcohol dependence; depression; family history; glutamate; ketamine; NMDA receptor ID ASTERISK-D COHORT; MOOD DISORDERS; RATING-SCALE; MICE LACKING; KETAMINE; DEPRESSION; NEUROTRANSMISSION; SUBUNIT AB Background: A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence. This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect. Methods: Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80,120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores. Results: Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence. Conclusions: A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist. C1 NIMH, Lab Mol Pathophysiol & Expt Therapeut, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. Dept Hlth & Human Serv, Bethesda, MD USA. RP Zarate, CA (reprint author), 10 Ctr Dr,CRC,Unit 7 SE,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural Research Program FX This study was supported by the Intramural Research Program at the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression (to CZ). Ioline Henter provided invaluable editoral assistance. NR 21 TC 108 Z9 112 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2009 VL 65 IS 2 BP 181 EP 184 DI 10.1016/j.biopsych.2008.09.029 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 391KB UT WOS:000262231100014 PM 18996507 ER PT J AU Boswell, CA Regino, CAS Baidoo, KE Wong, KJ Milenic, DE Kelley, JA Lai, CC Brechbiel, MW AF Boswell, C. Andrew Regino, Celeste A. S. Baidoo, Kwamena E. Wong, Karen J. Milenic, Diane E. Kelley, James A. Lai, Christopher C. Brechbiel, Martin W. TI A novel side-bridged hybrid phosphonate/acetate pendant cyclam: Synthesis, characterization, and (64)Cu small animal PET imaging SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Positron emission tomography; Copper-64; Side-bridged cyclam; Bifunctional chelating agent ID IN-VIVO; MACROCYCLIC LIGANDS; THERMODYNAMIC STABILITY; COPPER(II) COMPLEXES; MONOCLONAL-ANTIBODY; DERIVATIVES; LYMPHOMA; LYM-1; MICE; 1,4,8,11-TETRAAZACYCLOTETRADECANE AB Copper-64 (t(1/2) = 12.7 h; beta(+): 0.653 MeV, 17.4%; beta: 0.578 MeV, 39%) is produced in a biomedical cyclotron and has applications in both imaging and therapy. Macrocyclic chelators are widely used as bifunctional chelators to bind copper radionuclides to antibodies and peptides owing to their relatively high kinetic stability. A novel side-bridged cyclam featuring both pendant acetate and phosphonate groups was synthesized using a Kabachnik-Fields approach followed by hydrobromic acid deprotection. The Cu(II) complex of the novel ligand was synthesized, radiolabeling with (64)Cu was demonstrated, and in vitro (serum) stability was performed. In addition, in vivo distribution and clearance of the (64)Cu-labeled complex was visualized by positron emission tomography (PET) imaging. This novel chelate may be useful in (64)Cu-mediated diagnostic positron emission tomography (PET) imaging as well as targeted radiotherapeutic applications. Published by Elsevier Ltd. C1 [Boswell, C. Andrew; Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Regino, Celeste A. S.; Wong, Karen J.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kelley, James A.; Lai, Christopher C.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov OI Boswell, Charles/0000-0002-0426-9846 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 39 TC 27 Z9 27 U1 1 U2 20 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 JAN 15 PY 2009 VL 17 IS 2 BP 548 EP 552 DI 10.1016/j.bmc.2008.11.073 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 398CF UT WOS:000262708300013 PM 19101152 ER PT J AU Choi, HK Choi, S Lee, Y Kang, DW Ryu, H Maeng, HJ Chung, SJ Pavlyukovets, VA Pearce, LV Toth, A Tran, R Wang, Y Morgan, MA Blumberg, PM Lee, J AF Choi, Hyun-Kyung Choi, Sun Lee, Yoonji Kang, Dong Wook Ryu, HyungChul Maeng, Han-Joo Chung, Suk-Jae Pavlyukovets, Vladimir A. Pearce, Larry V. Toth, Attila Tran, Richard Wang, Yun Morgan, Matthew A. Blumberg, Peter M. Lee, Jeewoo TI Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Resiniferatoxin; TRPV1 agonist ID ANALGESIC AGENTS; IODO-RESINIFERATOXIN; CAPSAICIN RECEPTOR; GANGLION NEURONS; VR1; ANTAGONIST; BINDING; TRPV1; RTX; DESENSITIZATION AB A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC(50) = 0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Choi, Hyun-Kyung; Kang, Dong Wook; Ryu, HyungChul; Maeng, Han-Joo; Chung, Suk-Jae; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Choi, Sun; Lee, Yoonji] Ewha Womans Univ, Coll Pharm, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Choi, Sun; Lee, Yoonji] Ewha Womans Univ, Natl Core Res Ctr Cell Signaling & Drug Discovery, Seoul 120750, South Korea. [Pavlyukovets, Vladimir A.; Pearce, Larry V.; Toth, Attila; Tran, Richard; Wang, Yun; Morgan, Matthew A.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr RI Toth, Attila/F-4859-2010 OI Toth, Attila/0000-0001-6503-3653 FU Korea Science and Engineering Foundation (KOSEF) [R11-2007-107-02001-0, R01-2007-000-20052-0]; Ministry of Education, Science and Technology [R15-2006-020]; KOSEF; National Institutes of Health, Center for Cancer Research, National Cancer Institute FX This research was supported by Grants R11-2007-107-02001-0 and R01-2007-000-20052-0 from the Korea Science and Engineering Foundation (KOSEF), the National Core Research Center program (No. R15-2006-020) of the Ministry of Education, Science and Technology and KOSEF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University, and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. NR 32 TC 5 Z9 5 U1 0 U2 2 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 JAN 15 PY 2009 VL 17 IS 2 BP 690 EP 698 DI 10.1016/j.bmc.2008.11.085 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 398CF UT WOS:000262708300031 PM 19135377 ER PT J AU Galal, AM Gul, W Slade, D Ross, SA Feng, S Hollingshead, MG Alley, MC Kaur, G ElSohly, MA AF Galal, Ahmed M. Gul, Waseem Slade, Desmond Ross, Samir A. Feng, Shixia Hollingshead, Melinda G. Alley, Michael C. Kaur, Gurmeet ElSohly, Mahmoud A. TI Synthesis and evaluation of dihydroartemisinin and dihydroartemisitene acetal dimers showing anticancer and antiprotozoal activity SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Artemisinin; Dihydroartemisinin; Dihydroartemisitene; Acetal dimers; Anticancer activity; Antiangiogenesis activity; Antimalarial activity; Antileishmanial activity ID PLASMODIUM-FALCIPARUM MALARIA; ARTEMISININ DERIVATIVES; IN-VIVO; TUMOR-CELLS; ANTIMALARIAL; CYTOTOXICITY; ANALOGS; DRUGS; ASSIGNMENTS; ARTESUNATE AB Twelve artemisinin acetal dimers were synthesized and tested for antitumor activity in the National Cancer Institute (NCI) in vitro human tumor 60 cell line assay, producing a mean GI(50) concentration between 8.7 (least active) and 0.019 mu M (most active). The significant activity of the compounds in this preliminary screen led to additional in vitro antitumor and antiangiogenesis studies. Several active dimers were also evaluated in the in vivo NCI hollow fiber assay followed by a preliminary xenograft study. The title compounds were found to be active against solid tumor-derived cell lines and showed good correlation with other artemisinin-based molecules in the NCI database. The dimers were also evaluated for their antimalarial and antileishmanial activities. The antimalarial activity ranged from 0.3 to 32 nM (IC(50)), compared to 9.9 nM for artemisinin. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Galal, Ahmed M.; Gul, Waseem; Slade, Desmond; Ross, Samir A.; ElSohly, Mahmoud A.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Gul, Waseem; Feng, Shixia; ElSohly, Mahmoud A.] ElSohly Labs Inc, Oxford, MS 38655 USA. [Ross, Samir A.] Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. [Hollingshead, Melinda G.; Alley, Michael C.; Kaur, Gurmeet] NCI, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 21701 USA. [ElSohly, Mahmoud A.] Univ Mississippi, Sch Pharm, Dept Pharmaceut, University, MS 38677 USA. RP Galal, AM (reprint author), Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. EM amgalalv@olemiss.edu FU United States Department of Agriculture [58-6408-7-012]; National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX The authors thank the United States Department of Agriculture, Agriculture Research Service Specific Cooperative Agreement No. 58-6408-7-012, for partial support of this work. The authors are also grateful to Mr. Frank T. Wiggers, Dr. Chuck Dunbar and Mr. John Trott for the NMR, the HRESIFTMS analyses and conducting the antimalarial and antileishmanial screens, respectively. This research was supported [in part] by the Developmental Therapeutics Program of the NIH, National Cancer Institute. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-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. NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. Animal care was provided in accordance with procedures outlines in the Guide for Care and Use of Laboratory Animals (NIH publication NO. 86-23, 1985). NR 47 TC 36 Z9 42 U1 1 U2 17 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 JAN 15 PY 2009 VL 17 IS 2 BP 741 EP 751 DI 10.1016/j.bmc.2008.11.050 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 398CF UT WOS:000262708300037 PM 19084416 ER PT J AU Ballet, S Feytens, D De Wachter, R De Vlaeminck, M Marczak, ED Salvadori, S de Graaf, C Rognan, D Negri, L Lattanzi, R Lazarus, LH Tourwe, D Balboni, G AF Ballet, Steven Feytens, Debby De Wachter, Rien De Vlaeminck, Magali Marczak, Ewa D. Salvadori, Severo de Graaf, Chris Rognan, Didier Negri, Lucia Lattanzi, Roberta Lazarus, Lawrence H. Tourwe, Dirk Balboni, Gianfranco TI Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Opioid peptidomimetics; Constrained amino acids ID RECEPTOR SELECTIVITY; EXTRACELLULAR LOOP; DELTA ANTAGONISTS; HIGHLY POTENT; AMINO-ACIDS; CHI-SPACE; ANALOGS; PHARMACOPHORE; PEPTIDES; BINDING AB Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent l-selective agonists (Structures 5 and 12) as well as potent and selective delta-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small pepti-domimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure activity data. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Ballet, Steven; Feytens, Debby; De Wachter, Rien; De Vlaeminck, Magali; Tourwe, Dirk] Vrije Univ Brussels, Dept Organ Chem, B-1050 Brussels, Belgium. [Marczak, Ewa D.; Lazarus, Lawrence H.] Natl Inst Environm Hlth Sci, Med Chem Grp, LP, Res Triangle Pk, NC 27709 USA. [Salvadori, Severo] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [de Graaf, Chris; Rognan, Didier] Univ Louis Pasteur Strasbourg 1, CNRS, UMR 7175 LC1, F-67401 Illkirch Graffenstaden, France. [Negri, Lucia; Lattanzi, Roberta] Univ Rome, Dept Physiol & Pharmacol Vittorio Ersparmer, I-00815 Rome, Italy. [Balboni, Gianfranco] Univ Cagliari, Dept Pharmaceut Sci, I-09124 Cagliari, Italy. [Balboni, Gianfranco] Univ Cagliari, Ctr Biotechnol, I-09124 Cagliari, Italy. RP Tourwe, D (reprint author), Vrije Univ Brussels, Dept Organ Chem, Pl Laan 2, B-1050 Brussels, Belgium. EM datourwe@vub.ac.be RI Rognan, Didier/B-9939-2014; OI LATTANZI, Roberta/0000-0002-6377-9256; de Graaf, Chris/0000-0002-1226-2150; SALVADORI, Severo/0000-0002-8224-2358 FU Scientific Research - Flanders (Belgium) [G.0036.04, G.0008.08]; NIH; NIEHS; European grant 'Normolife' [LSHCCT2006-037733] FX D. Feytens is a Research Assistant for the Fund for Scientific Research - Flanders (Belgium). This work was supported in part by the Intramural Research Program of NIH and NIEHS and by the Fund for Scientific Research - Flanders ( Belgium, Grants G.0036.04 and G.0008.08) and European grant 'Normolife' (LSHCCT2006-037733). NR 41 TC 17 Z9 17 U1 0 U2 9 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 JAN 15 PY 2009 VL 19 IS 2 BP 433 EP 437 DI 10.1016/j.bmcl.2008.11.051 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 386UU UT WOS:000261908900032 PM 19062273 ER PT J AU Ghosh, MC Baatar, D Collins, G Carter, A Indig, F Biragyn, A Taub, DD AF Ghosh, Manik C. Baatar, Dolgor Collins, Gary Carter, Arnell Indig, Fred Biragyn, Arya Taub, Dennis D. TI Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck SO BLOOD LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; RHO-FAMILY PROTEINS; NEGATIVE REGULATION; ENDOTHELIAL-CELLS; GLUCOCORTICOIDS; LYMPHOCYTES; EXPRESSION; ADHESION; PHOSPHORYLATION; MIGRATION AB Dexamethasone (DM) is a synthetic member of the glucocorticoid ( GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly used to treat chronic inflammatory disorders, severe allergies, and other disease states. Although GCs are known to mediate well-defined transcriptional effects via GC receptors (GCR), there is increasing evidence that GCs also initiate rapid non-genomic signaling events in a variety of cell types. Here, we report that DM induces the phosphorylation of Lck and the activation of other downstream mediators, including p59Fyn, Zap70, Rac1, and Vav in resting but not activated human T cells. DM treatment also augments CXCL12-mediated signaling in resting T cells through its cell surface receptor, CXCR4 resulting in the enhanced actin polymerization, Rac activation, and cell migration on ligand exposure. Lck was found to be a critical intermediate in these DM-induced signaling activities. Moreover, DM-mediated Lck phosphorylation in T cells was dependent on the presence of both the GCR and the CD45 molecule. Overall, these results elucidate additional nongenomic effects of DM and the GCR on resting human T cells, inducing Lck and downstream kinase activation and augmenting chemokine signaling and function. (Blood. 2009; 113: 575-584) C1 [Taub, Dennis D.] NIA, Immunol Lab, Clin Immunol Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Indig, Fred] NIA, Intramural Res Program, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Taub, DD (reprint author), NIA, Immunol Lab, Clin Immunol Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. EM taubd@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 53 TC 22 Z9 22 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 JAN 15 PY 2009 VL 113 IS 3 BP 575 EP 584 DI 10.1182/blood-2008-04-151803 PG 10 WC Hematology SC Hematology GA 394ZO UT WOS:000262491900014 PM 18840710 ER PT J AU Stockwin, LH Vistica, DT Kenney, S Schrump, DS Butcher, DO Raffeld, M Shoemaker, RH AF Stockwin, Luke H. Vistica, David T. Kenney, Susan Schrump, David S. Butcher, Donna O. Raffeld, Mark Shoemaker, Robert H. TI Gene expression profiling of alveolar soft-part sarcoma (ASPS) SO BMC CANCER LA English DT Article ID SKELETAL-MUSCLE DIFFERENTIATION; REGULATORY PROTEIN EXPRESSION; TRANSCRIPTION FACTOR GENE; RENAL-CELL CARCINOMA; GROWTH-FACTOR; TFE3 GENE; MOLECULAR-CLONING; STRIATED-MUSCLE; BREAST-CANCER; BINDING AB Background: Alveolar soft-part sarcoma (ASPS) is an extremely rare, highly vascular soft tissue sarcoma affecting predominantly adolescents and young adults. In an attempt to gain insight into the pathobiology of this enigmatic tumor, we performed the first genome-wide gene expression profiling study. Methods: For seven patients with confirmed primary or metastatic ASPS, RNA samples were isolated immediately following surgery, reverse transcribed to cDNA and each sample hybridized to duplicate high-density human U133 plus 2.0 microarrays. Array data was then analyzed relative to arrays hybridized to universal RNA to generate an unbiased transcriptome. Subsequent gene ontology analysis was used to identify transcripts with therapeutic or diagnostic potential. A subset of the most interesting genes was then validated using quantitative RT-PCR and immunohistochemistry. Results: Analysis of patient array data versus universal RNA identified elevated expression of transcripts related to angiogenesis (ANGPTL2, HIF-1 alpha, MDK, c-MET, VEGF, TIMP-2), cell proliferation (PRL, IGFBP1, NTSR2, PCSK1), metastasis (ADAM9, ECM1, POSTN) and steroid biosynthesis (CYP17A1 and STS). A number of muscle-restricted transcripts (ITGB1BP3/MIBP, MYF5, MYF6 and TRIM63) were also identified, strengthening the case for a muscle cell progenitor as the origin of disease. Transcript differentials were validated using real-time PCR and subsequent immunohistochemical analysis confirmed protein expression for several of the most interesting changes (MDK, c-MET, VEGF, POSTN, CYP17A1, ITGB1BP3/MIBP and TRIM63). Conclusion: Results from this first comprehensive study of ASPS gene expression identifies several targets involved in angiogenesis, metastasis and myogenic differentiation. These efforts represent the first step towards defining the cellular origin, pathogenesis and effective treatment strategies for this atypical malignancy. C1 [Vistica, David T.; Kenney, Susan; Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA. [Stockwin, Luke H.] NCI, Drug Mech Grp, Dev Therapeut Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Raffeld, Mark] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Butcher, Donna O.] NCI, Pathol Histotechnol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Shoemaker, RH (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA. EM Stockwin@ncifcrf.gov; vistica@dtpax2.ncifcrf.gov; skenney@ncifcrf.gov; david_schrump@nih.gov; butcherd@ncifcrf.gov; mraff@mail.nih.gov; shoemaker@dtpax2.ncifcrf.gov FU National Cancer Institute, National Institutes of Health [NO1-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 No. NO1-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. We also recognize the intellectual contributions to this manuscript made by Dr. Ming Zhao ( NCI, Bethesda). NR 61 TC 27 Z9 30 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JAN 15 PY 2009 VL 9 AR 22 DI 10.1186/1471-2407-9-22 PG 11 WC Oncology SC Oncology GA 417DF UT WOS:000264054900002 PM 19146682 ER PT J AU Matrone, MA Whipple, RA Balzer, EM Cho, EH Yoon, JR Martin, SS AF Matrone, M. A. Whipple, R. A. Balzer, E. M. Cho, E. H. Yoon, J. R. Martin, S. S. TI Metastasis-associated microtentacles are induced in detached and circulating breast tumor cells by expression of the microtubule-binding protein, Tau SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Univ Maryland, Sch Med, Marlene & Stewart Greenebaum NCI Canc Ctr, Baltimore, MD 21201 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 JAN 15 PY 2009 VL 69 IS 2 SU S BP 76S EP 76S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200050 ER PT J AU Matrone, MA Whiplle, RA Balzer, EM Cho, EH Yoon, JR Martin, SS AF Matrone, M. A. Whiplle, R. A. Balzer, E. M. Cho, E. H. Yoon, J. R. Martin, S. S. TI c-MYC amplification and correlation with patient outcome in early stage HER2+breast cancer from the NCCTG adjuvant intergroup trial N9831 SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 [Matrone, M. A.; Whiplle, R. A.; Balzer, E. M.; Cho, E. H.; Yoon, J. R.; Martin, S. S.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum NCI Canc Ctr, Baltimore, MD 21201 USA. RI Cho, Edward/B-3727-2012 OI Cho, Edward/0000-0002-0278-334X NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 SU S BP 76S EP 77S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200051 ER PT J AU Ganz, PA Land, SR Geyer, CE Costantino, JP Pajon, ER Fehrenbacher, L Atkins, JN Polikoff, JA Vogel, VG Erban, JK Livingston, RB Perez, EA Mamounas, EP Wolmark, A Swain, SM AF Ganz, P. A. Land, S. R. Geyer, C. E. Costantino, J. P. Pajon, E. R. Fehrenbacher, L. Atkins, J. N. Polikoff, J. A. Vogel, V. G. Erban, J. K. Livingston, R. B. Perez, E. A. Mamounas, E. P. Wolmark, A. Swain, S. M. TI NSABP B-30: definitive analysis of quality of life (QOL) and menstrual history (MH) outcomes from a randomized trial evaluating different schedules and combinations of adjuvant therapy containing doxorubicin, docetaxel and cyclophosphamide in women with operable, node-positive breast cancer. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 NSABP, Pittsburgh, PA USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Univ Pittsburgh, Grad Sch Publ Hlth, NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Colarado Canc Res Prog, Denver, CO USA. Kaiser Permanente No Calif, Vallejo, CA USA. SE Canc Control Consortium CCOP, Goldsboro, NC USA. So Calif Kaiser Permanente, San Diego, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. ECOG, Philadelphia, PA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ Arizona, Arizona Canc Ctr, Arizona Hlth Sci Ctr, Ann Arbor, MI USA. NCCTG, Rochester, MN USA. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. Aultman Hlth Fdn, Canton, OH USA. Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 81S EP 82S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200065 ER PT J AU Swain, SM Jeong, JH Geyer, CE Costantino, JP Pajon, ER Fehrenbacher, L Atkins, JN Polikoff, J Vogel, VG Erban, JK Livingston, RB Perez, EA Mamounas, EP Ganz, PA Land, SR Wolmark, N AF Swain, S. M. Jeong, J-H Geyer, C. E. Costantino, J. P. Pajon, E. R. Fehrenbacher, L. Atkins, J. N. Polikoff, J. Vogel, V. G. Erban, J. K. Livingston, R. B. Perez, E. A. Mamounas, E. P. Ganz, P. A. Land, S. R. Wolmark, N. TI NSABP B-30: definitive analysis of patient outcome from a randomized trial evaluating different schedules and combinations of adjuvant therapy containing doxorubicin, docetaxel and cyclophosphamide in women with operable, node-positive breast cancer. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 NSABP, Pittsburgh, PA USA. Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. Univ Pittsburgh, NSABP Biostat Ctr, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Pittsburgh, Dept Biostat, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Colorado Canc Res Prog, Denver, CO USA. Kaiser Permanente No Calif, Vallejo, CA USA. SE Canc Control Consortium CCOP, Goldsboro, NC USA. So Calif Kaiser Permanente, San Diego, CA USA. Univ Pittsburgh, Pittsburgh, PA USA. ECOG, Philadelphia, PA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. SWOG, Ann Arbor, MI USA. Univ Arizona, Arizona Canc Ctr, Arizona Hlth Sci Ctr, Tucson, AZ USA. NCCTG, Rochester, NY USA. Mayo Clin, Jacksonville, FL 32224 USA. Aultman Hlth Fdn, Canton, OH USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 JAN 15 PY 2009 VL 69 IS 2 BP 81S EP 81S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200064 ER PT J AU Ramaswamy, B Bhalla, K Cohen, B Pellegrino, C Hershman, D Chuang, E Somlo, G Goetz, M Swaby, R Hopkins, U Christos, P Espinoza-Delgado, I Sparano, JA AF Ramaswamy, B. Bhalla, K. Cohen, B. Pellegrino, C. Hershman, D. Chuang, E. Somlo, G. Goetz, M. Swaby, R. Hopkins, U. Christos, P. Espinoza-Delgado, I Sparano, J. A. TI Phase I-II study of the historic deacetylase inhibitor (HDACi) vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer (MBC): New York Cancer Consortium trial P7703 SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Ohio State Univ, Columbus, OH 43210 USA. Med Coll Georgia, Augusta, GA 30912 USA. Montefiore Einstein Canc Ctr, Bronx, NY USA. NY Presbyterian Hosp, New York, NY USA. Weill Cornell Univ, New York, NY USA. Mayo Clin, Rochester, MN 55905 USA. Fox Chase Canc Ctr, Philadelphia, PA USA. NCI, Bethesda, MD 20892 USA. City Hope Natl Med Ctr, Duarte, CA USA. RI Ramaswamy, Bhuvaneswari/E-3919-2011 NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 92S EP 93S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200097 ER PT J AU Harvie, M Chapman, M Cuzick, J Flyvbjerg, A Jebb, S Mattson, M Howell, A AF Harvie, M. Chapman, M. Cuzick, J. Flyvbjerg, A. Jebb, S. Mattson, M. Howell, A. TI The effect of intermittent versus continuous energy restriction on biomarkers of breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 S Manchester Univ Hosp Trust, Manchester, Lancs, England. Wolfson Inst, London, England. Aarhus Univ, Aarhus, Denmark. MRC Human Nutr Res Grp, Cambridge, England. NIA, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2009 VL 69 IS 2 BP 95S EP 96S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200107 ER PT J AU Weyandt, JD Snyder, C Lynch, HT Gillanders, E Holmes, TN Bailey-Wilson, J Ellsworth, RE AF Weyandt, J. D. Snyder, C. Lynch, H. T. Gillanders, E. Holmes, T. N. Bailey-Wilson, J. Ellsworth, R. E. TI Identification of BRCA1 and BRCA2 genetic modifiers SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Windber Res Inst, Windber, PA USA. Creighton Univ, Omaha, NE 68178 USA. Natl Human Genome Inst, NIH, Baltimore, MD USA. Henry M Jackson Fdn, Windber, PA USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 117S EP 118S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200173 ER PT J AU Hassan, S Ferrario, C Saragovi, U Quenneville, L Gaboury, L Baccarelli, A Salvucci, O Basik, M AF Hassan, S. Ferrario, C. Saragovi, U. Quenneville, L. Gaboury, L. Baccarelli, A. Salvucci, O. Basik, M. TI Combination of low plasma stromal cell-derived factor-1 and phosphorylated-CXCR4: independent prognostic marker for breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 McGill Univ, Montreal, PQ, Canada. Univ Montreal, Montreal, PQ, Canada. Univ Milan, Milan, Italy. IRCCS Maggiore Policlin Hosp, Milan, Italy. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 JAN 15 PY 2009 VL 69 IS 2 BP 126S EP 126S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200200 ER PT J AU Korde, LA Mueller, CM Nichols, K Loud, JT Struewing, J Greene, MH Mai, PL AF Korde, L. A. Mueller, C. M. Nichols, K. Loud, J. T. Struewing, J. Greene, M. H. Mai, P. L. TI Breast cancer risk in mutation-negative members of known BRCA1/2 mutation-positive families SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Natl Canc Inst, Rockville, MD USA. Westat Corp, Rockville, MD USA. NHGRI, Rockville, MD USA. RI Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 134S EP 134S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200224 ER PT J AU Muccio, DD Lubet, RA Atigadda, VR Brouillette, WJ Grubbs, CJ AF Muccio, D. D. Lubet, R. A. Atigadda, V. R. Brouillette, W. J. Grubbs, C. J. TI Effects of methyl derivatives of the rexinoid UAB30 on methyinitrosourea (MNU) induced mammary cancers and on various indicators of toxicity. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Univ Alabama, Birmingham, AL USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 138S EP 138S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200239 ER PT J AU Townsend, RR Rohrs, H Leduc, R Yi, Y Yao, R Malone, JP Edrman-Gilmore, P Grubbs, CJ You, M Lubet, RA AF Townsend, R. R. Rohrs, H. Leduc, R. Yi, Y. Yao, R. Malone, J. P. Edrman-Gilmore, P. Grubbs, C. J. You, M. Lubet, R. A. TI Identification of urinary biomarkers to distinguish tumor bearing and control rats in the methylnitrosourea (MNU) - induced model of mammary carcinogenesis: use of label-free, comparative, ultra-high resolution nano-LC mass spectrometry. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Washington Univ, St Louis, MO USA. Univ Alabama, Birmingham, AL USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 138S EP 139S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200240 ER PT J AU Grubbs, CJ Iwata, KK Buck, E Juliana, MM Lubet, RA AF Grubbs, C. J. Iwata, K. K. Buck, E. Juliana, M. M. Lubet, R. A. TI Preventive effects of the EGFr inhibitor erlotinib in ER+ methyinitrosourea (MNU) induced and in ER- MMTV/Neu/P53KO mammary cancer models. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual Meeting of the San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Univ Alabama, Birmingham, AL USA. OSI Pharmaceut, Farmingdale, NY USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 SU S BP 139S EP 139S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200243 ER PT J AU Lu, Y Liu, P Wang, Y Grubbs, C Lubet, R You, M AF Lu, Y. Liu, P. Wang, Y. Grubbs, C. Lubet, R. You, M. TI A gene expression signature predicts cbemopreventive response of an EGFR inhibitor in a rat mammary cancer model. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Washington Univ, St Louis, MO USA. Washinton Univ, St Louis, MO USA. Univ Alabama, Birmingham, AL USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 139S EP 139S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200242 ER PT J AU Duchnowska, R Jassem, J Shen, C Thorat, M Li, L Morimiya, A Zhao, Q Biernat, W Mandat, T Staszkiewicz, R Och, W Szostak, W Gugala, K Trojanowski, T Czartoryska-Arlukowicz, B Szczylik, C Nakshatri, H Steeg, P Sledge, G Badve, S AF Duchnowska, R. Jassem, J. Shen, C. Thorat, M. Li, L. Morimiya, A. Zhao, Q. Biernat, W. Mandat, T. Staszkiewicz, R. Och, W. Szostak, W. Gugala, K. Trojanowski, T. Czartoryska-Arlukowicz, B. Szczylik, C. Nakshatri, H. Steeg, P. Sledge, G. Badve, S. TI Molecular characteristics of matched brain metastasis (BM) versus the primary breast cancer (PBC). SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Mil Inst Med, Warsaw, Poland. Med Univ, Gdansk, Poland. Indiana Univ, Indianapolis, IN 46204 USA. Gen Hosp, Olsztyn, Poland. Med Univ, Lublin, Poland. Reg Canc Ctr, Bialystok, Poland. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2009 VL 69 IS 2 BP 164S EP 164S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200319 ER PT J AU Anderson, WF Rosenberg, PS Jatoi, I Pfeiffer, RM AF Anderson, W. F. Rosenberg, P. S. Jatoi, I Pfeiffer, R. M. TI The black to white breast cancer incidence rate crossover. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 NCI, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Bethesda, MD USA. RI Pfeiffer, Ruth /F-4748-2011 NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 182S EP 182S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583200376 ER PT J AU Shelton, PM Nguyen, B Chen, A Burger, AM AF Shelton, P. M. Nguyen, B. Chen, A. Burger, A. M. TI Transcriptional gene expression profiles indicate response of breast cancer cell lines to aminoflavone prodrug. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Univ Maryland, Baltimore, MD 21201 USA. Tigris Pharmaceut Inc, Bonita Springs, FL USA. NCI, Rockville, MD USA. Wayne State Univ, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2009 VL 69 IS 2 BP 201S EP 201S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201020 ER PT J AU Yamaji, D Robinson, GW Muller, WJ Hennighausen, L AF Yamaji, D. Robinson, G. W. Muller, W. J. Hennighausen, L. TI Deletion of STAT5 prevents HER2/Neu/ErbB2-induced mammary tumor development SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 NIDDK, Natl Inst Hlth, Bethesda, MD USA. McGill Univ, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2009 VL 69 IS 2 BP 218S EP 218S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201073 ER PT J AU Stout Gergich, NL Levy, E Springer, B Pfalzer, L McGarvey, C Gerber, L Soballe, P AF Stout Gergich, N. L. Levy, E. Springer, B. Pfalzer, L. McGarvey, C. Gerber, L. Soballe, P. TI Pre operative assessment enables the early detection and treatment of shoulder impairments related to breast cancer treatment. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Natl Naval Med Ctr, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Univ Michigan, Flint, MI 48503 USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 277S EP 277S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201260 ER PT J AU Mohebtash, M Madan, R Arlen, R Jacquin, J Mary, P Oksook, H Myrna, R Jeffrey, S James, G AF Mohebtash, M. Madan, R. Arlen, R. Jacquin, J. Mary, P. Oksook, H. Myrna, R. Jeffrey, S. James, G. TI Immunotherapy with MUC1/CEA vaccine alone or combined with chemotherapy in patients with metastatic breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 [Mohebtash, M.; Madan, R.; Arlen, R.; Jacquin, J.; Mary, P.; Oksook, H.; Myrna, R.; Jeffrey, S.; James, G.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2009 VL 69 IS 2 BP 287S EP 288S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201290 ER PT J AU Gierach, GL Loud, JT Chow, CK Prindiville, SA Eng-Wong, J Soballe, PW Giambartolomei, C Mai, PL Gail, MH Greene, MH AF Gierach, G. L. Loud, J. T. Chow, C. K. Prindiville, S. A. Eng-Wong, J. Soballe, P. W. Giambartolomei, C. Mai, P. L. Gail, M. H. Greene, M. H. TI Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 NCI, Rockville, MD USA. Natl Naval Med Ctr, Bethesda, MD USA. RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 301S EP 301S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201329 ER PT J AU Glynn, SA Boersma, BJ Howe, TM Ridnour, L Wink, D Yi, M Yvantis, H Ambs, S AF Glynn, S. A. Boersma, B. J. Howe, T. M. Ridnour, L. Wink, D. Yi, M. Yvantis, H. Ambs, S. TI Aberrant inducible nitric oxide synthase expression predicts poor survival in estrogen receptor negative breast cancer, and is associated with a gene expression signature similar to that of basal-like breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 NCI, Bethesda, MD 20892 USA. NCI, Frederick SAIC Frederick Inc, Frederick, MD 21701 USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. RI Glynn, Sharon/D-7136-2013; Boersma, Brenda/A-9270-2009 OI Glynn, Sharon/0000-0003-1459-2580; Boersma, Brenda/0000-0002-8992-2735 NR 0 TC 0 Z9 0 U1 0 U2 2 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 JAN 15 PY 2009 VL 69 IS 2 BP 320S EP 321S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201391 ER PT J AU Eng-Wong, J Reynolds, JC Venzon, D Wedam, S Prindiville, S Zujewski, JA Korde, L AF Eng-Wong, J. Reynolds, J. C. Venzon, D. Wedam, S. Prindiville, S. Zujewski, J. A. Korde, L. TI Effect of exemestane on bone mineral density in postmenopausal women at increased risk for breast cancer. SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Georgetown Univ, Washington, DC USA. NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 326S EP 326S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201409 ER PT J AU Capala, J Kramer-Marek, G Lee, SB Hassan, M Kiesewetter, DO Puri, A Chernomordik, V Gandjbakhche, A Griffiths, G Blumenthal, R AF Capala, J. Kramer-Marek, G. Lee, S. B. Hassan, M. Kiesewetter, D. O. Puri, A. Chernomordik, V Gandjbakhche, A. Griffiths, G. Blumenthal, R. TI Molecular targeting of HER2 for diagnosis and therapy of breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 [Capala, J.; Kramer-Marek, G.; Lee, S. B.; Hassan, M.; Kiesewetter, D. O.; Puri, A.; Chernomordik, V; Gandjbakhche, A.; Griffiths, G.; Blumenthal, R.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 JAN 15 PY 2009 VL 69 IS 2 BP 349S EP 349S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201479 ER PT J AU Shoghi, KI He, J Su, Y Yan, Y Rowland, D Garbow, J Mach, RH Lubet, RA You, M AF Shoghi, K., I He, J. Su, Y. Yan, Y. Rowland, D. Garbow, J. Mach, R. H. Lubet, R. A. You, M. TI Multi-modality imaging of N-methyl-N-nitrosourea-induced mammary tumors by MRI and small animal PET SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 Washington Univ, Sch Med, St Louis, MO USA. Univ Calif Davis, Davis, CA 95616 USA. NIH, Bethesda, MD 20892 USA. RI Rowland, Douglas/F-3104-2014; Shoghi, Kooresh/H-7398-2014 OI Rowland, Douglas/0000-0001-8059-6905; Shoghi, Kooresh/0000-0003-3204-457X NR 0 TC 0 Z9 0 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 JAN 15 PY 2009 VL 69 IS 2 BP 350S EP 350S PG 1 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201483 ER PT J AU Glynn, SA Boersma, BJ Howe, TM Ridnour, L Wink, D Edvardsen, H Borresen-Dale, AL Ambs, S AF Glynn, S. A. Boersma, B. J. Howe, T. M. Ridnour, L. Wink, D. Edvardsen, H. Borresen-Dale, A-L Ambs, S. TI A functional SNP in the leader sequence of the manganese superoxide dimutase gene is a predictor of breast cancer patient survival and response to chemotherapy SO CANCER RESEARCH LA English DT Meeting Abstract CT 31st Annual San Antonio Breast Cancer Symposium CY DEC 10-14, 2008 CL San Antonio, TX C1 NCI, Bethesda, MD 20892 USA. Rikshosp Radiumhosp Med Ctr, Oslo, Norway. RI Boersma, Brenda/A-9270-2009; Glynn, Sharon/D-7136-2013; boersma, bendiks/O-2823-2013 OI Boersma, Brenda/0000-0002-8992-2735; Glynn, Sharon/0000-0003-1459-2580; NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2009 VL 69 IS 2 BP 366S EP 367S PG 2 WC Oncology SC Oncology GA 396HQ UT WOS:000262583201533 ER PT J AU Aprelikova, O Pandolfi, S Tackett, S Ferreira, M Salnikow, K Ward, Y Risinger, JI Barrett, JC Niederhuber, J AF Aprelikova, Olga Pandolfi, Silvia Tackett, Sean Ferreira, Mark Salnikow, Konstantin Ward, Yvona Risinger, John I. Barrett, J. Carl Niederhuber, John TI Melanoma Antigen-11 Inhibits the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 and Activates Hypoxic Response SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTIONAL ACTIVITY; PROLINE HYDROXYLATION; ANDROGEN RECEPTOR; FACTOR HIF; PROSTATE-CANCER; HIF-1-ALPHA; EXPRESSION; OXYGEN; FACTOR-1-ALPHA; PROTEIN AB Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic switch, is regulated by reduced oxygen availability. Normally, HIF-alpha proteins are maintained at low levels, controlled by site-specific hydroxylation carried out by HIF prolyl hydroxylases (PHD) and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitin ligase. Using a yeast two-hybrid screen, we identified an interaction between melanoma antigen-11 (MAGE-11) cancer-testis antigen and the major HIF-a hydroxylating enzyme PHD2. The interaction was confirmed by a pull-down assay, coimmunoprecipitation, and colocalization in both normoxic and hypoxic conditions. Furthermore, MAGE-9, the closest homologue of MAGE-11, was also found to interact with PHD2. MAGE-11 inhibited PHD activity without affecting protein levels. This inhibition was accompanied by stabilization of ectopic or endogenous HIF-1 alpha protein. Knockdown of MAGE-11 by small interfering RNA results in decreased hypoxic induction of HIF-1 alpha and its target genes. Inhibition of PHD by MAGE-11, and following activation of HIFs, is a novel tumor-associated HIF regulatory mechanism. This finding provides new insights into the significance of MAGE expression in tumors and may provide valuable tools for therapeutic intervention because of the restricted expression of the MAGE gene family in cancers, but not in normal tissues. [Cancer Res 2009;69(2):616-24] C1 [Aprelikova, Olga; Ferreira, Mark; Ward, Yvona; Niederhuber, John] NCI, Lab Tumor & Stem Cell Biol, Bethesda, MD 20892 USA. [Aprelikova, Olga; Pandolfi, Silvia; Tackett, Sean; Risinger, John I.; Barrett, J. Carl] NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. [Salnikow, Konstantin] NCI, Comparat Carcinogenesis Lab, Bethesda, MD 20892 USA. [Risinger, John I.] Mem Hlth Univ Med Ctr, Curtis & Elizabeth Anderson Canc Inst, Savannah, GA 31404 USA. RP Aprelikova, O (reprint author), NCI, Lab Tumor & Stem Cell Biol, Bldg 37,Room 1042,9000 Rockville Pike, Bethesda, MD 20892 USA. EM apreliko@mail.nih.gov OI Tackett, Sean/0000-0001-5369-7225 FU NIH National Cancer Institute Center for Cancer Research Intramural Research Program FX NIH National Cancer Institute Center for Cancer Research Intramural Research Program. NR 45 TC 33 Z9 37 U1 1 U2 3 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 JAN 15 PY 2009 VL 69 IS 2 BP 616 EP 624 DI 10.1158/0008-5472.CAN-08-0811 PG 9 WC Oncology SC Oncology GA 396HN UT WOS:000262582900031 PM 19147576 ER PT J AU Yin, YZ Yuan, HY Zeng, X Kopelovich, L Glazert, RI AF Yin, Yuzhi Yuan, Hongyan Zeng, Xiao Kopelovich, Levy Glazert, Robert I. TI Inhibition of Peroxisome Proliferator-Activated Receptor gamma Increases Estrogen Receptor-Dependent Tumor Specification SO CANCER RESEARCH LA English DT Article ID MAMMARY EPITHELIAL-CELLS; DMBA-INDUCED MAMMARY; BREAST-CANCER CELLS; PPAR-GAMMA; BETA-CATENIN; STEM-CELL; MEDIATED ACTIVATION; COACTIVATOR PGC-1; RESPONSE ELEMENTS; PROGENITOR CELLS AB Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism, adipocyte differentiation, and tumor suppression and proliferation. To understand the role of PPAR gamma in tumorigenesis, transgenic mice were generated with mammary gland-directed expression of the dominant-negative transgene Pax8PPAR gamma. Transgenic mice were phenotypically indistinguishable from wild-type (WT) mice, but mammary epithelial cells expressed a greater percentage of CD29(hi)/CD24(neg), CK5(+), and double-positive CK14/CK18 cells. These changes correlated with reduced PTEN and increased Ras and extracellular signal-regulated kinase (ERK) and AKT activation. Although spontaneous tumorigenesis did not occur, transgenic animals were highly susceptible to progestin/7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis, which in contrast to WT mice resulted in a high tumor multiplicity and, most importantly, in the appearance of predominantly estrogen receptor alpha-positive (ER+) ductal adenocarcinomas. Tumors expressed a similar PTENlo /pERK(hi)/pAKT(hi) phenotype as mammary epithelium and exhibited high activation of estrogen response element-dependent reporter gene activity. Tumorigenesis in MMTV-Pax8PPAR gamma mice was insensitive to the chemopreventive effect of a PPAR gamma agonist but was profoundly inhibited by the ER antagonist fulvestrant. These results reveal important new insights into the previously unrecognized role of PPAR gamma in the specification of mammary lineage and the development of ER+ tumors. [Cancer Res 2009;69(2):687-94] C1 [Yin, Yuzhi; Yuan, Hongyan; Zeng, Xiao; Glazert, Robert I.] Georgetown Univ, Dept Oncol, Washington, DC 20007 USA. [Yin, Yuzhi; Yuan, Hongyan; Zeng, Xiao; Glazert, Robert I.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Kopelovich, Levy] NCI, Chemoprevent Agent Dev & Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Glazert, RI (reprint author), Georgetown Univ, Dept Oncol, 3970 Reservoir Rd,NW Res Bldg,Room W318, Washington, DC 20007 USA. EM glazerr@georgetown.edu FU NCI NIH HHS [R01 CA111482, N01 CN043309, N01 CN43330, R01 CA11482]; NCRR NIH HHS [C06 RR014567, C06 RR14567] NR 62 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2009 VL 69 IS 2 BP 687 EP 694 DI 10.1158/0008-5472.CAN-08-2446 PG 8 WC Oncology SC Oncology GA 396HN UT WOS:000262582900040 PM 19147585 ER PT J AU Russo, AL Kwon, HC Burgan, WE Carter, D Beam, K Weizheng, X Zhang, J Slusher, BS Chakravarti, A Tofilon, PJ Camphausen, K AF Russo, Andrea L. Kwon, Hyuk-Chan Burgan, William E. Carter, Donna Beam, Katie Weizheng, Xu Zhang, Jie Slusher, Barbara S. Chakravarti, Arnab Tofilon, Philip J. Camphausen, Kevin TI In vitro and In vivo Radiosensitization of Glioblastoma Cells by the Poly (ADP-Ribose) Polymerase Inhibitor E7016 SO CLINICAL CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; POLY(ADP-RIBOSE) POLYMERASE; 3-AMINOBENZAMIDE; TEMOZOLOMIDE; LINES AB Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors are undergoing clinical evaluation for cancer therapy, Because PARP inhibition has been shown to enhance tumor cell sensitivity to radiation, we investigated the in vitro and in vivo effects of the novel PARP inhibitor E7016. Experimental Design: The effect of E7016 on the in vitro radiosensitivity of tumor cell lines was evaluated using clonogenic survival. DNA damage and repair were measured using gamma H2AX foci and neutral comet assay. Mitotic catastrophe was determined by immunostaining. Tumor growth delay was evaluated in mice for the effect of E7016 on in vivo (U251) tumor radiosensitivity. Results: Cell lines exposed to E7016 preirradiation yielded an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 from 1.4 to 1.7. To assess DNA double-strand breaks repair, gamma H2AX measured at 24 hours postirradiation had significantly more foci per cell in the E7016/irradiation group versus irradiation alone. Neutral comet assay further suggested unrepaired double-strand breaks with significantly greater DNA damage at 6 hours postirradiation in the combination group versus irradiation alone. Mitotic catastrophe staining revealed a significantly greater number of cells staining positive at 24 hours postirradiation in the combination group. In vivo, mice treated with E7016/irradiation/temozolomide had an additional growth delay of six days compared with the combination of temozolomide and irradiation. Conclusions: These results indicate that E7016 can enhance tumor cell radiosensitivity in vitro and in vivo through the inhibition of DNA repair. Moreover, enhanced growth delay with the addition of E7016 to temozolomide and radiotherapy in a glioma mouse model suggests a potential role for this drug in the treatment of glioblastoma multiforme. C1 [Russo, Andrea L.; Kwon, Hyuk-Chan; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Burgan, William E.; Carter, Donna; Beam, Katie] NCI, Mol Radiat Therapeut Branch, Bethesda, MD 20892 USA. [Russo, Andrea L.] Howard Hughes Med Inst NIH Res Scholar, Bethesda, MD USA. [Burgan, William E.; Carter, Donna; Beam, Katie] NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. [Weizheng, Xu; Zhang, Jie; Slusher, Barbara S.] Eisai Res Inst, Baltimore, MD USA. [Chakravarti, Arnab] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Tofilon, Philip J.] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Program, Tampa, FL 33682 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr 3B42, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU NIH; National Cancer Institute FX Grant support: Intramural Research Program of the NIH, National Cancer Institute. 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 22 TC 97 Z9 102 U1 2 U2 11 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 JAN 15 PY 2009 VL 15 IS 2 BP 607 EP 612 DI 10.1158/1078-0432.CCR-08-2079 PG 6 WC Oncology SC Oncology GA 397VD UT WOS:000262689300023 PM 19147766 ER PT J AU Chung, JY Hong, SM Choi, BY Cho, H Yu, E Hewitt, SM AF Chung, Joon-Yong Hong, Seung-Mo Choi, Byeong Yeob Cho, HyungJun Yu, Eunsil Hewitt, Stephen M. TI The Expression of Phospho-AKT, Phospho-mTOR, and PTEN in Extrahepatic Cholangiocarcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED ENDOMETRIAL CARCINOMA; BILE-DUCT CARCINOMAS; PROGNOSTIC-SIGNIFICANCE; BILIARY-TRACT; CLASSIFICATION PROBLEMS; TISSUE MICROARRAYS; STAGING SYSTEM; PROTEIN-KINASE; CELL-LINES; CANCER AB Purpose: The protein kinase B (AKT) pathway plays a key role in the regulation of cellular survival, apoptosis, and protein translation, and has been shown to have prognostic significance in a number of cancers. We sought to define its role in extrahepatic cholangiocarcinoma. Experimental Design: Two hundred twenty-one extrahepatic cholangiocarcinoma patients with clinicopathologic data, including survival, were arrayed into tissue microarrays. Phosphorylated AKT (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein expressions were studied with multiplex tissue immunoblotting assay. Results: Expressions of p-AKTand p-mTOR were significantly increased in extrahepatic cholangiocarcinoma cases compared with normal and dysplastic bile duct epithelium (P < 0.05 both). Decreased PTEN expression was observed in patients with increasing depth of invasion (P < 0.05),T classification (P < 0.05), and stage grouping (P < 0.05), and the presence of invasion of the pancreas (P ( 0.05) and duodenum (P < 0.05). Decreased PTEN expression (P = 0.004) as well as decreased PTEN/p-AKT (P = 0.003) and PTEN/p-mTOR (P = 0.009) expression showed shorter survival by univariate but not by multivariate analysis. Conclusions: The AKT pathway is activated in a subset of extrahepatic cholangiocarcinoma. Elevated PTEN expression correlates with longer survival. Quantitative data obtained by multiplex tissue immunoblotting may provide additional information than assessment of immunohistochemistry alone. Quantitative analysis of PTEN, PTEN/p-AKT and PTEN/p-mTOR shows differences in survival by univariate analysis. C1 [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Hong, Seung-Mo] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Choi, Byeong Yeob; Cho, HyungJun] Korea Univ, Dept Stat, Seoul, South Korea. [Yu, Eunsil] Univ Ulsan, Dept Pathol, Asan Med Ctr, Seoul, South Korea. RP Hewitt, SM (reprint author), Adv Technol Ctr, TARP Lab, MSC 4605, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Hong, Seung-Mo/0000-0002-8888-6007; Chung, Joon-Yong/0000-0001-5041-5982 FU NIH; National Cancer Institute; Center for Cancer Research; Korean Government [KRF-2007-331-C00065] FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund; KRF-2007-331-C00065). NR 39 TC 53 Z9 59 U1 0 U2 5 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 JAN 15 PY 2009 VL 15 IS 2 BP 660 EP 667 DI 10.1158/1078-0432.CCR-08-1084 PG 8 WC Oncology SC Oncology GA 397VD UT WOS:000262689300029 PM 19147772 ER PT J AU Ghosh, P Albert, PS AF Ghosh, Pulak Albert, Paul S. TI A Bayesian analysis for longitudinal semicontinuous data with an application to an acupuncture clinical trial SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article ID PROFILING PROVIDERS; HEALTH-CARE; MODEL AB In many biomedical applications, researchers encounter semicontinuous data where data are either continuous or zero. When the data are collected over time the observations may be correlated. Analysis of this kind of longitudinal semicontinuous data is challenging due to the presence of strong skewness in the data. A flexible class of zero-inflated models in a longitudinal setting is developed. A Bayesian approach is used to analyze longitudinal data from an acupuncture clinical trial, in which the effects of active acupuncture,sham acupuncture and standard medical care is compared on chemotherapy-induced nausea inpatients who were treated for advanced breast cancer. A spline model is introduced into the linear predictor of the model to explore the possibility of a nonlinear treatment effect. Possible serial correlation between successive observations is also accounted using the Brownian motion. Thus, the approach taken in this paper provides for a more flexible modeling framework and, with the use of WinBUGS, provides for a computationally simpler approach than direct maximum-likelihood. The Bayesian methodology is illustrated with the acupuncture clinical trial data. (C) 2008 Elsevier B.V. All rights reserved.. C1 [Ghosh, Pulak] Emory Univ, Dept Biostat, Atlanta, GA 30322 USA. [Ghosh, Pulak] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Albert, Paul S.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Ghosh, P (reprint author), Emory Univ, Dept Biostat, Atlanta, GA 30322 USA. EM pulakghosh@gmail.com FU Intramural NIH HHS [Z99 HD999999] NR 28 TC 15 Z9 16 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 EI 1872-7352 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD JAN 15 PY 2009 VL 53 IS 3 BP 699 EP 706 DI 10.1016/j.csda.2008.09.011 PG 8 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 414AU UT WOS:000263837100012 PM 19763231 ER PT J AU Matsuda, M Chitnis, AB AF Matsuda, Miho Chitnis, Ajay B. TI Interaction with Notch determines endocytosis of specific Delta ligands in zebrafish neural tissue SO DEVELOPMENT LA English DT Article DE Notch signaling; Endocytosis; DeltaD; DeltaA; DeltaC; Neurogenesis; Zebrafish; Lateral inhibition; Cis inhibition ID NEUROGENIC GENE-DELTA; MIND BOMB; LATERAL INHIBITION; UBIQUITIN LIGASES; DSL PROTEINS; DROSOPHILA; EXPRESSION; HOMOLOG; ACTIVATION; HINDBRAIN AB Mind bomb1 (Mib1)-mediated endocytosis of the Notch ligand DeltaD is essential for activation of Notch in a neighboring cell. Although most DeltaD is localized in cytoplasmic puncta in zebrafish neural tissue, it is on the plasma membrane in mib1 mutants because Mib1-mediated endocytosis determines the normal subcellular localization of DeltaD. Knockdown of Notch increases cell surface DeltaA and DeltaD, but not DeltaC, suggesting that, like Mib1, Notch regulates endocytosis of specific ligands. Transplant experiments show that the interaction with Notch, both in the same cell (in cis) and in neighboring cells (in trans), regulates DeltaD endocytosis. Whereas DeltaD endocytosis following interaction in trans activates Notch in a neighboring cell, endocytosis of DeltaD and Notch following an interaction in cis is likely to inhibit Notch signaling by making both unavailable at the cell surface. The transplantation experiments reveal a heterogeneous population of progenitors: in some, cis interactions are more important; in others, trans interactions are more important; and in others, both cis and trans interactions are likely to contribute to DeltaD endocytosis. We suggest that this heterogeneity represents the process by which effective lateral inhibition leads to diversification of progenitors into cells that become specialized to deliver or receive Delta signals, where trans and cis interactions with Notch play differential roles in DeltaD endocytosis. C1 [Matsuda, Miho; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neural Dev Dynam, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Chitnis, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neural Dev Dynam, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM chitnisa@mail.nih.gov RI Matsuda, Miho/G-1616-2011 FU Intramural Research Program of the NIH/ NICHD; JSPS research fellowship FX We thank Julian Lewis ( Cancer Research UK, London) for providing zdC1 and zdD2 antibodies; Motoyuki Itoh ( Nagoya University, Japan) for valuable discussions and preliminary exploration of these questions; and all the members of Chitnis laboratory for their comments. This work was supported by the Intramural Research Program of the NIH/ NICHD. This work was also supported by a JSPS research fellowship ( M. M.). Deposited in PMC for release after 12 months. NR 41 TC 40 Z9 40 U1 0 U2 1 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 JAN 15 PY 2009 VL 136 IS 2 BP 197 EP 206 DI 10.1242/dev.027938 PG 10 WC Developmental Biology SC Developmental Biology GA 387BU UT WOS:000261927500004 PM 19056830 ER PT J AU Ishibe, S Karihaloo, A Ma, H Zhang, J Marlier, A Mitobe, M Togawa, A Schmitt, R Czyczk, J Kashgarian, M Geller, DS Thorgeirsson, SS Cantley, LG AF Ishibe, Shuta Karihaloo, Anil Ma, Hong Zhang, Junhui Marlier, Arnaud Mitobe, Mitchihiro Togawa, Akashi Schmitt, Roland Czyczk, Jan Kashgarian, Michael Geller, David S. Thorgeirsson, Snorri S. Cantley, Lloyd G. TI Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology SO DEVELOPMENT LA English DT Article DE Kidney; Met receptor; Ureteric bud; Branching; Mouse ID URETERAL BUD; KIDNEY DEVELOPMENT; EPITHELIAL MORPHOGENESIS; EGF RECEPTOR; BRANCHING MORPHOGENESIS; FACTOR/SCATTER FACTOR; TYROSINE KINASE; C-MET; HEPATOCYTE; MICE AB Ureteric bud (UB) branching during kidney development determines the final number of nephrons. Although hepatocyte growth factor and its receptor Met have been shown to stimulate branching morphogenesis in explanted embryonic kidneys, loss of Met expression is lethal during early embryogenesis without obvious kidney abnormalities. Met(fl/fl);HoxB7-Cre mice, which lack Met expression selectively in the UB, were generated and found to have a reduction in final nephron number. These mice have increased Egf receptor expression in both the embryonic and adult kidney, and exogenous Egf can partially rescue the branching defect seen in kidney explants. Met(fl/fl); HoxB7-Cre; wa-2/wa-2 mice, which lack normal Egfr and Met signaling, exhibit small kidneys with a marked decrease in UB branching at E14.5 as well as a reduction in final glomerular number. These mice developed progressive interstitial fibrosis surrounding collecting ducts with kidney failure and death by 3-4 weeks of age. Thus, in support of previous in vitro findings, Met and the Egf receptor can act cooperatively to regulate UB branching and mediate maintenance of the normal adult collecting duct. C1 [Ishibe, Shuta; Karihaloo, Anil; Ma, Hong; Zhang, Junhui; Marlier, Arnaud; Mitobe, Mitchihiro; Togawa, Akashi; Geller, David S.; Cantley, Lloyd G.] Yale Univ, Sch Med, Nephrol Sect, New Haven, CT 06510 USA. [Czyczk, Jan; Kashgarian, Michael] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schmitt, Roland] Hannover Med Sch, Dept Nephrol, D-3000 Hannover, Germany. RP Ishibe, S (reprint author), Yale Univ, Sch Med, Nephrol Sect, New Haven, CT 06510 USA. EM shuta.ishibe@yale.edu; lloyd.cantley@yale.edu FU R01; American Heart Association; [DK65109] FX This work was supported by an R01 award to L. G. C. (DK65109) and an American Heart Association Fellow-to-Faculty and American Society of Nephrology Gottschalk award to S. I. Deposited in PMC for release after 12 months. NR 55 TC 57 Z9 57 U1 0 U2 0 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 JAN 15 PY 2009 VL 136 IS 2 BP 337 EP 345 DI 10.1242/dev.024463 PG 9 WC Developmental Biology SC Developmental Biology GA 387BU UT WOS:000261927500017 PM 19103805 ER PT J AU Bras, J Simon-Sanchez, J Federoff, M Morgadinho, A Januario, C Ribeiro, M Cunha, L Oliveira, C Singleton, AB AF Bras, Jose Simon-Sanchez, Javier Federoff, Monica Morgadinho, Ana Januario, Cristina Ribeiro, Maria Cunha, Luis Oliveira, Catarina Singleton, Andrew B. TI Lack of replication of association between GIGYF2 variants and Parkinson disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID WHOLE-GENOME ASSOCIATION; MUTATIONS; GENE; FAMILIES; LINKAGE; OMI/HTRA2; SAMPLE; PARK11 AB Mutations in GIGYF2 have recently been described as causative of Parkinson's disease in Europeans. In an attempt to replicate these results in independent populations, we sequenced the entire coding region of GIGYF2 in a large series of Portuguese and North American samples. We report the finding of two of the previously published mutations in neurologically normal Control individuals. This suggests that mutations in GIGYF2 are not strongly related to the development of the disease in either of these populations. C1 [Singleton, Andrew B.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bras, Jose; Oliveira, Catarina] Univ Coimbra, Ctr Neurosci & Cell Biol, P-3000 Coimbra, Portugal. [Simon-Sanchez, Javier] CSIC, Inst Biomed Valencia, Dept Genom & Prote, Unidad Genet Mol, Valencia 46010, Spain. [Morgadinho, Ana; Januario, Cristina; Ribeiro, Maria; Cunha, Luis; Oliveira, Catarina] Coimbra Univ Hosp, Neurol Serv, P-3000 Coimbra, Portugal. [Singleton, Andrew B.] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, Intramural Res Program, NIH, Room 1A1014,Bldg 35,35 Lincoln Dr, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Bras, Jose/D-3366-2009; Oliveira, Catarina/F-3685-2010; Bras, Jose/A-1428-2011; Singleton, Andrew/C-3010-2009; OI Oliveira, Catarina/0000-0001-6942-4328 FU National Institute on Aging; National Institutes of Health; Department of Health and Human Services [Z01-AG000957-05]; Fundacao para a Ciencia e Tecnologia [SFRH/BD/29647/2006] FX This work was supported 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 Fundacao para a Ciencia e Tecnologia grant (SFRH/BD/29647/2006). NR 20 TC 35 Z9 38 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2009 VL 18 IS 2 BP 341 EP 346 DI 10.1093/hmg/ddn340 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 386QK UT WOS:000261897500012 PM 18923002 ER PT J AU Fitzgerald, PJ AF Fitzgerald, Paul J. TI Is norepinephrine an etiological factor in some types of cancer? SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE norepinerthrine; pharmacology; clonidine; adrenoceptor; rodent; hypertension; epidemiology; pheochromocytoma ID NITRO-N-NITROSOGUANIDINE; BETA-ADRENERGIC RECEPTORS; LOW-PROTEIN DIET; WISTAR RATS; GASTRIC CARCINOGENESIS; BREAST-CANCER; PROSTATE-CANCER; COLON CARCINOGENESIS; TRICYCLIC ANTIDEPRESSANTS; CELL-LINES AB I examine evidence that the signaling molecule norepinephrine (NE) is an etiological factor in some types of cancer. In support of this hypothesis, I cite the following 7 lines of evidence: (i) rodent studies of tumorigenesis in the context or NE manipulation; (ii) human studies or tricyclic antidepressant use and cancer rate; (iii) existence of pheochromocytoma, a cancer of the adrenal glands; (iv) cancer rate in families with individuals who have bipolar disorder; (v) hypertension and cancer risk; (vi) excessive body weight and cancer risk; and (vii) psychological stressors and cancer risk. Three aspects or the body's NE system are consistent with it playing an etiological role in various types of cancer: (i) NE circulates in the blood and can thereby access organ systems throughout the body, in addition to direct peripheral release by the sympathetic nervous system and being released within the brain; i I many of the hotly's organs possess NE receptors oil the outer surface of at least some or their cells; (iii) by binding to its extracellular receptors, NE affects intracellular second messenger systems that could influence carcinogenesis. Most importantly, use of existing pharmaceutical drugs that either lower the level of NE (such as clonidine) or block NE receptors may lower the probability of an individual developing cancer, and this hypothesis could be tested iminediately fly all epidemiologist through examination or existing medical records. (C) 2008 Wiley-Liss, life. C1 [Fitzgerald, Paul J.] Johns Hopkins Univ, Krieger Mind Brain Inst, Baltimore, MD 21218 USA. RP Fitzgerald, PJ (reprint author), NIAAA, 5625 Fishers Lane,Room TS20, Bethesda, MD 20852 USA. EM pfitz@mbi.mb.jhu.edu NR 82 TC 36 Z9 38 U1 0 U2 3 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 JAN 15 PY 2009 VL 124 IS 2 BP 257 EP 263 DI 10.1002/ijc.24063 PG 7 WC Oncology SC Oncology GA 388HJ UT WOS:000262010600001 PM 19004004 ER PT J AU Negri, E Boffetta, P Berthiller, J Castellsague, X Curado, MP Dal Maso, L Daudt, AW Fabianova, E Fernandez, L Wunsch, V Franceschi, S Hayes, RB Herrero, R Koifman, S Lazarus, P Lence, JJ Levi, F Mates, D Matos, E Menezes, A Muscat, J Eluf-Neto, J Olshan, AF Rudnai, P Shangina, O Sturgis, EM Szeszenia-Dabrowska, N Talamini, R Wei, Q Winn, DM Zaridze, D Lissowska, J Zhang, ZF Ferro, G Brennan, P La Vecchia, C Hashibe, M AF Negri, Eva Boffetta, Paolo Berthiller, Julien Castellsague, Xavier Curado, Maria Paula Dal Maso, Luigino Daudt, Alexander W. Fabianova, Eleonora Fernandez, Leticia Wunsch-Filho, Victor Franceschi, Silvia Hayes, Richard B. Herrero, Rolando Koifman, Sergio Lazarus, Philip Lence, Juan J. Levi, Fabio Mates, Dana Matos, Elena Menezes, Ana Muscat, Joshua Eluf-Neto, Jose Olshan, Andrew F. Rudnai, Peter Shangina, Oxana Sturgis, Erich M. Szeszenia-Dabrowska, Neonilia Talamini, Renato Wei, Qingyi Winn, Deborah M. Zaridze, David Lissowska, Jolanta Zhang, Zuo-Feng Ferro, Gilles Brennan, Paul La Vecchia, Carlo Hashibe, Mia TI Family history of cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology consortium SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE head and neck cancer; family history; pooled analysis; tobacco; alcohol ID SQUAMOUS-CELL CARCINOMA; UPPER AERODIGESTIVE TRACT; ORAL-CANCER; PHARYNGEAL CANCER; PUERTO-RICO; RISK; SMOKING; ALCOHOL; TOBACCO; DRINKING AB Alcohol and tobacco consumption are well-recognized risk factors for head and neck cancer (HNC). Evidence suggests that genetic predisposition may also play a role. Only a few epidemiologic studies, however, have considered the relation between HNC risk and family history of HNC and other cancers. We pooled individual-level data across 12 case-control studies including 8,967 HNC cases and 13,627 controls. We obtained pooled odds ratios (OR) using fixed and random effect models and adjusting for potential confounding factors. All statistical tests were two-sided. A family history of HNC in first-degree relatives increased the risk of HNC (OR = 1.7, 95% confidence interval, CI, 1.2-2.3). The risk was higher when the affected relative was a sibling (OR = 2.2, 95% CI 1.6-3.1) rather than a parent (OR = 1.5, 95% CI 1.1-1.8) and for more distal HNC anatomic sites (hypopharynx and larynx). The risk was also higher, or limited to, in subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.5-9.5) among subjects with family history, who were alcohol and tobacco users. A weak but significant association (OR = 1.1, 95% CI 1.0-1.2) emerged for family history of other tobacco-related neoplasms, particularly with laryngeal cancer (OR = 1.3, 95% CI 1.1-1.5). No association was observed for family history of nontobacco-related neoplasms and the risk of HNC (OR = 1.0, 95% CI 0.9-1.1). Familial factors play a role in the etiology of HNC. In both subjects with and without family history of HNC, avoidance of tobacco and alcohol exposure may be the best way to avoid HNC. (C) 2008 Wiley-Liss, Inc, C1 [Hashibe, Mia] Int Agcy Res Canc, Lifestyle Environm & Canc Grp, F-69008 Lyon, France. [Negri, Eva; La Vecchia, Carlo] Ist Ric Farmacol Mario Negri, Milan, Italy. [Castellsague, Xavier] Inst Catala Oncol, Barcelona, Spain. [Dal Maso, Luigino; Talamini, Renato] Aviano Canc Ctr, Dept Epidemiol, I-33081 Aviano, Italy. [Daudt, Alexander W.] Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Fabianova, Eleonora] Specialized State Hlth Inst, Banska Bystrica, Slovakia. [Fernandez, Leticia; Wunsch-Filho, Victor; Lence, Juan J.] Natl Inst Oncol & Radiobiol, Havana, Cuba. [Hayes, Richard B.; Winn, Deborah M.] Natl Canc Inst, Bethesda, MD USA. [Herrero, Rolando] Inst Invest Epidemiol, San Jose, Costa Rica. [Koifman, Sergio] Fundacao Oswaldo Cruz, Escola Nacl Saude Publ, Rio De Janeiro, Brazil. [Lazarus, Philip; Muscat, Joshua] Penn State Coll Med, Hershey, PA USA. [Levi, Fabio] Univ Lausanne, Inst Social & Prevent Med, Lausanne, Switzerland. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. [Matos, Elena] Univ Buenos Aires, Inst Oncol Angel H Roffo, Buenos Aires, DF, Argentina. [Menezes, Ana] Univ Fed Pelotas, Pelotas, Brazil. [Eluf-Neto, Jose] Univ Sao Paulo, Sao Paulo, Brazil. [Olshan, Andrew F.] UNC, Sch Publ Hlth, Chapel Hill, NC USA. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Shangina, Oxana; Zaridze, David] Russian Acad Med Sci, Canc Res Ctr, Moscow, Russia. [Sturgis, Erich M.; Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Lodz, Poland. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [La Vecchia, Carlo] Univ Milan, Ist Stat Med & Biometria, I-20122 Milan, Italy. RP Hashibe, M (reprint author), Int Agcy Res Canc, Lifestyle Environm & Canc Grp, 150 Cours Albert Thomas, F-69008 Lyon, France. EM hashibe@iarc.fr RI Wunsch Filho, Victor/C-4475-2012; Negri, Eva/B-7244-2013; Inca, Inct/K-2204-2013; Zaridze, David/K-5605-2013; Epidemiologicas, Centro de pesquisas /D-4561-2013; Eluf-Neto, Jose/B-2522-2009; Menezes, Ana/G-7266-2012; Szeszenia-Dabrowska, Neonila/F-7190-2010; Castellsague Pique, Xavier/N-5795-2014; Curado, Maria Paula/M-6200-2013; OI Negri, Eva/0000-0001-9712-8526; Eluf-Neto, Jose/0000-0001-7504-2115; Castellsague Pique, Xavier/0000-0002-0802-3595; Curado, Maria Paula/0000-0001-8172-2483; mates, dana/0000-0002-6219-9807; Lissowska, Jolanta/0000-0003-2695-5799; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute; US National Institutes of Health [R03 CA113157] FX Grant sponsor: National Cancer Institute, US National Institutes of Health: Grant number: R03 CA113157. NR 41 TC 58 Z9 59 U1 0 U2 10 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 JAN 15 PY 2009 VL 124 IS 2 BP 394 EP 401 DI 10.1002/ijc.23848 PG 8 WC Oncology SC Oncology GA 388HJ UT WOS:000262010600019 PM 18814262 ER PT J AU Kamangar, F Diaw, L Wei, WQ Abnet, CC Wang, GQ Roth, MJ Liu, B Lu, N Giffen, C Qiao, YL Dawsey, SM AF Kamangar, Farin Diaw, Lena Wei, Wen-Qiang Abnet, Christian C. Wang, Guo-Qing Roth, Mark. J. Liu, Bing Lu, Ning Giffen, Carol Qiao, You-Lin Dawsey, Sanford M. TI Serum pepsinogens and risk of esophageal squamous dysplasia SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE esophageal cancer; squamous dysplasia; pepsinogen; China ID HELICOBACTER-PYLORI INFECTION; CHRONIC ATROPHIC GASTRITIS; CELL CARCINOMA; PERNICIOUS-ANEMIA; CANCER; CHINA; POPULATION; LINXIAN; ADENOCARCINOMA; HISTOLOGY AB Pepsinogens are a class of endopeptidases that are secreted by the gastric epithelium and released into the circulation. Low serum pepsinogen I (PGI) and low serum pepsinogen I/pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy, and have recently been shown to be associated with increased risk of esophageal squamous cell carcinoma (ESCC). We conducted the current study to test whether these markers are also associated with esophageal squamous dysplasia (ESD), the precursor lesion of ESCC. We measured serum PGI and PGII, using enzyme-linked immunosorbent assays, in 125 case subjects (patients with moderate or severe ESD) and 250 sex-matched control subjects (no ESD) selected from an endoscopic screening study in Linxian, China. We used conditional logistic regression models adjusted for age, smoking and place of residence to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Serum PGI showed no statistically significant association with ESD, whether analyzed as a dichotomous, ordinal (quartiles) or continuous variable. Lower serum PGI/II ratio, however, showed a dose-response association with increased risk of ESD, with an adjusted OR (95% CI) of 2.12 (1.08-4.18), comparing the lowest versus the highest quartile. The association between the lower serum PGI/II ratio and log OR of ESD was nearly linear, and the p-value for the continuous association was 0.03. Lower serum PGI/II ratio was linearly associated with higher risk of ESD. This result is consistent with recent findings that gastric atrophy may increase the risk of ESCC. 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 [Kamangar, Farin; Abnet, Christian C.; Roth, Mark. J.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Diaw, Lena] NCI, Adv Technol Ctr, Bethesda, MD 20892 USA. [Wei, Wen-Qiang; Wang, Guo-Qing; Liu, Bing; Lu, Ning; Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. [Giffen, Carol] Informat Management Serv Inc, Bethesda, MD USA. RP Kamangar, F (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 3034, Bethesda, MD 20892 USA. EM kamangaf@mail.nih.gov RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 FU National Cancer Institute; NIH [N01-RC-47702] FX Grant sponsor: Intramural Research Program, National Cancer Institute: Grant sponsor: NIH; Grant number: N01-RC-47702. NR 31 TC 21 Z9 21 U1 0 U2 2 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 JAN 15 PY 2009 VL 124 IS 2 BP 456 EP 460 DI 10.1002/ijc.23918 PG 5 WC Oncology SC Oncology GA 388HJ UT WOS:000262010600028 PM 18844222 ER PT J AU De Lay, N Gottesman, S AF De Lay, Nicholas Gottesman, Susan TI The Crp-Activated Small Noncoding Regulatory RNA CyaR (RyeE) Links Nutritional Status to Group Behavior SO JOURNAL OF BACTERIOLOGY LA English DT Article ID OUTER-MEMBRANE PROTEINS; CAMP RECEPTOR PROTEIN; CATABOLITE REPRESSION CONTROL; ENVELOPE STRESS-RESPONSE; ESCHERICHIA-COLI; PSEUDOMONAS-AERUGINOSA; SALMONELLA-TYPHIMURIUM; CARBON METABOLISM; GLOBAL REGULATOR; DOWN-REGULATION AB Small noncoding regulatory RNAs (sRNAs) play a key role in regulating the expression of many genes in Escherichia coli and other bacteria. Many of the sRNAs identified in E. coli bind to mRNAs in an Hfq-dependent manner and stimulate or inhibit translation of the mRNAs. Several sRNAs are regulated by well-studied global regulators. Here, we report characterization of the CyaR (RyeE) sRNA, which was previously identified in a global search for sRNAs in E. coli. We demonstrated that CyaR is positively regulated by the global regulator Crp under conditions in which cyclic AMP levels are high. We showed by using microarray analysis and Northern blotting that several genes are negatively regulated by CyaR, including ompX, encoding a major outer membrane protein; luxS, encoding the autoinducer-2 synthase; nadE, encoding an essential NAD synthetase; and yqaE, encoding a predicted membrane protein with an unknown function. Using translational lacZ fusions to yqaE, ompX, nadE, and luxS, we demonstrated that the negative regulation of these genes by CyaR occurs at the posttranscriptional level and is direct. Different portions of a highly conserved 3' region of CyaR are predicted to pair with sequences near the ribosome binding site of each of these targets; mutations in this sequence affected regulation, and compensatory mutations in the target mRNA restored regulation, confirming that there is direct regulation by the sRNA. These results provide insight into the mechanisms by which Crp negatively regulates genes such as luxS and ompX and provide a link between catabolite repression, quorum sensing, and nitrogen assimilation in E. coli. C1 [De Lay, Nicholas; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37,Room 5132, Bethesda, MD 20892 USA. EM susang@helix.nih.gov FU NIH National Cancer Institute Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH National Cancer Institute Center for Cancer Research. NR 72 TC 90 Z9 91 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JAN 15 PY 2009 VL 191 IS 2 BP 461 EP 476 DI 10.1128/JB.01157-08 PG 16 WC Microbiology SC Microbiology GA 389TP UT WOS:000262117700002 PM 18978044 ER PT J AU Domenech, P Kobayashi, H LeVier, K Walker, GC Barry, CE AF Domenech, Pilar Kobayashi, Hajime LeVier, Kristin Walker, Graham C. Barry, Clifton E., III TI BacA, an ABC Transporter Involved in Maintenance of Chronic Murine Infections with Mycobacterium tuberculosis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI SBMA; SINORHIZOBIUM-MELILOTI; LIPID-A; ANTIMICROBIAL ACTIVITY; LEGUME SYMBIOSIS; GENETIC-ANALYSIS; MUTAGENESIS; RESISTANCE; PROTEIN; IDENTIFICATION AB BacA is an inner membrane protein associated with maintenance of chronic infections in several diverse host-pathogen interactions. To understand the function of the bacA gene in Mycobacterium tuberculosis (Rv1819c), we insertionally inactivated this gene and analyzed the resulting mutant for a variety of phenotypes. BacA deficiency in M. tuberculosis did not affect sensitivity to detergents, acidic pH, and zinc, indicating that there was no global compromise in membrane integrity, and a comprehensive evaluation of the major lipid constituents of the cell envelope failed to reveal any significant differences. Infection of mice with this mutant revealed no impact on establishment of infection but a profound effect on maintenance of extended chronic infection and ultimate outcome. As in alphaproteobacteria, deletion of BacA in M. tuberculosis led to increased bleomycin resistance, and heterologous expression of the M. tuberculosis BacA homolog in Escherichia coli conferred sensitivity to antimicrobial peptides. These results suggest a striking conservation of function for BacA-related proteins in transport of a critical molecule that determines the outcome of the host-pathogen interaction. C1 [Domenech, Pilar; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Kobayashi, Hajime; LeVier, Kristin; Walker, Graham C.] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, Bldg 33,Room 2W20D,33 North Dr, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012; OI /0000-0001-7243-8261 FU NIH, NIAID; National Institutes of Health [GM31010] FX This research was supported by the Intramural Research Programs of the NIH, NIAID. This work was also supported by National Institutes of Health grant GM31010 to G. C. W. G. C. W. is an American Cancer Society Research Professor. NR 45 TC 37 Z9 42 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JAN 15 PY 2009 VL 191 IS 2 BP 477 EP 485 DI 10.1128/JB.01132-08 PG 9 WC Microbiology SC Microbiology GA 389TP UT WOS:000262117700003 PM 18996991 ER PT J AU Ichikawa, N Iwabuchi, K Kurihara, H Ishii, K Kobayashi, T Sasaki, T Hattori, N Mizuno, Y Hozumi, K Yamada, Y Arikawa-Hirasawa, E AF Ichikawa, Naoki Iwabuchi, Kazuhisa Kurihara, Hidetake Ishii, Kumiko Kobayashi, Toshihide Sasaki, Takako Hattori, Nobutaka Mizuno, Yoshikuni Hozumi, Kentaro Yamada, Yoshihiko Arikawa-Hirasawa, Eri TI Binding of laminin-1 to monosialoganglioside GM1 in lipid rafts is crucial for neurite outgrowth SO JOURNAL OF CELL SCIENCE LA English DT Article DE GM1; Integrin; Laminin; Lipid rafts; Neurite outgrowth ID NERVE GROWTH-FACTOR; EXTRACELLULAR-MATRIX MOLECULES; MELANOMA B16 CELLS; PC12 CELLS; ALPHA-1 CHAIN; G-DOMAIN; GLYCOSIGNALING DOMAIN; NEURONAL DEVELOPMENT; INTEGRIN ACTIVATION; HIPPOCAMPAL-NEURONS AB Laminin-1, an extracellular matrix molecule, promotes neurite outgrowth through the interaction of integrin and actin. Monosialoganglioside GM1 in the lipid rafts associates with and activates the NGF receptor TrkA, and enhances neurite outgrowth. However, the role of GM1 in laminin-1-induced neurite outgrowth was still unclear. Here, we describe that laminin-1 binds to GM1 through a carbohydrate moiety and a specific conformation of GM1, induces focal formation of large clusters of GM1, and enhances the relocation of TrkA in the membrane of dorsal root ganglion (DRG) and PC12 cells. We found that laminin-1-mediated clustering of GM1 causes the translocation and enrichment of beta 1 integrin in lipid rafts where TrkA colocalizes with beta 1 integrin - and the activation of Lyn, Akt and MAPK to promote the outgrowth of neurites. Our results suggest that the binding of laminin-1 to GM1 facilitates the formation of a focal microdomain in the membrane, and enhances signal transduction that promotes neurite outgrowth by linking NGF-TrkA signaling with the laminin-integrin signaling pathways. C1 [Ichikawa, Naoki; Mizuno, Yoshikuni; Arikawa-Hirasawa, Eri] Juntendo Univ, Sch Med, Res Inst Dis Old Age, Tokyo 113, Japan. [Ichikawa, Naoki; Hattori, Nobutaka; Mizuno, Yoshikuni; Arikawa-Hirasawa, Eri] Juntendo Univ, Sch Med, Dept Neurol, Tokyo 113, Japan. [Iwabuchi, Kazuhisa] Juntendo Univ, Sch Med, Inst Environm & Gender Specif Med, Tokyo 113, Japan. [Kurihara, Hidetake] Juntendo Univ, Sch Med, Dept Anat, Tokyo 113, Japan. [Ishii, Kumiko; Kobayashi, Toshihide] RIKEN Frontier Res Syst, Sphingolipid Funct Lab, Saitama, Japan. [Sasaki, Takako] Shriners Hosp Children, Res Ctr, Portland, OR 97201 USA. [Hozumi, Kentaro; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Arikawa-Hirasawa, E (reprint author), Juntendo Univ, Sch Med, Res Inst Dis Old Age, Tokyo 113, Japan. EM ehirasaw@med.juntendo.ac.jp RI Kobayashi, Toshihide/B-6298-2015 OI Kobayashi, Toshihide/0000-0002-4811-7270 FU Ministry of Education, Culture, Sports, Science and Technology of Japan [17082008]; National Institutes of Health, National Institute of Dental and Craniofacial Research, USA FX We thank Hynda Kleinman and Alessandro Prinetti for their valuable suggestions. This work was supported in part by a High Technology Research Center Grant and Grants-in-Aid 17082008 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (E.A.-H.) and the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research, USA (Y.Y.). NR 72 TC 48 Z9 49 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JAN 15 PY 2009 VL 122 IS 2 BP 289 EP 299 DI 10.1242/jcs.030338 PG 11 WC Cell Biology SC Cell Biology GA 390AU UT WOS:000262137500016 PM 19118221 ER PT J AU Danish, M Gardner, ER Chen, XH Figg, WD AF Danish, Matthew Gardner, Erin R. Chen, Xiaohong Figg, William D. TI Determination of a benzamide histone deacetylase inhibitor, MS-275, in human plasma by liquid chromatography with mass-spectrometric detection SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Histone deacetylase inhibitor; LC/MS; MS-275; Benzanilide AB An analytical method was developed and validated for the quantitative determination of the histone deacetylase inhibitor MS-275 in human plasma. Calibration curves were linear in the concentration range of 1-250 ng/mL. Sample pretreatment involved a liquid-liquid extraction of 0.1 mL aliquots of plasma with methyl tert-butyl ether. MS-275 and the internal standard, benzanilide, were separated on a Zorbax SB-Phenyl column (4.6mrn x 75 mm I.D., 3.5 mu m), using a mobile phase composed of methanol and 10 mM ammonium formate (pH 2.9). The column eluent was monitored by mass spectrometry with electrospray ionization. Accuracy and precision of three concentrations of quality control samples ranged from 96.56 to 107.02% and 0.97 to 4.29%, respectively. This method represents an improvement over the previously published analytical assay for this agent, increasing the accuracy and precision (through addition of a suitable internal standard) and expanding the analytical range. The developed method was applied to study the pharmacokinetics of MS-275 in 724 clinical samples. Published by Elsevier B.V. C1 [Danish, Matthew; Chen, Xiaohong; Figg, William D.] NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Gardner, Erin R.] NCI, Clin Pharmacol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU National Cancer Institute; National Institutes of Health [NOI-CO-12400] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 6 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 15 PY 2009 VL 877 IS 3 BP 355 EP 359 DI 10.1016/j.jchromb.2008.12.018 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 400OJ UT WOS:000262877500038 PM 19117815 ER PT J AU Xu, M Sharma, A Wiest, DL Sen, JM AF Xu, Mai Sharma, Archna Wiest, David L. Sen, Jyoti Misra TI Pre-TCR-Induced beta-Catenin Facilitates Traversal through beta-Selection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; GLYCOGEN-SYNTHASE KINASE-3; WNT SIGNALING PATHWAY; THYMOCYTES IN-VIVO; POSITIVE SELECTION; TRANSCRIPTIONAL ACTIVATION; GAMMA-CATENIN; HMG-BOX; EXPRESSION; GENE AB Pre-TCR induced signals regulate development of the alpha beta TCR lineage cells at the beta-selection checkpoint. We have previously shown that conditional deletion of beta-catenin, a central mediator of Wnt-beta-catenin-T cell factor signaling pathway, impairs traversal through the beta-selection checkpoint. We now provide a molecular basis for the impairment. We demonstrate that pre-TCR signals specifically stabilize beta-catenin in CD4(-)CD8(-) double negative thymocytes during beta-selection. Pre-TCR induced Erk activity was required to stabilize beta-catenin. Enforced expression of stabilized beta-catenin was sufficient to mediate aspects of beta-selection including sustained expression of early growth response (Egr) genes. Consistently, deletion of beta-catenin reduced induction of Egr gene expression by the pre-TCR signal and blocked efficient beta-selection. Thus, we demonstrate that pre-TCR induced beta-catenin sustains expression of Egr genes that facilitate traversal through the beta-selection checkpoint. The Journal of Immunology, 2009, 182: 751-758. C1 [Sen, Jyoti Misra] NIA, Lymphocyte Dev Unit, Immunol Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Wiest, David L.] Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. RP Sen, JM (reprint author), NIA, Lymphocyte Dev Unit, Immunol Lab, NIH,Biomed Res Ctr, 08C218,251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM Jyoti-Sen@nih.gov RI Sharma, Archna/R-9377-2016; OI Sharma, Archna/0000-0003-4745-0220; Wiest, David/0000-0002-0792-3188 FU National Institute on Aging at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging at the National Institutes of Health. NR 59 TC 20 Z9 20 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 JAN 15 PY 2009 VL 182 IS 2 BP 751 EP 758 PG 8 WC Immunology SC Immunology GA 393RO UT WOS:000262390600003 PM 19124717 ER PT J AU Xu, M Sharma, A Hossain, MZ Wiest, DL Sen, JM AF Xu, Mai Sharma, Archna Hossain, M. Zulfiquer Wiest, David L. Sen, Jyoti Misra TI Sustained Expression of Pre-TCR Induced beta-Catenin in Post-beta-Selection Thymocytes Blocks T Cell Development SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ROR-GAMMA-T; TRANSCRIPTION FACTORS; POSITIVE SELECTION; IN-VIVO; TRANSGENIC MICE; RECEPTOR; SIGNALS; DIFFERENTIATION; SURVIVAL; CHAIN AB Pre-TCR and IL-7R signals regulate beta-selection of thymocytes and then must be down-regulated for further development. However, the molecular events that control down-regulation remain unknown. We and others have previously shown that beta-catenin in cooperation with TCF regulates beta-selection. In this paper, we demonstrate that beta-catenin expression is stringently regulated by intrathymic signals, it is expressed at the highest levels in the pre-TCR signaled thymocytes, and is down-regulated in post-beta-selection thymocytes. Pre-TCR-induced beta-catenin regulates initial stages of pre-TCR signaling including expression of early growth response (Egr) genes but must be down-regulated to express ROR gamma t, which is essential for maturation to the CD4(+)CD8(+) double positive (DP) stage. Sustained expression of beta-catenin results in the generation of IL-7R-, Egr-, and TGF beta-expressing pre-DP thymocytes that are blocked in development. These data are consistent with a model in which post-beta-selection, pre-TCR-induced beta-catenin expression must return to background levels for efficient transition to the DP stage. The Journal of Immunology, 2009, 182: 759-765. C1 [Sen, Jyoti Misra] NIA, Lymphocyte Dev Unit, Immunol Lab, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Wiest, David L.] Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. RP Sen, JM (reprint author), NIA, Lymphocyte Dev Unit, Immunol Lab, NIH,Biomed Res Ctr, 08C218,251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM Jyoti-Sen@NIH.GOV RI Sharma, Archna/R-9377-2016; OI Sharma, Archna/0000-0003-4745-0220; Wiest, David/0000-0002-0792-3188 FU National Institute on Aging at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging at the National Institutes of Health. NR 49 TC 14 Z9 14 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 JAN 15 PY 2009 VL 182 IS 2 BP 759 EP 765 PG 7 WC Immunology SC Immunology GA 393RO UT WOS:000262390600004 PM 19124718 ER PT J AU Wolf, AI Buehler, D Hensley, SE Cavanagh, LL Wherry, EJ Kastner, P Chan, S Weninger, W AF Wolf, Amaya I. Buehler, Darya Hensley, Scott E. Cavanagh, Lois L. Wherry, E. John Kastner, Philippe Chan, Susan Weninger, Wolfgang TI Plasmacytoid Dendritic Cells Are Dispensable during Primary Influenza Virus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; A VIRUS; T-CELLS; I INTERFERON; DIFFERENTIATION; IMMUNITY; MICE; CHEMOKINES; CLEARANCE; MIGRATION AB Plasmacytoid dendritic cells (pDC) are thought to be pivotal in the first line of defense against viral infections. Although previous studies have suggested that pDC regulate the immune response against respiratory syncytial virus, their role in pulmonary infection with influenza virus has remained unclear. Using mice with GFP-tagged pDC, we observed a marked increase in pDC numbers in the lung airways 3 days after intranasal infection with influenza virus A/PR/8/34. To further investigate their potential involvement in the disease, we made use of pDC-deficient Ikaros(L/L) mice. In the absence of pDC, the recruitment of T cells to the bronchoalveolar space was delayed, which could be reversed by the adoptive transfer of pDC before infection. Surprisingly, however, when compared with wild-type animals, Ikaros(L/L) mice revealed a similar course of disease, as determined by weight loss, viral titers, levels of neutralizing Ab, and lung pathology. Moreover, the activation and differentiation of influenza-specific CD8(+) effector T cells was unaltered in the absence of pDC, as was the generation of CD8(+) memory T cells. Taken together, our study suggests that pDC regulate the accumulation of T cells in the bronchoalveolar space during early influenza virus infection, but are dispensable for the control of this disease. The Journal of Immunology, 2009, 182: 871-879. C1 [Wolf, Amaya I.; Buehler, Darya; Cavanagh, Lois L.; Wherry, E. John; Weninger, Wolfgang] Wistar Inst Anat & Biol, Program Immunol, Philadelphia, PA 19104 USA. [Hensley, Scott E.] NIAID, NIH, Bethesda, MD 20892 USA. [Kastner, Philippe; Chan, Susan] Illkirch CU Strasbourg, Inst Genet & Biol Mol & Cellulaire, Strasbourg, France. [Cavanagh, Lois L.; Weninger, Wolfgang] Centenary Inst Canc Med & Cell Biol, Newtown, NSW, Australia. [Weninger, Wolfgang] Univ Sydney, Discipline Dermatol, Camperdown, NSW, Australia. RP Weninger, W (reprint author), Centenary Inst, Locked Bag 6, Newtown, NSW 2042, Australia. EM w.weninger@centenary.org.au FU National Institutes of Health; National Health and Medical Research Council [512266]; New South Wales government FX This work was supported by a Special Population contract from the National Institutes of Health, National Health and Medical Research Council Grant 512266 and a Life Sciences Award from the New South Wales government. NR 31 TC 54 Z9 54 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 JAN 15 PY 2009 VL 182 IS 2 BP 871 EP 879 PG 9 WC Immunology SC Immunology GA 393RO UT WOS:000262390600016 PM 19124730 ER PT J AU Li, DM Wang, LL Yu, L Freundt, EC Jin, BQ Screaton, GR Xu, XN AF Li, Demin Wang, Lili Yu, Li Freundt, Eric C. Jin, Boquan Screaton, Gavin R. Xu, Xiao-Ning TI Ig-Like Transcript 4 Inhibits Lipid Antigen Presentation through Direct CD1d Interaction SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYELOMONOCYTIC CELLS; CRYSTAL-STRUCTURE; NKT CELLS; T-LYMPHOCYTES; CUTTING EDGE; HLA-G; RECEPTOR; MOLECULES; RECOGNITION; BINDING AB NKT cells recognize lipid Ags presented by CD1d molecules and play an important role in the regulation of innate and adaptive immune responses. In this study, we report the identification of a membrane-associated protein, Ig-like transcript 4 (ILT4), as a novel human CD1d receptor that inhibits CD1d-mediated immune responses. We found that native CD1d tetramer generated by mammalian cells was able to specifically bind human monocytes in the peripheral blood, and this binding was at least partly mediated by monocyte-expressed ILT4. The interaction between ILT4 and CD1d involves the two N-terminal domains of ILT4 and the Ag-binding groove of CD1d (alpha 1/alpha 2 domain). This interaction has been identified on the cell surface as well as in the endosomal and lysosomal compartments. Functional analysis showed that ILT4 could block the loading of lipid Ags such as alpha-GalCer, and consequently inhibited NKT recognition. The interaction between ILT4 and CD1d may provide new insights into the regulation of NKT-mediated immunity. The Journal of Immunology, 2009, 182: 1033-1040. C1 [Li, Demin; Wang, Lili; Freundt, Eric C.; Xu, Xiao-Ning] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Immunol Unit,MRC, Oxford OX3 9DS, England. [Yu, Li; Freundt, Eric C.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Jin, Boquan] Fourth Mil Med Univ, Dept Immunol, Xian 710032, Peoples R China. [Screaton, Gavin R.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Med, London, England. RP Li, DM (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Human Immunol Unit,MRC, Oxford OX3 9DS, England. EM demin.li@imm.ox.ac.uk FU Medical Research Council U.K.; Chinese National Natural Science Foundation [30371346] FX This work was supported by Medical Research Council U.K. and Chinese National Natural Science Foundation (30371346). NR 32 TC 21 Z9 22 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 JAN 15 PY 2009 VL 182 IS 2 BP 1033 EP 1040 PG 8 WC Immunology SC Immunology GA 393RO UT WOS:000262390600032 PM 19124746 ER PT J AU Backman, CM Zhang, YJ Malik, N Shan, LF Hoffer, B Westphal, H Tomac, AC AF Backman, Cristina M. Zhang, YaJun Malik, Nasir Shan, Lufei Hoffer, BarryJ. Westphal, Heiner Tomac, Andreas C. TI Generalized tetracycline induced Cre recombinase expression through the ROSA26 locus of recombinant mice SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Cre-loxP; ROSA26; Conditional; Tetracycline; Knockin ID DOUBLE GENE CONSTRUCT; TRANSGENIC MICE; INDUCIBLE EXPRESSION; MAMMALIAN-CELLS; BRAIN; MUTAGENESIS; GENERATION; PROMOTERS; REPORTER; VECTOR AB Inducible Cre recombinase systems have been developed to bypass initial lethal phenotypes and to provide access to later embryonic or adult phenotypes. Here we describe the generation of a recombinant mouse that combines a tetracycline dependent switch with generalized Cre recombinase expression by targeting the ubiquitously expressed ROSA26 locus. This transgenic strain was developed using a simplified gene delivery system integrating both elements, the reverse tetracycline controlled trans-activator (rtTA) and rtTA inducible promoter into a single vector. In this transgenic strain, the endogenous ROSA26 promoter drives rtTA expression through a splice acceptor site. The tetracycline inducible promoter, cloned in opposite orientation to the ROSA26 locus and separated from the rtTA element by a 5 kb human p53 intron, drives Cre recombinase expression. Crossing these mice with a Cre reporter strain showed that Cre DNA-mediated recombination was ubiquitously and effectively induced during various prenatal developmental windows. Background Cre recombinase expression levels were observed in some tissues in the absence of the inducer, mostly during late embryonic developmental stages and in adult animals. Background recombination levels were low during development and most prominent in nervous tissue. Cre recombinase expression could not be effectively induced in adult animals. While rtTA mRNA levels were high in developmental and adult tissues, Cre recombinase mRNA levels remained low after doxycycline treatment. The mouse strain described here provides a valuable tool to further analyze the function of genes during specific developmental windows, by allowing the effective inactivation of their function throughout defined stages of embryonic development. Published by Elsevier B.V. C1 [Backman, Cristina M.; Zhang, YaJun; Malik, Nasir; Shan, Lufei; Hoffer, BarryJ.; Tomac, Andreas C.] Natl Inst Drug Abuse, Cellular Neurobiol Sect, Cellular Neurobiol Branch, NIH, Baltimore, MD 21224 USA. [Westphal, Heiner] NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Backman, CM (reprint author), Natl Inst Drug Abuse, Cellular Neurobiol Sect, Cellular Neurobiol Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM cbackman@mail.nih.gov RI backman, cristina/C-1276-2013 FU [NIH] FX This study was supported by the Intramural Research Program of the NIH. NR 30 TC 6 Z9 6 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 JAN 15 PY 2009 VL 176 IS 1 BP 16 EP 23 DI 10.1016/j.jneumeth.2008.08.024 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 375MK UT WOS:000261117800002 PM 18801387 ER PT J AU Urie, KG Angulo, D Lee, JC Kozak, JJ Gray, HB Winkler, JR AF Urie, Kristopher G. Angulo, David Lee, Jennifer C. Kozak, John J. Gray, Harry B. Winkler, Jay R. TI Synchronous vs Asynchronous Chain Motion in alpha-Synuclein Contact Dynamics SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID UNFOLDED POLYPEPTIDE-CHAINS; END-TO-END; CYTOCHROME-C; INTRACHAIN DIFFUSION; LOOP FORMATION; RANDOM WALKS; SPEED LIMIT; PROTEINS; EFFICIENCY; LATTICES AB alpha-Synuclein (alpha-syn) is an intrinsically unstructured 140-residue neuronal protein of uncertain function that is implicated in the etiology of Parkinson's disease. Tertiary contact formation rate constants in (alpha-syn, determined from diffusion-limited electron-transfer kinetics measurements, are poorly approximated by simple random polymer theory. One source of the discrepancy between theory and experiment may be that interior-loop formation rates are not well approximated by end-to-end contact dynamics models. We have addressed this issue with Monte Carlo simulations to model asynchronous and synchronous motion of contacting sites in a random polymer. These simulations suggest that a dynamical drag effect may slow interior-loop formation rates by about a factor of 2 in comparison to end-to-end loops of comparable size. The additional deviations from random coil behavior in alpha-syn likely arise from clustering of hydrophobic residues in the disordered polypeptide. C1 [Urie, Kristopher G.; Angulo, David; Kozak, John J.] Depaul Univ, Dept Chem, Chicago, IL 60604 USA. [Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Gray, Harry B.; Winkler, Jay R.] CALTECH, Beckman Inst, Pasadena, CA 91125 USA. RP Kozak, JJ (reprint author), Depaul Univ, Dept Chem, 243 S Wabash Ave, Chicago, IL 60604 USA. EM kozak@depaul.edu; hbgray@caltech.edu; winklerj@caltech.edu RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU National Institutes of Health [GM068461, DK19038]; Ellison Medical Foundation; Intramural Research Program of the National Institutes of Health; National Heart, Lung, and Blood Institute FX This research was supported by grants from the National Institutes of Health (GM068461 to J.R.W.; DK19038 to H.B.G.) and the Ellison Medical Foundation (Senior Scholar Award in Aging to H.B.G.), and by the Intramural Research Program of the National Institutes of Health, the National Heart, Lung, and Blood Institute (J.C.L.). NR 30 TC 5 Z9 5 U1 0 U2 4 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 JAN 15 PY 2009 VL 113 IS 2 BP 522 EP 530 DI 10.1021/jp806727e PG 9 WC Chemistry, Physical SC Chemistry GA 392TF UT WOS:000262324400017 PM 19099437 ER PT J AU Larue, RS Andresdottir, V Blanchard, Y Conticello, SG Derse, D Emerman, M Greene, WC Jonsson, SR Landau, NR Lochelt, M Malik, HS Malim, MH Munk, C O'Brien, SJ Pathak, VK Strebel, K Wain-Hobson, S Yu, XF Yuhki, N Harris, RS AF LaRue, Rebecca S. Andresdottir, Valgerdur Blanchard, Yannick Conticello, Silvestro G. Derse, David Emerman, Michael Greene, Warner C. Jonsson, Stefan R. Landau, Nathaniel R. Loechelt, Martin Malik, Harmit S. Malim, Michael H. Muenk, Carsten O'Brien, Stephen J. Pathak, Vinay K. Strebel, Klaus Wain-Hobson, Simon Yu, Xiao-Fang Yuhki, Naoya Harris, Reuben S. TI Guidelines for Naming Nonprimate APOBEC3 Genes and Proteins SO JOURNAL OF VIROLOGY LA English DT Editorial Material ID POLYNUCLEOTIDE (DEOXY)CYTIDINE DEAMINASES; ADAPTIVE EVOLUTION; AID/APOBEC FAMILY; IN-VIVO; RESTRICTION; MECHANISM; INFECTION; VIF C1 [LaRue, Rebecca S.; Jonsson, Stefan R.; Harris, Reuben S.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Inst Mol Virol, Beckman Ctr Genome Engn,Comparat & Mol Biol Grad, Minneapolis, MN 55455 USA. [Andresdottir, Valgerdur; Jonsson, Stefan R.] Univ Iceland, Inst Expt Pathol, IS-112 Reykjavik, Iceland. [Blanchard, Yannick] AFSSA LERAPP, Unite Genet Viral & Biosecur, F-22440 Ploufragan, France. [Conticello, Silvestro G.] Inst Toscano Tumori, Core Res Lab, I-50139 Florence, Italy. [Derse, David; Pathak, Vinay K.] NCI, Ctr Canc Res, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Emerman, Michael; Malik, Harmit S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Greene, Warner C.] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Landau, Nathaniel R.] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Loechelt, Martin] German Canc Res Ctr, Res Program Infect & Canc, Div Genome Modificat & Carcinogenesis, D-69120 Heidelberg, Germany. [Malim, Michael H.] Kings Coll London, Guys Hosp, Sch Med, Dept Infect Dis, London SE1 9RT, England. [Muenk, Carsten] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany. [O'Brien, Stephen J.; Yuhki, Naoya] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Strebel, Klaus] NIAID, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. [Wain-Hobson, Simon] Inst Pasteur, Mol Retrovirol Unit, F-75015 Paris, France. [Yu, Xiao-Fang] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. RP Harris, RS (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Inst Mol Virol, Beckman Ctr Genome Engn,Comparat & Mol Biol Grad, 321 Church St SE,6-155 Jackson Hall, Minneapolis, MN 55455 USA. EM rsh@umn.edu RI Conticello, Silvestro/G-9113-2011; Malik, Harmit/E-8519-2012; OI Malim, Michael/0000-0002-7699-2064; Malik, Harmit/0000-0001-6005-0016; Conticello, Silvestro/0000-0002-4244-1846 FU Medical Research Council [G0401570] NR 23 TC 100 Z9 103 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 494 EP 497 DI 10.1128/JVI.01976-08 PG 4 WC Virology SC Virology GA 388UO UT WOS:000262045000001 PM 18987154 ER PT J AU Morner, A Douagi, I Forsell, MNE Sundling, C Dosenovic, P O'Dell, S Dey, B Kwong, PD Voss, G Thorstensson, R Mascola, JR Wyatt, RT Hedestam, GBK AF Moerner, Andreas Douagi, Iyadh Forsell, Mattias N. E. Sundling, Christopher Dosenovic, Pia O'Dell, Sijy Dey, Barna Kwong, Peter D. Voss, Gerald Thorstensson, Rigmor Mascola, John R. Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI Human Immunodeficiency Virus Type 1 Env Trimer Immunization of Macaques and Impact of Priming with Viral Vector or Stabilized Core Protein SO JOURNAL OF VIROLOGY LA English DT Article ID SEMLIKI-FOREST-VIRUS; ENVELOPE GLYCOPROTEIN TRIMERS; VENEZUELAN EQUINE ENCEPHALITIS; ALPHAVIRUS REPLICON PARTICLES; T-CELL RESPONSES; NEUTRALIZING ANTIBODIES; CANDIDATE VACCINE; CD4-BOUND STATE; RHESUS-MONKEYS; HIV-1 VACCINE AB Currently there is limited information about the quality of immune responses elicited by candidate human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env)-based immunogens in primates. Here we describe a comprehensive analysis of neutralizing antibody and T-cell responses obtained in cynomolgus macaques by three selected immunization regimens. We used the previously described YU2-based gp140 protein trimers administered in an adjuvant, preceded by two distinct priming strategies: either alphavirus replicon particles expressing matched gp140 trimers or gp120 core proteins stabilized in the CD4-bound conformation. The rationale for priming with replicon particles was to evaluate the impact of the expression platform on trimer immunogenicity. The stable core proteins were chosen in an attempt to expand selectively lymphocytes recognizing common determinants between the core and trimers to broaden the immune response. The results presented here demonstrate that the platform by which Env trimers were delivered in the priming ( either protein or replicon vector) had little impact on the overall immune response. In contrast, priming with stable core proteins followed by a trimer boost strikingly focused the T-cell response on the core sequences of HIV-1 Env. The specificity of the T-cell response was distinctly different from that of the responses obtained in animals immunized with trimers alone and was shown to be mediated by CD4(+) T cells. However, this regimen showed limited or no improvement in the neutralizing antibody responses, suggesting that further immunogen design efforts are required to successfully focus the B-cell response on conserved neutralizing determinants of HIV-1 Env. C1 [Moerner, Andreas; Douagi, Iyadh; Forsell, Mattias N. E.; Sundling, Christopher; Dosenovic, Pia; Thorstensson, Rigmor; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17177 Stockholm, Sweden. [Moerner, Andreas; Douagi, Iyadh; Forsell, Mattias N. E.; Sundling, Christopher; Dosenovic, Pia; Thorstensson, Rigmor; Hedestam, Gunilla B. Karlsson] Swedish Inst Infect Dis Control, S-17182 Solna, Sweden. [Forsell, Mattias N. E.; Dey, Barna; Kwong, Peter D.; Mascola, John R.; Wyatt, Richard T.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Voss, Gerald] GlaxoSmithKline Biol, Rixensart, Belgium. RP Hedestam, GBK (reprint author), Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Box 280, S-17177 Stockholm, Sweden. EM gunilla.karlsson.hedestam@ki.se OI Morner, Andreas/0000-0002-3654-1728; Sundling, Christopher/0000-0002-6138-690X FU Swedish International Development Agency (Sida)/Department of Research Cooperation (SAREC); National Institute of Allergy and Infectious Diseases; National Institutes of Health intramural research program; Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative; Swedish Research Council FX This study was supported by a grant from the Swedish International Development Agency (Sida)/Department of Research Cooperation (SAREC) to G.K.H. and R.T. and by the National Institute of Allergy and Infectious Diseases, National Institutes of Health intramural research program, for P.D.K., J.R.M., and R.T.W. Funding was also received from the Bill and Melinda Gates Foundation (P.D.K., J.R.M., and R.T.W.), the International AIDS Vaccine Initiative (P.D.K., R.T.W., and G.K.H.), and the Swedish Research Council (G.K.H.). NR 57 TC 47 Z9 47 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 540 EP 551 DI 10.1128/JVI.01102-08 PG 12 WC Virology SC Virology GA 388UO UT WOS:000262045000005 PM 19004960 ER PT J AU Poddar, A Reed, SC McPhillips, MG Spindler, JE McBride, AA AF Poddar, Atasi Reed, Shawna C. McPhillips, Maria G. Spindler, Jonathan E. McBride, Alison A. TI The Human Papillomavirus Type 8 E2 Tethering Protein Targets the Ribosomal DNA Loci of Host Mitotic Chromosomes SO JOURNAL OF VIROLOGY LA English DT Article ID RNA-POLYMERASE-I; TRANSCRIPTION FACTOR HUBF; NUCLEAR ANTIGEN 1; SACCHAROMYCES-CEREVISIAE; PLASMID MAINTENANCE; BROMODOMAIN PROTEIN; VIRAL-DNA; BINDING; BRD4; ASSOCIATION AB For many papillomaviruses, the viral protein E2 tethers the viral genome to the host mitotic chromosomes to ensure persistent, long-term maintenance of the genome during cell division. Our previous studies of E2 proteins from different genera of papillomaviruses have shown that they bind to different regions of the host chromosomes during mitosis. For example, bovine papillomavirus type 1 (BPV-1) E2 binds to all chromosomes as small speckles in complex with the cellular protein Brd4. In contrast, the human papillomavirus type 8 (HPV-8) E2 protein binds as large speckles at the pericentromeric regions of chromosomes. Here we show that these speckles do not contain Brd4, and unlike that of BPV-1, the N-terminal Brd4-interacting domain of HPV-8 E2 is not required for chromosome binding. In contrast to BPV-1 E2, the HPV-8 E2 protein targets the short arms of acrocentric mitotic chromosomes. Furthermore, the E2 protein interacts with the repeated ribosomal DNA genes found in this location and colocalizes with UBF, the RNA polymerase I transcription factor. Therefore, HPV-8 E2 genome tethering occurs by a Brd4-independent mechanism through a novel interaction with specific regions of mitotic chromosomes. Thus, a wide range of viruses have adopted the strategy of linking their genomes to host chromosomes, but individual viruses use different chromosomal targets. Characterization of these targets will enable the development of antiviral therapies to eliminate the viral genomes from infected cells. C1 [Poddar, Atasi; Reed, Shawna C.; McPhillips, Maria G.; Spindler, Jonathan E.; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU NIAID; NIH FX We thank Juraj Kabat for help with image processing. NR 42 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 640 EP 650 DI 10.1128/JVI.01936-08 PG 11 WC Virology SC Virology GA 388UO UT WOS:000262045000014 PM 19004936 ER PT J AU Ko, SY Cheng, C Kong, WP Wang, LS Kanekiyo, M Einfeld, D King, CR Gall, JGD Nabel, GJ AF Ko, Sung-Youl Cheng, Cheng Kong, Wing-Pui Wang, Lingshu Kanekiyo, Masaru Einfeld, David King, C. Richter Gall, Jason G. D. Nabel, Gary J. TI Enhanced Induction of Intestinal Cellular Immunity by Oral Priming with Enteric Adenovirus 41 Vectors SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD8-ALPHA(+) DENDRITIC CELLS; CD4(+) T-CELLS; ACUTE GASTROENTERITIS; IMMUNOGENICITY EVALUATION; GASTROINTESTINAL-TRACT; PROTECTIVE IMMUNITY; CANDIDATE VACCINE; HIV-1 INFECTION; PHASE-1 SAFETY AB Human immunodeficiency virus type 1 (HIV-1) infection is characterized by the rapid onset of intestinal T-cell depletion that initiates the progression to AIDS. The induction of protective immunity in the intestinal mucosa therefore represents a potentially desirable feature of a preventive AIDS vaccine. In this study, we have evaluated the ability of an enteric adenovirus, recombinant adenovirus 41 (rAd41), to elicit intestinal and systemic immune responses by different immunization routes, alone or in combination with rAd5. rAd41 expressing HIV envelope (Env) protein induced cellular immune responses comparable to those of rAd5-based vectors after either a single intramuscular injection or a DNA prime/rAd boost. Oral priming with rAd41-Env followed by intramuscular boosting with rAd5-Env stimulated a more potent CD8(+) T-cell response in the small intestine than the other immunization regimens. Furthermore, the direct injection of rAd41-Env into ileum together with intramuscular rAd5-Env boosting increased Env-specific cellular immunity markedly in mucosal as well as systemic compartments. These data demonstrate that heterologous rAd41 oral or ileal priming with rAd5 intramuscular boosting elicits enhanced intestinal mucosal cellular immunity and that oral or ileal vector delivery for primary immunization facilitates the generation of mucosal immunity. C1 [Ko, Sung-Youl; Cheng, Cheng; Kong, Wing-Pui; Wang, Lingshu; Kanekiyo, Masaru; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Einfeld, David; King, C. Richter; Gall, Jason G. D.] GenVec Inc, Gaithersburg, MD 20878 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU National Institutes of Health; Vaccine Research Center; NIAID; Bill and Melinda Gates Foundation FX This work was supported by the Intramural Research Program of the National Institutes of Health, Vaccine Research Center, NIAID, and by the Bill and Melinda Gates Foundation. NR 40 TC 16 Z9 17 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 748 EP 756 DI 10.1128/JVI.01811-08 PG 9 WC Virology SC Virology GA 388UO UT WOS:000262045000023 PM 18987146 ER PT J AU Hidajat, R Xiao, P Zhou, Q Venzon, D Summers, LE Kalyanaraman, VS Montefiori, DC Robert-Guroff, M AF Hidajat, Rachmat Xiao, Peng Zhou, Qifeng Venzon, David Summers, L. Ebonita Kalyanaraman, Vaniambadi S. Montefiori, David C. Robert-Guroff, Marjorie TI Correlation of Vaccine-Elicited Systemic and Mucosal Nonneutralizing Antibody Activities with Reduced Acute Viremia following Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge of Rhesus Macaques SO JOURNAL OF VIROLOGY LA English DT Article ID DEPENDENT CELLULAR CYTOTOXICITY; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; MONOCLONAL-ANTIBODIES; MEDIATED CYTOTOXICITY; RECOMBINANT VACCINES; VAGINAL TRANSMISSION; EFFECTOR-CELLS; HIV-INFECTION; PROTECTION AB Cell-mediated immunity and neutralizing antibodies contribute to control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection, but the role of nonneutralizing antibodies is not defined. Previously, we reported that sequential oral/oral or intranasal/oral (I/O) priming with replication-competent adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants, followed by intramuscular envelope protein boosting, elicited systemic and mucosal cellular immunity and exhibited equivalent, significant reductions of chronic viremia after rectal SIVmac251 challenge. However, I/O priming gave significantly better control of acute viremia. Here, systemic and mucosal humoral immunity were investigated for potential correlates with the acute challenge outcome. Strong serum binding but nonneutralizing antibody responses against SIVmac251 were induced in both groups. Antibody responses appeared earlier and overall were higher in the I/O group. Reduced acute viremia was significantly correlated with higher serum binding titer, stronger antibody-dependent cellular cytotoxicity activity, and peak prechallenge and 2-week-postchallenge antibody-dependent cell-mediated viral inhibition (ADCVI). The I/O group consistently displayed greater anti-envelope immunoglobulin A (IgA) antibody responses in bronchoalveolar lavage and a stronger rectal anti-envelope IgA anamnestic response 2 weeks postchallenge. Pre- and postchallenge rectal secretions inhibited SIV transcytosis across epithelial cells. The inhibition was significantly higher in the I/O group, although a significant correlation with reduced acute viremia was not reached. Overall, the replicating Ad5hr-SIV priming/envelope boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities. The pattern of elevated immune responses in the I/O group is consistent with its better control of acute viremia mediated, at least in part, by ADCVI activity and transcytosis inhibition. C1 [Hidajat, Rachmat; Xiao, Peng; Zhou, Qifeng; Summers, L. Ebonita; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Kalyanaraman, Vaniambadi S.] Adv Biosci Labs Inc, Kensington, MD 20895 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, 41 Medlars Dr Bldg,41 Rm D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU National Institutes of Health; National Cancer Institute FX We are very grateful to Marisa St. Claire, Steve Harbaugh, and Jeff Harbaugh (Bioqual, Inc., Gaithersburg, MD) for excellent care of the rhesus macaques and expert execution of all animal technical procedures. We thank Nancy Miller (DAIDS, NIAID, NIH) and Ronald C. Desrosiers, New England National Primate Research Center, Boston, MA, for the titrated SIVmac251 challenge stock. We also thank Ruth H. Florese for assistance with the RF-ADCC assay. The CEM-NKr cells were obtained from Peter Cresswell through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH.; This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 60 TC 86 Z9 87 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 791 EP 801 DI 10.1128/JVI.01672-08 PG 11 WC Virology SC Virology GA 388UO UT WOS:000262045000027 PM 18971271 ER PT J AU Trapp, S Derby, NR Singer, R Shaw, A Williams, VG Turville, SG Bess, JW Lifson, JD Robbiani, M AF Trapp, Susanna Derby, Nina R. Singer, Rachel Shaw, Andrew Williams, Vennansha G. Turville, Stuart G. Bess, Julian W., Jr. Lifson, Jeffrey D. Robbiani, Melissa TI Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G SO JOURNAL OF VIROLOGY LA English DT Article ID IFN-GAMMA-PRODUCTION; ACUTE HIV-1 INFECTION; CD4(+) T-CELLS; SIMIAN IMMUNODEFICIENCY; ANTIVIRAL ACTIONS; INNATE IMMUNITY; PROTEIN; MATURATION; INDUCTION; ALPHA AB Human immunodeficiency virus (HIV) is taken up by and replicates in immature dendritic cells (imDCs), which can then transfer virus to T cells, amplifying the infection. Strategies known to boost DC function were tested for their ability to overcome this exploitation when added after HIV exposure. Poly(I: C), but not single-stranded RNA (ssRNA) or a standard DC maturation cocktail, elicited type I interferon (IFN) and interleukin-12 (IL-12) p70 production and the appearance of unique small (15- to 20-kDa) fragments of APOBEC3G (A3G) and impeded HIV(Bal) replication in imDCs when added up to 60 h after virus exposure. Comparable effects were mediated by recombinant alpha/beta IFN (IFN-alpha/beta). Neutralizing the anti-IFN-alpha/beta receptor reversed poly(I:C)-induced inhibition of HIV replication and blocked the appearance of the small A3G proteins. The poly(I: C)-induced appearance of small A3G proteins was not accompanied by significant differences in A3G mRNA or A3G monomer expression. Small interfering RNA (siRNA) knockdown of A3G could not be used to reverse the poly(I: C)-induced protective effect, since siRNAs nonspecifically activated the DCs, inducing the appearance of the small A3G proteins and inhibiting HIV infection. Notably, the appearance of small A3G proteins coincided with the shift of high-molecular-mass inactive A3G complexes to the low-molecular-mass (LMM) active A3G complexes. The unique immune stimulation by poly(I:C) with its antiviral effects on imDCs marked by the expression of IFN-alpha/beta and active LMM A3G renders poly(I:C) a promising novel strategy to combat early HIV infection in vivo. C1 [Trapp, Susanna; Derby, Nina R.; Singer, Rachel; Shaw, Andrew; Williams, Vennansha G.; Turville, Stuart G.; Robbiani, Melissa] Populat Council, Ctr Biomed Res, HIV & AIDS Program, New York, NY 10065 USA. [Bess, Julian W., Jr.; Lifson, Jeffrey D.] NCI, SAIC Frederick, Ft Detrick, MD 21702 USA. RP Robbiani, M (reprint author), Populat Council, Ctr Biomed Res, HIV & AIDS Program, New York, NY 10065 USA. FU NIH [AI040877, DE015512, NO1-CO-12400] FX This work was supported by NIH grants AI040877 and DE015512 and in part with federal funds from the National Cancer Institute, NIH, under contract no. NO1-CO-12400. M. R. is a 2002 Elizabeth Glaser Scientist. The following reagents were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: anti-A3G, C terminal, from Jaisri Lingappa; 8E5/LAV from Thomas Folks; TZM.bl cells from John C. Kappes, Xiaoyun Wu, and Tranzyme Inc.; and 293-APOBEC3G-HA cell line from Xiao-Fang Yu. NR 76 TC 44 Z9 49 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 884 EP 895 DI 10.1128/JVI.00023-08 PG 12 WC Virology SC Virology GA 388UO UT WOS:000262045000036 PM 19004943 ER PT J AU Zhou, MS Huang, K Jung, KJ Cho, WK Klase, Z Kashanchi, F Pise-Masison, CA Brady, JN AF Zhou, Meisheng Huang, Keven Jung, Kyung-Jin Cho, Won-Kyung Klase, Zach Kashanchi, Fatah Pise-Masison, Cynthia A. Brady, John N. TI Bromodomain Protein Brd4 Regulates Human Immunodeficiency Virus Transcription through Phosphorylation of CDK9 at Threonine 29 SO JOURNAL OF VIROLOGY LA English DT Article ID RNA-POLYMERASE-II; CARBOXYL-TERMINAL DOMAIN; P-TEFB; PHOSPHATASE 2A; SUBSTRATE-SPECIFICITY; TYPE-1 TRANSCRIPTION; HIV-1 TRANSCRIPTION; 7SK SNRNA; IN-VITRO; CYCLIN-C AB Positive transcription elongation factor b (P-TEFb), composed of cyclin-dependent kinase 9 (CDK9) and cyclin T, is a global transcription factor for eukaryotic gene expression, as well as a key factor for human immunodeficiency virus (HIV) transcription elongation. P-TEFb phosphorylates the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAP II), facilitating the transition from nonprocessive to processive transcription elongation. Recently, the bromodomain protein Brd4 has been shown to interact with the low-molecular-weight, active P-TEFb complex and recruit P-TEFb to the HIV type 1 long terminal repeat (LTR) promoter. However, the subsequent events through which Brd4 regulates CDK9 kinase activity and RNAP II-dependent transcription are not clearly understood. Here we provide evidence that Brd4 regulates P-TEFb kinase activity by inducing a negative pathway. Moreover, by analyzing stepwise initiation and elongation complexes, we demonstrate that P-TEFb activity is regulated in the transcription complex. Brd4 induces phosphorylation of CDK9 at threonine 29 (T29) in the HIV transcription initiation complex, inhibiting CDK9 kinase activity. P-TEFb inhibition is transient, as Brd4 is released from the transcription complex between positions + 14 and + 36. Removal of the phosphate group at T29 by an incoming phosphatase released P-TEFb activity, resulting in increased RNAP II CTD phosphorylation and transcription. Finally, we present chromatin immunoprecipitation studies showing that CDK9 with phosphorylated T29 is associated with the HIV promoter region in the integrated and transcriptionally silent HIV genome. C1 [Zhou, Meisheng; Huang, Keven; Jung, Kyung-Jin; Cho, Won-Kyung; Pise-Masison, Cynthia A.; Brady, John N.] NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Klase, Zach; Kashanchi, Fatah] George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA. RP Brady, JN (reprint author), NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, Ctr Canc Res,NIH, Bldg 41,Room B201, Bethesda, MD 20892 USA. EM bradyj@exchange.nih.gov NR 48 TC 36 Z9 38 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 1036 EP 1044 DI 10.1128/JVI.01316-08 PG 9 WC Virology SC Virology GA 388UO UT WOS:000262045000050 PM 18971272 ER PT J AU Li, YX Svehla, K Louder, MK Wycuff, D Phogat, S Tang, M Migueles, SA Wu, XL Phogat, A Shaw, GM Connors, M Hoxie, J Mascola, JR Wyatt, R AF Li, Yuxing Svehla, Krisha Louder, Mark K. Wycuff, Diane Phogat, Sanjay Tang, Min Migueles, Stephen A. Wu, Xueling Phogat, Adhuna Shaw, George M. Connors, Mark Hoxie, James Mascola, John R. Wyatt, Richard TI Analysis of Neutralization Specificities in Polyclonal Sera Derived from Human Immunodeficiency Virus Type 1-Infected Individuals SO JOURNAL OF VIROLOGY LA English DT Article ID GP120 ENVELOPE GLYCOPROTEIN; HUMAN MONOCLONAL-ANTIBODIES; CORECEPTOR-BINDING-SITE; TYROSINE SULFATION; RECEPTOR-BINDING; CD4 RECEPTOR; HIV-1 ENTRY; INFECTION; RESPONSES; EPITOPE AB During human immunodeficiency virus type 1 (HIV-1) infection, patients develop various levels of neutralizing antibody (NAb) responses. In some cases, patient sera can potently neutralize diverse strains of HIV-1, but the antibody specificities that mediate this broad neutralization are not known, and their elucidation remains a formidable challenge. Due to variable and nonneutralizing determinants on the exterior envelope glycoprotein (Env), nonnative Env protein released from cells, and the glycan shielding that assembles in the context of the quaternary structure of the functional spike, HIV-1 Env elicits a myriad of binding antibodies. However, few of these antibodies can neutralize circulating viruses. We present a systematic analysis of the NAb specificities of a panel of HIV-1-positive sera, using methodologies that identify both conformational and continuous neutralization determinants on the HIV-1 Env protein. Characterization of sera included selective adsorption with native gp120 and specific point mutant variants, chimeric virus analysis, and peptide inhibition of viral neutralization. The gp120 protein was the major neutralizing determinant for most sera, although not all neutralization activity against all viruses could be identified. In some broadly neutralizing sera, the gp120-directed neutralization mapped to the CD4 binding region of gp120. In addition, we found evidence that regions of the gp120 coreceptor binding site may also be a target of neutralizing activity. Sera displaying limited neutralization breadth were mapped to the immunogenic V3 region of gp120. In a subset of sera, we also identified NAbs directed against the conserved, membrane-proximal external region of gp41. These data allow a more detailed understanding of the humoral responses to the HIV-1 Env protein and provide insights regarding the most relevant targets for HIV-1 vaccine design. C1 [Wyatt, Richard] NIAID, Struct Virol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Migueles, Stephen A.; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Shaw, George M.] Univ Alabama, Birmingham, AL USA. [Hoxie, James] Univ Penn, Philadelphia, PA 19104 USA. RP Wyatt, R (reprint author), NIAID, Struct Virol Sect, Vaccine Res Ctr, NIH, Bldg 40,Rm 4512,40 Convent Dr, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov FU NIH intramural research program; NIH; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation FX This work was supported in part by the NIH intramural research program. Funding was also provided by NIH, the International AIDS Vaccine Initiative, and the Bill and Melinda Gates Foundation. NR 48 TC 189 Z9 190 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 1045 EP 1059 DI 10.1128/JVI.01992-08 PG 15 WC Virology SC Virology GA 388UO UT WOS:000262045000051 PM 19004942 ER PT J AU Goila-Gaur, R Khan, MA Miyagi, E Strebel, K AF Goila-Gaur, Ritu Khan, Mohammad A. Miyagi, Eri Strebel, Klaus TI Differential Sensitivity of "Old" versus "New" APOBEC3G to Human Immunodeficiency Virus Type 1 Vif SO JOURNAL OF VIROLOGY LA English DT Article ID EDITING ENZYME APOBEC3G; ANTIVIRAL ACTIVITY; HIV-1 VIF; DEGRADATION; PROTEIN; DNA; INFECTIVITY; PROTEASOME; HYPERMUTATION; REPLICATION AB HIV-1 Vif counteracts the antiviral activity of APOBEC3G by inhibiting its encapsidation into virions. Here, we compared the relative sensitivity to Vif of APOBEC3G in stable HeLa cells containing APOBEC3G (HeLa-A3G cells) versus that of newly synthesized APOBEC3G. We observed that newly synthesized APOBEC3G was more sensitive to degradation than preexisting APOBEC3G. Nevertheless, preexisting and transiently expressed APOBEC3G were packaged with similar efficiencies into vif-deficient human immunodeficiency virus type 1 (HIV-1) virions, and Vif inhibited the encapsidation of both forms of APOBEC3G into HIV particles equally well. Our results suggest that HIV-1 Vif preferentially induces degradation of newly synthesized APOBEC3G but indiscriminately inhibits encapsidation of "old" and "new" APOBEC3G. C1 [Goila-Gaur, Ritu; Khan, Mohammad A.; Miyagi, Eri; Strebel, Klaus] NIAID, NIH, Viral Biochem Sect, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, NIH, Viral Biochem Sect, Mol Microbiol Lab, 4-312,4 Ctr Dr MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU NIH; NIAID FX This work was supported by a grant from the NIH Intramural AIDS Targeted Antiviral Program to K. S. and by the Intramural Research Program of the NIAID, NIH. NR 27 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2009 VL 83 IS 2 BP 1156 EP 1160 DI 10.1128/JVI.01734-08 PG 5 WC Virology SC Virology GA 388UO UT WOS:000262045000063 PM 19004939 ER PT J AU Wickremaratchi, MM Majounie, E Morris, HR Williams, NM Lewis, H Gill, SS Khan, S Heywood, P Hardy, J Wiles, CM Singleton, AB Quinn, NP AF Wickremaratchi, Mindhu M. Majounie, Elisa Morris, Huw R. Williams, Nigel M. Lewis, Helen Gill, Steven S. Khan, Sadaquate Heywood, Peter Hardy, John Wiles, Charles M. Singleton, Andrew B. Quinn, Niall P. TI Parkin-related Disease Clinically Diagnosed as a Pallido-Pyramidal Syndrome SO MOVEMENT DISORDERS LA English DT Letter ID RECESSIVE JUVENILE PARKINSONISM; EARLY-ONSET PARKINSONISM; LEWY BODY; MUTATIONS; GENE; DELETION C1 [Wickremaratchi, Mindhu M.; Majounie, Elisa; Morris, Huw R.; Wiles, Charles M.] Cardiff Univ, Sch Med, Dept Neurol, Cardiff, S Glam, Wales. [Majounie, Elisa; Morris, Huw R.; Williams, Nigel M.] Cardiff Univ, Sch Med, Psychol Med Genet Lab, Cardiff, S Glam, Wales. [Lewis, Helen; Gill, Steven S.; Khan, Sadaquate; Heywood, Peter] Frenchay Hosp, Inst Clin Neurosci, Bristol BS16 1LE, Avon, England. [Hardy, John; Singleton, Andrew B.] NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [Hardy, John] Dept Mol Neurosci, London, England. [Hardy, John] Reta Lila Weston Labs, London, England. [Quinn, Niall P.] Inst Neurol, Sobell Dept Neurosci & Movement Disorders, London WC1N 3BG, England. RP Wickremaratchi, MM (reprint author), Cardiff Univ, Sch Med, Dept Neurol, Cardiff, S Glam, Wales. EM morrishr@cf.ac.uk RI Hardy, John/C-2451-2009; Morris, Huw/B-8527-2008; Singleton, Andrew/C-3010-2009 OI Morris, Huw/0000-0002-5473-3774; FU Intramural NIH HHS; Medical Research Council [G0700943, G0701075]; NIA NIH HHS [Z01 AG000957-05]; Parkinson's UK [G-8047, G-0907] NR 22 TC 5 Z9 5 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN 15 PY 2009 VL 24 IS 1 BP 138 EP 140 DI 10.1002/mds.22181 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 402CW UT WOS:000262992800023 PM 18942080 ER PT J AU Chuang, KH Lee, JH Silva, AC Belluscio, L Koretsky, AP AF Chuang, Kai-Hsiang Lee, Jung Hee Silva, Afonso C. Belluscio, Leonardo Koretsky, Alan P. TI Manganese enhanced MRI reveals functional circuitry in response to odorant stimuli SO NEUROIMAGE LA English DT Article; Proceedings Paper CT 14th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine CY MAY 06-12, 2006 CL Seattle, WA SP Int Soc Magnet Resonance Med ID MOUSE OLFACTORY-BULB; RESONANCE-IMAGING MEMRI; OCULAR DOMINANCE; RAT-BRAIN; SYSTEM; COMBINATORIAL; ACTIVATION; MAPS; REPRESENTATIONS; ORGANIZATION AB To investigate the circuitry involved in detecting odorants in the rodent brain, we developed a method using manganese-enhanced MRI (MEMRI) to map the flow of neural information from the olfactory sensory neurons (OSNs) to the central layers of the olfactory bulb. Studies have shown that Mn(2+) enters active neurons and is transported anterogradely to axon terminals where it can cross synapses to functionally trace neural networks. Thus, by delivering MnCl(2) directly into the nasal cavity of mice and then exposing them to defined odorants, Mn(2+) is preferentially taken up by activated OSNs. Using the time course of the MRI signal, we generated maps of Mn(2+) accumulation in the olfactory bulb for both glomerular and mitral cell layers. Results demonstrated that overlapping yet distinct enhancement patterns were produced by exposure to either octanal, acetophenone, or carvone. Notably, areas of Mn(2+) accumulation in the mitral cell layer were similar to those in the glomerular layer consistent with neural information that passes from specific OSNs to specific mitral cells. Finally, by correlating specific Mn(2+) signal peaks to genetically labeled glomeruli that are known to be activated by the odorant octanal, we show that MEMRI maps can be resolved at the level of individual glomeruli. Published by Elsevier Inc. C1 [Chuang, Kai-Hsiang; Lee, Jung Hee; Silva, Afonso C.; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Belluscio, Leonardo] Natl Inst Neurol Disorders & Stroke, Dev Neural Plast Unit, NIH, Bethesda, MD 20892 USA. [Lee, Jung Hee] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Radiol, Seoul, South Korea. RP Chuang, KH (reprint author), Singapore Bioimaging Consortium, Lab Mol Imaging, 11 Biopolis Way 02-02, Singapore 138667, Singapore. EM chuangk@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015; lee, junghee/D-6130-2017; OI Koretsky, Alan/0000-0002-8085-4756; Chuang, Kai-Hsiang/0000-0002-8356-0657 FU Intramural NIH HHS [Z01 NS002989-08, Z99 NS999999] NR 48 TC 33 Z9 33 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2009 VL 44 IS 2 BP 363 EP 372 DI 10.1016/j.neuroimage.2008.08.046 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 392KH UT WOS:000262301100008 PM 18848997 ER PT J AU Bianciardi, M van Gelderen, P Duyn, JH Fukunaga, M de Zwart, JA AF Bianciardi, Marta van Gelderen, Peter Duyn, Jeff H. Fukunaga, Masaki de Zwart, Jacco A. TI Making the most of fMRI at 7 T by suppressing spontaneous signal fluctuations SO NEUROIMAGE LA English DT Article DE Evoked responses; Spontaneous signal fluctuations; Noise modeling; Correlated noise; Estimation precision; Temporal autocorrelation; BOLD fMRI; High field strength ID TEMPORAL AUTOCORRELATION; PHYSIOLOGICAL NOISE; BOLD SIGNAL; HUMAN BRAIN; VARIABILITY; SYSTEMS; MRI; RESPONSES; NETWORKS; HUMANS AB The presence of spontaneous BOLD fMRI signal fluctuations in human grey matter compromises the detection and interpretation of evoked responses and limits the sensitivity gains that are potentially available through coil arrays and high field systems. In order to overcome these limitations, we adapted and improved a recently described correlated noise suppression method (de Zwart et al., 2008), demonstrating improved precision in estimating the response to ultra-short visual stimuli at 7 T. In this procedure, the temporal dynamics of spontaneous signal fluctuations are estimated from a reference brain region outside the area targeted with the stimulus. Rather than using the average signal in this region as regressor, as proposed in the original method, we used principal component analysis to derive multiple regressors in order to optimally describe nuisance signals (e. g. spontaneous fluctuations) and separate these from evoked activity in the target region. Experimental results obtained from application of the original method showed a 66% improvement in estimation precision. The novel, enhanced version of the method, using 18 PCA-derived noise regressors, led to a 160% increase in precision. These increases were relative to a control condition without noise suppression, which was simulated by randomizing the time-course of the nuisance-signal regressor(s) without altering their power spectrum. The increase of estimation precision was associated with decreased autocorrelation levels of the residual errors. These results suggest that modeling of spontaneous fMRI signal fluctuations as multiple independent sources can dramatically improve detection of evoked activity, and fully exploit the potential sensitivity gains available with high field technology. Published by Elsevier Inc. C1 [Bianciardi, Marta; van Gelderen, Peter; Duyn, Jeff H.; Fukunaga, Masaki; de Zwart, Jacco A.] Natl Inst Neurol Disorders & Stroke, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. RP de Zwart, JA (reprint author), 10 Ctr Dr,Bldg 10,Room B1D-726,MSC 1065, Bethesda, MD 20892 USA. EM Jacco.deZwart@nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 FU Intramural Research Program; NIH; NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. NR 32 TC 19 Z9 19 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2009 VL 44 IS 2 BP 448 EP 454 DI 10.1016/j.neuroimage.2008.08.037 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 392KH UT WOS:000262301100015 PM 18835582 ER PT J AU Smith, BW Mitchell, DGV Hardin, MG Jazbec, S Fridberg, D Blair, RJR Ernst, M AF Smith, Bruce W. Mitchell, Derek G. V. Hardin, Michael G. Jazbec, Sandra Fridberg, Daniel Blair, R. James R. Ernst, Monique TI Neural substrates of reward magnitude, probability, and risk during a wheel of fortune decision-making task SO NEUROIMAGE LA English DT Article ID ANTERIOR CINGULATE CORTEX; EVENT-RELATED FMRI; VENTROMEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; NUCLEUS-ACCUMBENS; FINANCIAL REWARD; CHOICE SELECTION; ACTIVATION; RESPONSES; AMYGDALA AB Economic decision-making involves the weighting of magnitude and probability of potential gains/losses. While previous work has examined the neural systems involved in decision-making, there is a need to understand how the parameters associated with decision-making (e.g., magnitude of expected reward, probability of expected reward and risk) modulate activation within these neural systems. In the current fMRI study, we modified the monetary wheel of fortune (WOF) task [Ernst, M., Nelson, E. E., McClure, E. B., Monk, C.S., Munson, S., Eshel, N., et al. (2004). Choice selection and reward anticipation: an fMRI study. Neuropsychologia 42(12), 1585-1597.] to examine in 25 healthy young adults the neural responses to selections of different reward magnitudes, probabilities, or risks. Selection of high, relative to low, reward magnitude increased activity in insula, amygdala, middle and posterior cingulate cortex, and basal ganglia. Selection of low-probability, as opposed to high-probability reward, increased activity in anterior cingulate cortex, as did selection of risky, relative to safe reward. In summary, decision-making that did not involve conflict, as in the magnitude contrast, recruited structures known to support the coding of reward values, and those that integrate motivational and perceptual information for behavioral responses. In contrast, decision-making under conflict, as in the probability and risk contrasts, engaged the dorsal anterior cingulate cortex whose role in conflict monitoring is well established. However, decision-making under conflict failed to activate the structures that track reward values per se. Thus, the presence of conflict in decision-making seemed to significantly alter the pattern of neural responses to simple rewards. In addition, this paradigm further clarifies the functional specialization of the cingulate cortex in processes of decision-making. Published by Elsevier Inc. C1 [Hardin, Michael G.; Jazbec, Sandra; Blair, R. James R.; Ernst, Monique] NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bethesda, MD 20892 USA. [Smith, Bruce W.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Mitchell, Derek G. V.] Univ Western Ontario, Dept Psychiat, London, ON N6A 3K7, Canada. [Mitchell, Derek G. V.] Univ Western Ontario, Dept Anat & Cell Biol, London, ON, Canada. [Fridberg, Daniel] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. RP Ernst, M (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, 15K North Dr, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU National Institute of Mental Health Intramural Research Program FX This research was supported by the National Institute of Mental Health Intramural Research Program. We wish to thank Ellen Condon for her assistance with the data collection. NR 63 TC 77 Z9 80 U1 5 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2009 VL 44 IS 2 BP 600 EP 609 DI 10.1016/j.neuroimage.2008.08.016 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 392KH UT WOS:000262301100030 PM 18804540 ER PT J AU Porter, BO Anthony, KB Shen, J Hahn, B Keh, CE Maidarelli, F Blackwelder, WC Lane, HC Kovacs, JA Davey, RT Sereti, I AF Porter, Brian O. Anthony, Kara B. Shen, Jean Hahn, Barbara Keh, Chris E. Maidarelli, Frank Blackwelder, William C. Lane, Henry Clifford Kovacs, Joseph A. Davey, Richard T. Sereti, Irini TI Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial SO AIDS LA English DT Article DE CD4 lymphocyte count; HAART; HIV infections; interleukin-2; lipodystrophy; randomized controlled trial ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; ACTIVE ANTIRETROVIRAL THERAPY; INTERMITTENT INTERLEUKIN-2 THERAPY; CHRONICALLY HIV-1-INFECTED PATIENTS; SUBCUTANEOUS INTERLEUKIN-2; INTERNATIONAL TRIAL; CARDIOVASCULAR RISK; TYPE-1 INFECTION; RNA LEVELS AB Objective: To evaluate whether interleukin(IL)-2 in patients with chronic HIV infection can maintain CD4 T cell counts during 6 months of HAART interruption. Design: Prospective, randomized, controlled, open-label phase 11 noninferiority trial comparing IL-2 with HAART interruption or continuous HAART. Methods: Forty-one IL-2-experienced (three or more prior cycles) HIV-1-infected adults with CD4 cell count at least 500 cells/mu l were randomized in the ratio 2 :1 to interrupted (l=27) or continuous (C = 14) HAART for 6 months following an initial IL-2 cycle. Subsequent IL-2 cycles were triggered by CD4 T cell Counts less than 90% of baseline. Immune, metabolic, and quality of life indices were compared (Mann-Whitney and Fisher's exact tests), defining noninferiority as a percentage difference (C - l) in treatment Success (CD4 T cells >= 90% of baseline at 6 months) with a 95% confidence interval (CI) lower limit greater than -20%. Results: Demographic and immune parameters were similar between the groups at baseline. Median CD4 T cell count, HIV viral load, and treatment success differed significantly at 6 months (l: 866cells/mu l, 39389copies/ml, 48.10%; C: 1246cells/mu l, <50 copies/ml, 92.3%; P <= 0.001). Group I was inferior to C (% difference = -44.2%; 95% Cl: -64.2%, -11.2%; P=0.013). Minor statistically significant differences in HgbA1c and energy level occurred at 6 months(l>C). Following HAART interruption, single cases of acute retroviral syndrome, secondary syphilis, non-Hodgkin's lymphoma, and Kaposi's sarcoma recurrence were observed. Conclusion: IL-2 alone was inferior to IL-2 with HAART in maintaining baseline CD4 T cell counts. HAART interruption had a small impact on metabolic parameters and quality of life. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Porter, Brian O.; Anthony, Kara B.; Keh, Chris E.; Blackwelder, William C.; Lane, Henry Clifford; Davey, Richard T.; Sereti, Irini] NIAID, NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20982 USA. [Shen, Jean; Hahn, Barbara] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Maidarelli, Frank; Blackwelder, William C.] NCI, NIH, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, NIH, Warren G Magnuson Clin Ctr, Bldg 10,Room 11C103,10 Ctr Dr, Bethesda, MD 20982 USA. EM isereti@niaid.nih.gov FU National Institutes of Health (Bethesda, Maryland, USA); Novartis (Emeryville, California, USA) FX This work was funded through the National Institute of Allergy & Infectious Diseases Clinical and Molecular Retrovirology Section of the National Institutes of Health (Bethesda, Maryland, USA). Human recombinant IL-2 was provided by Novartis (Emeryville, California, USA). NR 62 TC 12 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 14 PY 2009 VL 23 IS 2 BP 203 EP 212 DI 10.1097/QAD.0b013e32831cc114 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 400OB UT WOS:000262876600007 PM 19098490 ER PT J AU Goedert, JJ AF Goedert, James J. TI Nonsmoking and other cofactors for Kaposi's sarcoma SO AIDS LA English DT Letter ID RISK-FACTORS; HOMOSEXUAL-MEN; AIDS; HERPESVIRUS; CANCER C1 NCI, Infect & Immunoepidemiol Branch, Rockville, MD 20852 USA. RP Goedert, JJ (reprint author), NCI, Infect & Immunoepidemiol Branch, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 14 PY 2009 VL 23 IS 2 BP 273 EP 274 DI 10.1097/QAD.0b013e32831f4674 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 400OB UT WOS:000262876600019 PM 19098500 ER PT J AU McDermott, MM Ades, P Guralnik, JM Dyer, A Ferrucci, L Liu, K Nelson, M Lloyd-Jones, D Van Horn, L Garside, D Kibbe, M Domanchuk, K Stein, JH Liao, YH Tao, HM Green, D Pearce, WH Schneider, JR McPherson, D Laing, ST McCarthy, WJ Shroff, A Criqui, MH AF McDermott, Mary M. Ades, Philip Guralnik, Jack M. Dyer, Alan Ferrucci, Luigi Liu, Kiang Nelson, Miriam Lloyd-Jones, Donald Van Horn, Linda Garside, Daniel Kibbe, Melina Domanchuk, Kathryn Stein, James H. Liao, Yihua Tao, Huimin Green, David Pearce, William H. Schneider, Joseph R. McPherson, David Laing, Susan T. McCarthy, Walter J. Shroff, Adhir Criqui, Michael H. TI Treadmill Exercise and Resistance Training in Patients With Peripheral Arterial Disease With and Without Intermittent Claudication A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ANKLE BRACHIAL INDEX; LOWER-EXTREMITY ISCHEMIA; PHYSICAL-ACTIVITY; LEG SYMPTOMS; CLINICAL CHARACTERISTICS; SUBSEQUENT DISABILITY; FUNCTIONAL IMPAIRMENT; CARDIOVASCULAR EVENTS; PERFORMANCE-MEASURES; SKELETAL-MUSCLE AB Context Neither supervised treadmill exercise nor strength training for patients with peripheral arterial disease ( PAD) without intermittent claudication have been established as beneficial. Objective To determine whether supervised treadmill exercise or lower extremity resistance training improve functional performance of patients with PAD with or without claudication. Design, Setting, and Participants Randomized controlled clinical trial performed at an urban academic medical center between April 1, 2004, and August 8, 2008, involving 156 patients with PAD who were randomly assigned to supervised treadmill exercise, to lower extremity resistance training, or to a control group. Main Outcome Measures Six- minute walk performance and the short physical performance battery. Secondary outcomes were brachial artery flow- mediated dilation, treadmill walking performance, the Walking Impairment Questionnaire, and the 36- Item Short Form Health Survey physical functioning ( SF- 36 PF) score. Results For the 6- minute walk, those in the supervised treadmill exercise group increased their distance walked by 35.9 m ( 95% confidence interval [ CI], 15.3- 56.5 m; P <. 001) compared with the control group, whereas those in the resistance training group increased their distance walked by 12.4 m ( 95% CI, - 8.42 to 33.3 m; P=. 24) compared with the control group. Neither exercise group improved its short physical performance battery scores. For brachial artery flow- mediated dilation, those in the treadmill group had a mean improvement of 1.53% ( 95% CI, 0.35%- 2.70%; P=. 02) compared with the control group. The treadmill group had greater increases in maximal treadmill walking time ( 3.44 minutes; 95% CI, 2.05- 4.84 minutes; P <. 001); walking impairment distance score ( 10.7; 95% CI, 1.56- 19.9; P=. 02); and SF- 36 PF score ( 7.5; 95% CI, 0.00- 15.0; P=. 02) than the control group. The resistance training group had greater increases in maximal treadmill walking time ( 1.90 minutes; 95% CI, 0.49-3.31 minutes; P=. 009); walking impairment scores for distance ( 6.92; 95% CI, 1.07-12.8; P=. 02) and stair climbing ( 10.4; 95% CI, 0.00- 20.8; P=. 03); and SF- 36 PF score ( 7.5; 95% CI, 0.0- 15.0; P=. 04) than the control group. Conclusions Supervised treadmill training improved 6- minute walk performance, treadmill walking performance, brachial artery flow- mediated dilation, and quality of life but did not improve the short physical performance battery scores of PAD participants with and without intermittent claudication. Lower extremity resistance training improved functional performance measured by treadmill walking, quality of life, and stair climbing ability. Trial Registration clinicaltrials. gov Identifier: NCT00106327. C1 [McDermott, Mary M.; Lloyd-Jones, Donald; Domanchuk, Kathryn; Green, David] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Dyer, Alan; Liu, Kiang; Lloyd-Jones, Donald; Van Horn, Linda; Garside, Daniel; Liao, Yihua; Tao, Huimin] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Kibbe, Melina; Pearce, William H.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Ades, Philip] Univ Vermont, Dept Med, Burlington, VT USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Lab Clin Epidemiol, Baltimore, MD 21224 USA. [Nelson, Miriam] Tufts Univ, Medford, MA 02155 USA. [Stein, James H.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI USA. [Schneider, Joseph R.] Cent DuPage Hosp, Dept Surg, Winfield, IL USA. [McPherson, David; Laing, Susan T.] Univ Texas Houston, Hlth Sci Ctr, Dept Med, Houston, TX USA. [McCarthy, Walter J.] Rush Univ, Sch Med, Dept Surg, Chicago, IL 60612 USA. [Shroff, Adhir] Univ Illinois, Dept Med, Chicago, IL USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu RI Lloyd-Jones, Donald/C-5899-2009 FU National Heart, Lung, and Blood Institute [R01-HL073551]; National Center for Research Resources [RR-00048]; National Institutes of Health; Intramural Research Program; National Institutes on Aging FX Supported by grants R01-HL073551 from the National Heart, Lung, and Blood Institute and by RR-00048 from the National Center for Research Resources, National Institutes of Health. This was also supported in part by the Intramural Research Program, National Institutes on Aging. NR 49 TC 160 Z9 169 U1 4 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 14 PY 2009 VL 301 IS 2 BP 165 EP 174 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 393VV UT WOS:000262405500018 PM 19141764 ER PT J AU Chandler, RK Fletcher, BW Volkow, ND AF Chandler, Redonna K. Fletcher, Bennett W. Volkow, Nora D. TI Treating Drug Abuse and Addiction in the Criminal Justice System Improving Public Health and Safety SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; HIV-INFECTED PRISONERS; METHADONE-MAINTENANCE; COCAINE ADDICTION; HEPATITIS-C; CORRECTIONAL POPULATIONS; COOCCURRING DISORDERS; ORBITOFRONTAL CORTEX; NEURAL SYSTEMS; SELF-CONTROL AB Despite increasing evidence that addiction is a treatable disease of the brain, most individuals do not receive treatment. Involvement in the criminal justice system often results from illegal drug- seeking behavior and participation in illegal activities that reflect, in part, disrupted behavior ensuing from brain changes triggered by repeated drug use. Treating drug- involved offenders provides a unique opportunity to decrease substance abuse and reduce associated criminal behavior. Emerging neuroscience has the potential to transform traditional sanction- oriented public safety approaches by providing new therapeutic strategies against addiction that could be used in the criminal justice system. We summarize relevant neuroscientific findings and evidence- based principles of addiction treatment that, if implemented in the criminal justice system, could help improve public heath and reduce criminal behavior. C1 [Chandler, Redonna K.; Fletcher, Bennett W.; Volkow, Nora D.] Natl Inst Drug Abuse, Serv Res Branch, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, Serv Res Branch, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 82 TC 152 Z9 152 U1 8 U2 32 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 JAN 14 PY 2009 VL 301 IS 2 BP 183 EP 190 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 393VV UT WOS:000262405500020 PM 19141766 ER PT J AU Driscoll, CA Yamaguchi, N Bar-Gal, GK Roca, AL Luo, SJ Macdonald, DW O'Brien, SJ AF Driscoll, Carlos A. Yamaguchi, Nobuyuki Bar-Gal, Gila Kahila Roca, Alfred L. Luo, Shujin Macdonald, David W. O'Brien, Stephen J. TI Mitochondrial Phylogeography Illuminates the Origin of the Extinct Caspian Tiger and Its Relationship to the Amur Tiger SO PLOS ONE LA English DT Article AB The Caspian tiger (Panthera tigris virgata) flourished in Central Asian riverine forest systems in a range disjunct from that of other tigers, but was driven to extinction in 1970 prior to a modern molecular evaluation. For over a century naturalists puzzled over the taxonomic validity, placement, and biogeographic origin of this enigmatic animal. Using ancient-DNA (aDNA) methodology, we generated composite mtDNA haplotypes from twenty wild Caspian tigers from throughout their historic range sampled from museum collections. We found that Caspian tigers carry a major mtDNA haplotype differing by only a single nucleotide from the monomorphic haplotype found across all contemporary Amur tigers (P. t. altaica). Phylogeographic analysis with extant tiger subspecies suggests that less than 10,000 years ago the Caspian/Amur tiger ancestor colonized Central Asia via the Gansu Corridor (Silk Road) from eastern China then subsequently traversed Siberia eastward to establish the Amur tiger in the Russian Far East. The conservation implications of these findings are far reaching, as the observed genetic depletion characteristic of modern Amur tigers likely reflects these founder migrations and therefore predates human influence. Also, due to their evolutionary propinquity, living Amur tigers offer an appropriate genetic source should reintroductions to the former range of the Caspian tiger be implemented. C1 [Driscoll, Carlos A.; Yamaguchi, Nobuyuki; Macdonald, David W.] Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Tubney, Oxon, England. [Driscoll, Carlos A.; Luo, Shujin; O'Brien, Stephen J.] NCI, Lab Genom Diversity, Bethesda, MD 20892 USA. [Bar-Gal, Gila Kahila] Hebrew Univ Jerusalem, Fac Agr Food & Environm Quality Sci, Koret Sch Vet Med, IL-91905 Jerusalem, Israel. [Roca, Alfred L.] NCI Frederick, SAIC Frederick, Lab Genom Diversity, Frederick, MD USA. [Roca, Alfred L.] Univ Illinois, Dept Animal Sci, Urbana, IL USA. RP Driscoll, CA (reprint author), Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Tubney, Oxon, England. EM bigscience@ncifcrf.gov; obrien@ncifcrf.gov OI Driscoll, Carlos/0000-0003-2392-505X FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The contents of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 21 Z9 25 U1 4 U2 48 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 JAN 14 PY 2009 VL 4 IS 1 AR e4125 DI 10.1371/journal.pone.0004125 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437IF UT WOS:000265479700002 PM 19142238 ER PT J AU Gruschus, JM Chen, PW Luo, RB Randazzo, PA AF Gruschus, James M. Chen, Pei-Wen Luo, Ruibai Randazzo, Paul A. TI Journey to the Ends of the Arf SO STRUCTURE LA English DT Editorial Material ID NUCLEOTIDE EXCHANGE FACTOR; GTP-BINDING PROTEINS; ADP-RIBOSYLATION; FAMILY; ARNO AB In this issue, Liu et al. (2009) used NMR to provide the most complete information to date on the structure of Arf1 and the role of myristate in GDP/GTP exchange. Unanticipated details lead to speculation about functions for the N and C termini of Arfs. C1 [Chen, Pei-Wen; Luo, Ruibai; Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Gruschus, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov RI Chen, Pei-Wen/B-7142-2015 FU Intramural NIH HHS NR 10 TC 2 Z9 2 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JAN 14 PY 2009 VL 17 IS 1 BP 2 EP 4 DI 10.1016/j.str.2008.12.002 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 395UT UT WOS:000262549700002 PM 19141275 ER PT J AU Niu, SL Doctrow, B Mitchell, DC AF Niu, Shui-Lin Doctrow, Brian Mitchell, Drake C. TI Rhodopsin Activity Varies in Proteoliposomes Prepared by Different Techniques SO BIOCHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; BIOLOGICAL MOLECULAR GENERATORS; METARHODOPSIN-II; MEMBRANE-PROTEINS; ELECTRIC-CURRENT; FUNCTIONAL RECONSTITUTION; OCTYL GLUCOSIDE; LIPOSOMES; OLIGOMERIZATION; PURIFICATION AB A variety of techniques are currently in use for preparing protein-containing lipid vesicles known as proteoliposomes. However, the functionality of membrane protein in proteoliposomes prepared by various techniques has rarely been evaluated directly. We prepared rhodopsin-containing proteoliposomes consisting of asolectin or native retinal rod outer segment disk lipids using n-octyl beta-D-glucopyranoside and the detergent dialysis (DD) and rapid dilution (RD) techniques and measured the activity of rhodopsin using equilibrium UV/vis and flash photolysis spectroscopy. A significant difference in rhodopsin activity was observed in proteoliposomes prepared by these techniques. The equilibrium constant of metarhodopsin I-metarhodopsin II is 30-45% higher, and the apparent rate constant of MU formation is up to 3-fold faster in proteoliposomes prepared by RD vs DD. The DD technique produced larger yet more heterogeneous vesicles, while the RD technique yielded smaller and more homogeneous vesicles, as determined by electron microscopy and isopicnic centrifugation. Both proteoliposomes and empty lipid vesicles lacking rhodopsin were formed in the DD preparation, while only proteoliposomes were formed in the RD preparation. Under identical conditions, proteoliposomes prepared by RD have a higher L/P ratio, which is consistent with the higher level of rhodopsin activity in RD proteoliposomes. Overall, the results presented here suggest that the RD technique has an advantage over the DD technique in terms of preserving optimal rhodopsin activity and controlling the lipid to protein ratio in the final proteoliposomes. C1 [Niu, Shui-Lin; Doctrow, Brian; Mitchell, Drake C.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Mitchell, DC (reprint author), Portland State Univ, Dept Phys, POB 751, Portland, OR 97207 USA. EM drakem@pdx.edu NR 46 TC 8 Z9 9 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 13 PY 2009 VL 48 IS 1 BP 156 EP 163 DI 10.1021/bi801835s PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 391WW UT WOS:000262265900017 PM 19090672 ER PT J AU Foroud, T Sauerbeck, L Brown, R Anderson, C Woo, D Kleindorfer, D Flaherty, ML Deka, R Hornung, R Meissner, I Bailey-Wilson, JE Langefeld, C Rouleau, G Connolly, ES Lai, DB Koller, DL Huston, J Broderick, JP AF Foroud, Tatiana Sauerbeck, Laura Brown, Robert Anderson, Craig Woo, Daniel Kleindorfer, Dawn Flaherty, Matthew L. Deka, Ranian Hornung, Richard Meissner, Irene Bailey-Wilson, Joan E. Langefeld, Carl Rouleau, Guy Connolly, E. Sander Lai, Dongbing Koller, Daniel L. Huston, John, III Broderick, Joseph P. CA FIA Study Investigators TI Genome screen in familial intracranial aneurysm SO BMC MEDICAL GENETICS LA English DT Article ID ABDOMINAL AORTIC-ANEURYSM; SUBARACHNOID HEMORRHAGE; CEREBRAL ANEURYSMS; LINKAGE DISEQUILIBRIUM; MR-ANGIOGRAPHY; HISTORY; ASSOCIATION; LOCUS; MAPS; MARKERS AB Background: Individuals with 1st degree relatives harboring an intracranial aneurysm (IA) are at an increased risk of IA, suggesting genetic variation is an important risk factor. Methods: Families with multiple members having ruptured or unruptured A were recruited and all available medical records and imaging data were reviewed to classify possible A subjects as definite, probable or possible A or not a case. A 6 K SNP genome screen was performed in 333 families, representing the largest linkage study of A reported to date. A 'narrow' (n = 705 definite A cases) and 'broad' (n = 866 definite or probable IA) disease definition were used in multipoint model-free linkage analysis and parametric linkage analysis, maximizing disease parameters. Ordered subset analysis (OSA) was used to detect gene x smoking interaction. Results: Model-free linkage analyses detected modest evidence of possible linkage (all LOD < 1.5). Parametric analyses yielded an unadjusted LOD score of 2.6 on chromosome 4q (162 cM) and 3.1 on chromosome 12p (50 cM). Significant evidence for a gene x smoking interaction was detected using both disease models on chromosome 7p (60 cM; p <= 0.01). Our study provides modest evidence of possible linkage to several chromosomes. Conclusion: These data suggest it is unlikely that there is a single common variant with a strong effect in the majority of the A families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms. C1 [Foroud, Tatiana; Lai, Dongbing; Koller, Daniel L.] Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. [Sauerbeck, Laura; Woo, Daniel; Kleindorfer, Dawn; Flaherty, Matthew L.; Deka, Ranian; Broderick, Joseph P.] Univ Cincinnati, Sch Med, Cincinnati, OH USA. [Anderson, Craig] Univ Sydney, George Inst Int Hlth, Sydney, NSW 2006, Australia. [Brown, Robert; Meissner, Irene; Huston, John, III] Mayo Clin, Rochester, MN USA. [Hornung, Richard] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Bailey-Wilson, Joan E.] NHGRI, Baltimore, MD USA. [Langefeld, Carl] Wake Forest Univ Med, Winston Salem, NC USA. [Rouleau, Guy] Univ Montreal, Ctr Excellence Neurom, Montreal, PQ, Canada. [Connolly, E. Sander] Columbia Univ, New York, NY USA. RP Foroud, T (reprint author), Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. EM tforoud@iupui.edu; SAUERBLR@ucmail.uc.edu; brown@mayo.edu; canderson@george.org.au; WOODL@ucmail.uc.edu; KLEINDDO@ucmail.uc.edu; matthew.flaherty@uc.edu; DEKAR@ucmail.uc.edu; richard.hornung@cchmc.org; meissner.irene@mayo.edu; jebw@nhgri.nih.gov; clangefe@wfubmc.edu; guy.rouleau@umontreal.ca; esc5@columbia.edu; dlai@iupui.edu; dkoller@iupui.edu; jhuston@mayo.edu; broderjp@ucmail.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU National Institute of Neurological Diseases and Stroke [ROI NS39512]; National Institutes of Health [NOI-HG-65403]; NHGRI FX This study was funded by a grant from the National Institute of Neurological Diseases and Stroke (NINDS ROI NS39512). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number NOI-HG-65403. This research was also supported in part by the Intramural Research Program of the NHGRI, NIH. NR 34 TC 12 Z9 13 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 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JAN 13 PY 2009 VL 10 AR 3 DI 10.1186/1471-2350-10-3 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 404BI UT WOS:000263125300002 PM 19144135 ER PT J AU Ruiz, MIG Floor, K Steinberg, SM Grunberg, K Thunnissen, FBJM Belien, JAM Meijer, GA Peters, GJ Smit, EF Rodriguez, JA Giaccone, G AF Ruiz, M. I. Galleges Floor, K. Steinberg, S. M. Grunberg, K. Thunnissen, F. B. J. M. Belien, J. A. M. Meijer, G. A. Peters, G. J. Smit, E. F. Rodriguez, J. A. Giaccone, G. TI Combined assessment of EGFR pathway-related molecular markers and prognosis of NSCLC patients SO BRITISH JOURNAL OF CANCER LA English DT Article DE EGFR pathway; NSCLC; prognosis; CMET; KRAS; biomarkers ID GROWTH-FACTOR-RECEPTOR; CELL LUNG-CANCER; GENE COPY NUMBER; TYROSINE KINASE INHIBITOR; IN-SITU-HYBRIDIZATION; K-RAS MUTATION; TISSUE MICROARRAY; ONCOLOGY-GROUP; E-CADHERIN; GEFITINIB AB The purpose of this study is to evaluate the prognostic value of the combined assessment of multiple molecular markers related to the epidermal growth factor receptor (EGFR) pathway in resected non-small cell lung cancer (NSCLC) patients. Tumour specimens of 178 NSCLC patients were collected and analysed for EGFR and KRAS mutation status by DNA sequencing, and for EGFR copy number by fluorescent in situ hybridisation. Tissue microarrays were generated and used to determine the expression of multiple EGFR pathway-related proteins by immunohistochemistry. We analysed the association between each marker and patient prognosis. Univariate analyses for each clinical variable and each molecular marker were performed using Kaplan-Meier curves and log-rank tests. From these results, we selected the variables KRAS mutations and expression of cytoplasmic EGFR, granular pERK, nuclear pSTAT3, cytoplasmic E-cadherin and cytoplasmic pCMET to enter into a Cox proportional hazards model, along with stage as the strongest clinical variable related with prognosis. Of the EGFR-related markers evaluated here, the markers EGFR, pERK, pSTAT3, E-cadherin, pCMET and mutations in KRAS were associated with survival when analysed in combination in our patient cohort, with P = 0.00015 as the P-value for a test of the additional impact of markers on prognosis, after taking stage into consideration. Confirmation of the impact of these markers in independent studies will be necessary. C1 [Giaccone, G.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Ruiz, M. I. Galleges; Floor, K.; Peters, G. J.; Rodriguez, J. A.] Vrije Univ Amsterdam, Dept Med Oncol, Med Ctr, Amsterdam, Netherlands. [Steinberg, S. M.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Grunberg, K.; Thunnissen, F. B. J. M.; Belien, J. A. M.; Meijer, G. A.] Vrije Univ Amsterdam, Dept Pathol, Med Ctr, Amsterdam, Netherlands. [Smit, E. F.] Vrije Univ Amsterdam, Dept Pulm Dis, Med Ctr, Amsterdam, Netherlands. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Grunberg, Katrien/M-9715-2015; Giaccone, Giuseppe/E-8297-2017; OI Grunberg, Katrien/0000-0003-1164-4365; Giaccone, Giuseppe/0000-0002-5023-7562; Thunnissen, Erik/0000-0001-5355-8508 NR 48 TC 22 Z9 23 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 13 PY 2009 VL 100 IS 1 BP 145 EP 152 DI 10.1038/sj.bjc.6604781 PG 8 WC Oncology SC Oncology GA 391XO UT WOS:000262267700022 PM 19050706 ER PT J AU Liao, WT Fujita, K Xiao, Q Tchikov, V Yang, WS Gunsor, M Garfield, S Goldsmith, P Ei-Deiry, WS Schutze, S Srinivasula, SM AF Liao, Wentao Fujita, Ken-ichi Xiao, Qi Tchikov, Vladimir Yang, Wensheng Gunsor, Michele Garfield, Susan Goldsmith, Paul Ei-Deiry, Wafik S. Schutze, Stefan Srinivasula, Srinivasa M. TI Response: CARP1 regulates induction of NF-kappa B by TNF alpha SO CURRENT BIOLOGY LA English DT Letter ID UBIQUITIN LIGASE; DEFICIENT MICE; DEATH C1 [Liao, Wentao; Fujita, Ken-ichi; Xiao, Qi; Srinivasula, Srinivasa M.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. [Tchikov, Vladimir; Schutze, Stefan] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany. [Yang, Wensheng; Ei-Deiry, Wafik S.] Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regulat, Dept Med Hematol Oncol,Inst Translat Med & Therap, Philadelphia, PA 19104 USA. [Yang, Wensheng; Ei-Deiry, Wafik S.] Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regulat, Dept Genet,Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Yang, Wensheng; Ei-Deiry, Wafik S.] Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regulat, Dept Genet,Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Yang, Wensheng; Ei-Deiry, Wafik S.] Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regulat, Dept Pharmacol,Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Yang, Wensheng; Ei-Deiry, Wafik S.] Univ Penn, Sch Med, Abramson Comprehens Canc Ctr, Philadelphia, PA 19104 USA. [Gunsor, Michele; Goldsmith, Paul] NCI, Antibody & Prot Purificat Unit, OSTP OD CCR, NIH, Bethesda, MD 20892 USA. [Garfield, Susan] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Liao, WT (reprint author), NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. EM srinivsr@mail.nih.gov RI Schutze, Stefan/C-8596-2011; Liao, Wentao/F-7913-2011 NR 11 TC 4 Z9 6 U1 0 U2 3 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 JAN 13 PY 2009 VL 19 IS 1 BP R17 EP R19 DI 10.1016/j.cub.2008.11.041 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 396HZ UT WOS:000262584100010 ER PT J AU Resnick, SM Espeland, MA Jaramillo, SA Hirsch, C Stefanick, ML Murray, AM Ockene, J Davatzikos, C AF Resnick, S. M. Espeland, M. A. Jaramillo, S. A. Hirsch, C. Stefanick, M. L. Murray, A. M. Ockene, J. Davatzikos, C. CA Womens Hlth Initiative Memory Stud TI Postmenopausal hormone therapy and regional brain volumes The WHIMS-MRI Study SO NEUROLOGY LA English DT Article ID HEALTH INITIATIVE MEMORY; ESTROGEN PLUS PROGESTIN; RANDOMIZED CONTROLLED-TRIAL; CONJUGATED EQUINE ESTROGENS; MILD COGNITIVE IMPAIRMENT; REPLACEMENT THERAPY; MAGNETIC-RESONANCE; ALZHEIMERS-DISEASE; WOMEN; DEMENTIA AB Objectives: To determine whether menopausal hormone therapy (HT) affects regional brain volumes, including hippocampal and frontal regions. Methods: Brain MRI scans were obtained in a subset of 1,403 women aged 71-89 years who participated in the Women's Health Initiative Memory Study (WHIMS). WHIMS was an ancillary study to the Women's Health Initiative, which consisted of two randomized, placebo-controlled trials: 0.625 mg conjugated equine estrogens (CEE) with or without 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet. Scans were performed, on average, 3.0 years post-trial for the CEE + MPA trial and 1.4 years post-trial for the CEE-Alone trial; average on-trial follow-up intervals were 4.0 years for CEE + MPA and 5.6 years for CEE-Alone. Total brain, ventricular, hippocampal, and frontal lobe volumes, adjusted for age, clinic site, estimated intracranial volume, and dementia risk factors, were the main outcome variables. Results: Compared with placebo, covariate-adjusted mean frontal lobe volume was 2.37 cm(3) lower among women assigned to HT (p = 0.004), mean hippocampal volume was slightly (0.10 cm3) lower (p = 0.05), and differences in total brain volume approached significance (p = 0.07). Results were similar for CEE + MPA and CEE-Alone. HT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores + 90). Conclusions: Conjugated equine estrogens with or without MPA are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women experiencing cognitive deficits before initiating hormone therapy. Neurology (R) 2009; 72: 135-142 C1 [Resnick, S. M.] NIA, Lab Personal & Cognit, Intramural Res Program, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. [Espeland, M. A.; Jaramillo, S. A.] Wake Forest Univ, Div Publ Hlth Sci, Sch Med, Winston Salem, NC 27109 USA. [Hirsch, C.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Hirsch, C.] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Stefanick, M. L.] Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Murray, A. M.] Hennepin Cty Med Ctr, Chron Dis Res Grp, Minneapolis, MN 55415 USA. [Ockene, J.] Univ Massachusetts, Worcester, MA 01605 USA. [Davatzikos, C.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Resnick, SM (reprint author), NIA, Lab Personal & Cognit, Intramural Res Program, NIH,Biomed Res Ctr, 04B317,251 Bayview Blvd, Baltimore, MD 21224 USA. EM susan.resnick@nih.gov FU National Heart, Lung, and Blood Institute of the NIH; US Department of Health and Human Services; Wyeth Pharmaceuticals, Inc., FX The Women's Health Initiative and WHIMS-MRI Study are funded by the National Heart, Lung, and Blood Institute of the NIH, US Department of Health and Human Services. WHIMS was funded in part by Wyeth Pharmaceuticals, Inc., St. Davids, PA. S. M. R. is supported by the Intramural Research Program, National Institute on Aging, NIH. NR 40 TC 94 Z9 97 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 13 PY 2009 VL 72 IS 2 BP 135 EP 142 DI 10.1212/01.wnl.0000339037.76336.cf PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 393SM UT WOS:000262393200006 PM 19139364 ER PT J AU Krammer, C Kryndushkin, D Suhre, MH Kremmer, E Hofmann, A Pfeifer, A Scheibel, T Wickner, RB Schatzl, HM Vorberg, I AF Krammer, Carmen Kryndushkin, Dmitry Suhre, Michael H. Kremmer, Elisabeth Hofmann, Andreas Pfeifer, Alexander Scheibel, Thomas Wickner, Reed B. Schaetzl, Hermann M. Vorberg, Ina TI The yeast Sup35NM domain propagates as a prion in mammalian cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PrP; Sup35 ID SACCHAROMYCES-CEREVISIAE; HET-S; PSI+ PRION; IN-VITRO; PROTEIN; DETERMINANT; STRAINS; PSI(+); CHAPERONES; HSP104 AB Prions are infectious, self-propagating amyloid-like protein aggregates of mammals and fungi. We have studied aggregation propensities of a yeast prion domain in cell culture to gain insights into general mechanisms of prion replication in mammalian cells. Here, we report the artificial transmission of a yeast prion across a phylogenetic kingdom. HA epitope-tagged yeast Sup35p prion domain NM was stably expressed in murine neuroblastoma cells. Although cytosolically expressed NM-HA remained soluble, addition of fibrils of bacterially produced Sup35NM to the medium efficiently induced appearance of phenotypically and biochemically distinct NM- HA aggregates that were inherited by daughter cells. Importantly, NM-HA aggregates also were infectious to recipient mammalian cells expressing soluble NM-HA and, to a lesser extent, to yeast. The fact that the yeast Sup35NM domain can propagate as a prion in neuroblastoma cells strongly argues that cellular mechanisms support prion-like inheritance in the mammalian cytosol. C1 [Krammer, Carmen; Schaetzl, Hermann M.; Vorberg, Ina] Tech Univ Munich, Inst Virol, D-81675 Munich, Germany. [Kryndushkin, Dmitry; Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Scheibel, Thomas] Univ Bayreuth, FAN D, Lehrstuhl Biomaterialien Gebaude, D-95447 Bayreuth, Germany. [Kremmer, Elisabeth] Helmholtz Zentrum Munchen, Inst Mol Immunol, D-81377 Munich, Germany. [Hofmann, Andreas; Pfeifer, Alexander] Univ Bonn, Inst Pharmacol & Toxicol, D-53133 Bonn, Germany. RP Vorberg, I (reprint author), Tech Univ Munich, Inst Virol, Trogerstr 30, D-81675 Munich, Germany. EM vorberg@virologie.med.tum.de RI Schatzl, Hermann/G-4958-2011; Suhre, Michael/C-5145-2009; Scheibel, Thomas/I-1170-2014 OI Suhre, Michael/0000-0002-2279-7765; Scheibel, Thomas/0000-0002-0457-2423 FU Deutsche Forschungsgemeinschaft [SFB 596 B14, VO 1277/1-2]; European Commission [LSHB-CT-2005-018805]; European Union NoE Neuroprion; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Fonds der Chemischen Industrie FX We thank members of the Vorberg and Schatzl laboratories for constructive comments on this work and D. Vorberg for help with statistics. Financial support for this work was provided by the Deutsche Forschungsgemeinschaft SFB 596 B14, VO 1277/1-2, the European Commission (Grant TSEUR LSHB-CT-2005-018805), the European Union NoE Neuroprion, and in part by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. M. H. S. was supported by a scholarship of the Fonds der Chemischen Industrie. NR 42 TC 32 Z9 33 U1 0 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 JAN 13 PY 2009 VL 106 IS 2 BP 462 EP 467 DI 10.1073/pnas.0811571106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399MM UT WOS:000262804000021 PM 19114662 ER PT J AU Li, W Kotoshiba, S Berthet, C Hilton, MB Kaldis, P AF Li, Weimin Kotoshiba, Shuhei Berthet, Cyril Hilton, Mary Beth Kaldis, Philipp TI Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G(1)/S transition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell cycle; p27; retinoblastoma protein; Skp2 ID RETINOBLASTOMA GENE FAMILY; CYCLIN-DEPENDENT KINASES; CELL-CYCLE; TARGETED DISRUPTION; EMBRYONIC LETHALITY; CDK INHIBITORS; RB; P27(KIP1); LACKING; GROWTH AB The G(1)/S-phase transition is a well-toned switch in the mammalian cell cycle. Cdk2, Cdk4, and the rate-limiting tumor suppressor retinoblastoma protein (Rb) have been studied in separate animal models, but interactions between the kinases and Rb in vivo have yet to be investigated. To further dissect the regulation of the G(1) to S-phase progression, we generated Cdk2(-/-)Cdk4(-/-)Rb(-/-) (TKO) mutant mice. TKO mice died at midgestation with major defects in the circulatory systems and displayed combined phenotypes of Rb-/- and Cdk2(-/-)Cdk4(-/-) mutants. However, TKO mouse embryonic fibroblasts were not only resistant to senescence and became immortal but displayed enhanced S-phase entry and proliferation rates similar to wild type. These effects were more remarkable in hypoxic compared with normoxic conditions. Interestingly, depletion of the pocket proteins by HPV-E7 or p107/p130 shRNA in the absence of Cdk2/Cdk4 elicited a mechanism for the G(1)/S regulation with increased levels of p27(Kip1) binding to Cdk1/cyclin E complexes. Our work indicates that the G(1)/S transition can be controlled in different ways depending on the situation, resembling a regulatory network. C1 [Li, Weimin; Kotoshiba, Shuhei; Berthet, Cyril; Hilton, Mary Beth; Kaldis, Philipp] Natl Canc Inst, Mouse Canc Genet Program, Canc Res Ctr, Frederick, MD 21702 USA. [Kotoshiba, Shuhei; Kaldis, Philipp] Natl Univ Singapore, Inst Mol & Cell Biol, Cell Div & Canc Lab, Singapore 138673, Singapore. RP Kaldis, P (reprint author), Natl Canc Inst, Mouse Canc Genet Program, Canc Res Ctr, Bldg 560-22-56,1050 Boyles St, Frederick, MD 21702 USA. EM kaldis@imcb.a-star.edu.sg RI Kaldis, Philipp/G-2714-2010; ASTAR, IMCB/E-2320-2012 OI Kaldis, Philipp/0000-0002-7247-7591; FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; A* STAR of Singapore FX We thank Matt McCollum and Angie Smith for animal care; Anton Berns for the Rbflox/flox mice; Keith Rogers, Donna Butcher, Roberta Smith, and the Pathology/Histotechnology Laboratory, National Cancer Institute for tissue sectioning and staining; Jerrold Ward for the placenta pathology; Stephen J. Lockett for helping with confocal microscopy; Julien Sage (Stanford University, Stanford, CA) for shRNA vectors for p107/p130; members of P. K.'s laboratory for discussions and support; and Stefan Lim, Shuhui Lim, and Kasim Diril for comments on the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and A* STAR of Singapore. NR 42 TC 23 Z9 28 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 JAN 13 PY 2009 VL 106 IS 2 BP 486 EP 491 DI 10.1073/pnas.0804177106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399MM UT WOS:000262804000025 PM 19129496 ER PT J AU Merrikh, H Ferrazzoli, AE Bougdour, A Olivier-Mason, A Lovett, ST AF Merrikh, Houra Ferrazzoli, Alexander E. Bougdour, Alexandre Olivier-Mason, Anique Lovett, Susan T. TI A DNA damage response in Escherichia coli involving the alternative sigma factor, RpoS SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oxidative stress; posttranslational regulation; replication stress; SOS response; DNA repair ID GENE-EXPRESSION; RNA-POLYMERASE; HYDROGEN-PEROXIDE; EXONUCLEASE-III; REGULATOR RSSB; STABILITY; REGULON; IDENTIFICATION; PATHWAYS; SUBUNIT AB We isolated an Escherichia coli mutant in the iraD gene, sensitive to various forms of DNA damage. Our data are consistent with the function of IraD to promote accumulation of the alternative transcription sigma factor, RpoS, by binding to the adaptor RssB protein that targets RpoS for degradation. Our results demonstrate the physiological importance of this mode of regulation for DNA damage tolerance. Although RpoS is best known for its regulation of genes induced in stationary phase, our work underscores the importance of the RpoS regulon in a DNA damage response in actively growing cells. We show that iraD transcription is induced by DNA damage by a mechanism independent of the SOS response. The IraD and SOS regulatory pathways appear to act synergistically to ensure survival of cells faced with oxidative or DNA damaging stress during cellular growth. C1 [Merrikh, Houra; Ferrazzoli, Alexander E.; Olivier-Mason, Anique; Lovett, Susan T.] Brandeis Univ, Dept Biol, Waltham, MA 02254 USA. [Merrikh, Houra; Ferrazzoli, Alexander E.; Olivier-Mason, Anique; Lovett, Susan T.] Brandeis Univ, Rosenstiel Basic Med Sci Ctr, Waltham, MA 02254 USA. [Bougdour, Alexandre] Natl Canc Inst, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lovett, ST (reprint author), Brandeis Univ, Dept Biol, Waltham, MA 02254 USA. EM lovett@brandeis.edu RI Bougdour, Alexandre/K-3795-2014; OI Bougdour, Alexandre/0000-0002-5895-0020; Lovett, Susan/0000-0003-2792-1857 FU General Medical Sciences Institute of the National Institutes of Health (NIH) [GM051753]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We are indebted to Susan Gottesman for strains, reagents, and helpful discussions. We also thank Hirotada Mori, Barry Wanner, and Malcolm Winkler for strains. This work was supported by Grant GM051753 from the General Medical Sciences Institute of the National Institutes of Health (NIH) (to STL) and, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (A. B.). NR 38 TC 37 Z9 37 U1 0 U2 11 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 JAN 13 PY 2009 VL 106 IS 2 BP 611 EP 616 DI 10.1073/pnas.0803665106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399MM UT WOS:000262804000047 PM 19124769 ER PT J AU Dreher, JC Kohn, P Kolachana, B Weinberger, DR Berman, KF AF Dreher, Jean-Claude Kohn, Philip Kolachana, Bhaskar Weinberger, Daniel R. Berman, Karen Faith TI Variation in dopamine genes influences responsivity of the human reward system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE COMT; DAT; fMRI; genetic variation ID CATECHOL-O-METHYLTRANSFERASE; OBSESSIVE-COMPULSIVE DISORDER; MESSENGER-RNA EXPRESSION; COMT VAL(108/158) MET; PREFRONTAL CORTEX; VAL(158)MET GENOTYPE; TRANSPORTER AVAILABILITY; BIPOLAR DISORDER; HUMAN BRAIN; POLYMORPHISM AB In humans, dopamine neurotransmission is influenced by functional polymorphisms in the dopamine transporter (DAT1) and catechol-O-methyltransferase (COMT) genes. Here, we used event-related functional magnetic resonance imaging to directly investigate the neurofunctional effects of the Val(158)Met COMT and variable number of tandem repeat DAT1 polymorphisms on distinct components of the reward system in humans. The results revealed a main effect of COMT genotype in the ventral striatum and lateral prefrontal cortex during reward anticipation (P < 0.001, uncorrected) and in the orbitofrontal cortex at the time of reward delivery (P < 0.005), met/met individuals exhibiting the highest activation. The main effect of DAT1 genotype was seen in robust blood-oxygen-level-dependent response differences in the caudate nucleus and ventral striatum during reward anticipation (P < 0.001) and in the lateral prefrontal cortex and midbrain at the time of reward delivery, with carriers of the DAT1 9-repeat allele showing the highest activity. Moreover, an interaction between the COMT and DAT1 genes was found in the ventral striatum and lateral prefrontal cortex during reward anticipation and in the lateral prefrontal and orbitofrontal cortices as well as in the midbrain at the time of reward delivery, with carriers of the DAT1 9-repeat allele and COMT met/met allele exhibiting the highest activation, presumably reflecting functional change consequent to higher synaptic dopamine availability. Taken together, these results indicate that genetically influenced variations in dopamine transmission modulate the response of brain regions involved in anticipation and reception of rewards and suggest that these responses may contribute to individual differences in reward-seeking behavior and in predisposition to neuropsychiatric disorders. C1 [Dreher, Jean-Claude; Kohn, Philip; Berman, Karen Faith] NIMH, Sect Integrat Neuroimaging, Bethesda, MD 20892 USA. [Kohn, Philip; Kolachana, Bhaskar; Weinberger, Daniel R.; Berman, Karen Faith] NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. RP Dreher, JC (reprint author), Univ Lyon 1, CNRS, Cognit Neurosci Ctr, Reward & decis Making Team, F-69365 Lyon, France. EM dreher@isc.cnrs.fr; bermank@mail.nih.gov NR 44 TC 189 Z9 195 U1 0 U2 10 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 JAN 13 PY 2009 VL 106 IS 2 BP 617 EP 622 DI 10.1073/pnas.0805517106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399MM UT WOS:000262804000048 PM 19104049 ER PT J AU Yang, YZ AF Yang, Yingzi TI Growth and Patterning in the Limb: Signaling Gradients Make the Decision SO SCIENCE SIGNALING LA English DT Article ID APICAL ECTODERMAL RIDGE; VERTEBRATE LIMB; HIND-LIMB; IN-VITRO; BUD; CHONDROGENESIS; WNT; DIFFERENTIATION; MORPHOGENESIS; MUSCULATURE AB The vertebrate limb bud provides a unique system to investigate the coordinated regulation of growth and patterning, two key processes that govern the formation of a complex multicellular organism from a fertilized egg. Two studies have advanced our understanding of limb development by elucidating that signaling gradients from the limb ecotoderm, including the apical ectoderm ridge (AER), act in concert to establish a basic pattern of tissue layers by coordinating cell proliferation and cell fate determination. These studies reveal that cell proliferation and fate determination in development can be two faces of the same coin in that they are regulated by the same signaling pathways. Alterations in the duration and range of the signaling gradients may underlie many of the morphological differences in the evolution of vertebrate limbs. C1 NHGRI, Dev Genet Sect, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Yang, YZ (reprint author), NHGRI, Dev Genet Sect, Genet Dis Res Branch, Bldg 49,Room 4A68,49 Convent Dr,MSC 4472, Bethesda, MD 20892 USA. EM yingzi@mail.nih.gov NR 33 TC 13 Z9 13 U1 1 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JAN 13 PY 2009 VL 2 IS 53 AR pe3 DI 10.1126/scisignal.253pe3 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567UE UT WOS:000275471300002 PM 19141858 ER PT J AU Cook, NR Obarzanek, E Cutler, JA Buring, JE Rexrode, KM Kumanyika, SK Appel, LJ Whelton, PK AF Cook, Nancy R. Obarzanek, Eva Cutler, Jeffrey A. Buring, Julie E. Rexrode, Kathryn M. Kumanyika, Shiriki K. Appel, Lawrence J. Whelton, Paul K. CA Trials Hypertension Prevention Col TI Joint Effects of Sodium and Potassium Intake on Subsequent Cardiovascular Disease The Trials of Hypertension Prevention Follow-up Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID URINARY ALBUMIN EXCRETION; LOWER BLOOD-PRESSURE; DIETARY POTASSIUM; SALT REDUCTION; ELECTROLYTE EXCRETION; OBSERVATIONAL DATA; RANDOMIZED-TRIALS; MEASUREMENT ERROR; NATIONAL-HEALTH; JAPANESE MEN AB Background: Previous studies of dose-response effects of usual sodium and potassium intake on subsequent cardiovascular disease (CVD) have largely relied on suboptimal measures of intake. Methods: Two trials of sodium reduction and other interventions collected 24-hour urinary excretions intermittently during 18 months from September 17, 1987, to January 12, 1990 (Trials of Hypertension Prevention [TOHP] I), and during 36 months from December 18, 1990, to April 7, 1995 (TOHP II), among adults with pre-hypertension aged 30 to 54 years. Among adults not assigned to an active sodium reduction intervention, we assessed the relationship of a mean of 3 to 7 twenty-four hour urinary excretions of sodium and potassium and their ratio with subsequent CVD (stroke, myocardial infarction, coronary revascularization, or CVD mortality) through 10 to 15 years of posttrial follow-up. Results: Among 2974 participants, follow-up information was obtained on 2275 participants (76.5%), with 193 CVD events. After adjustment for baseline variables and lifestyle changes, there was a nonsignificant trend in CVD risk across sex-specific quartiles of urinary sodium excretion (rate ratio [RR] from lowest to highest, 1.00, 0.99, 1.16, and 1.20; P=.38 for trend) and potassium excretion (RR, 1.00, 0.94, 0.91, and 0.64; P=.08 for trend) but a significant trend across quartiles of the sodium to potassium excretion ratio (RR, 1.00, 0.84, 1.18, and 1.50; P=.04 for trend). In models containing both measures simultaneously, linear effects were as follows: RR, 1.42; 95% confidence interval (CI), 0.99 to 2.04 per 100 mmol/24 h of urinary sodium excretion (P=.05); and 0.67; 0.41 to 1.10 per 50 mmol/24 h of urinary potassium excretion (P=.12). A model containing the sodium to potassium excretion ratio (RR, 1.24; 95% CI, 1.05-1.46; P=.01) had the lowest Bayes information criterion (best fit). Conclusion: A higher sodium to potassium excretion ratio is associated with increased risk of subsequent CVD, with an effect stronger than that of sodium or potassium alone. C1 [Cook, Nancy R.; Buring, Julie E.; Rexrode, Kathryn M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Obarzanek, Eva; Cutler, Jeffrey A.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Appel, Lawrence J.] Johns Hopkins Univ, Dept Med, Johns Hopkins Sch Med, Baltimore, MD USA. [Kumanyika, Shiriki K.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Whelton, Paul K.] Loyola Univ, Med Ctr, Loyola Univ Hlth Syst, Maywood, IL 60153 USA. RP Cook, NR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. EM ncook@rics.bwh.harvard.edu OI Rexrode, Kathryn/0000-0003-3387-8429 FU National Heart, Lung, and Blood Institute [HL37849, HL37852, HL37853, HL37854, HL37872, HL37884, HL37899, HL37904, HL37906, HL37907, HL37924, HL57915]; National Institutes of Health FX TOHP I and II were supported by cooperative agreements HL37849, HL37852, HL37853, HL37854, HL37872, HL37884, HL37899, HL37904, HL37906, HL37907, and HL37924, and the TOHP Follow-up Study was supported by grant HL57915, all from the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 56 TC 150 Z9 153 U1 1 U2 21 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 JAN 12 PY 2009 VL 169 IS 1 BP 32 EP 40 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 393UL UT WOS:000262398800004 PM 19139321 ER PT J AU Hindorff, LA Burke, W Laberge, AM Rice, KM Lumley, T Leppig, K Rosendaal, FR Larson, EB Psaty, BM AF Hindorff, Lucia A. Burke, Wylie Laberge, Anne-Marie Rice, Kenneth M. Lumley, Thomas Leppig, Kathleen Rosendaal, Frits R. Larson, Eric B. Psaty, Bruce M. TI Motivating Factors for Physician Ordering of Factor V Leiden Genetic Tests SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID OF-THE-LITERATURE; VENOUS THROMBOEMBOLISM; MYOCARDIAL-INFARCTION; PRIMARY-CARE; THROMBOPHILIA; RISK; GUIDELINES; SERVICES; STROKE AB Background: The factor V Leiden (FVL) genetic test is used by many physicians despite its uncertain clinical utility. Methods: We investigate whether self-reported motivations and behaviors concerning FVL genetic testing differ between 2 groups of primary care physicians defined by frequency of previous FVL test use. In January 2007, 112 physicians (60 frequent and 52 infrequent FVL test users) at Group Health, a large health care delivery system, were surveyed. Survey content areas included primary reasons and motivating factors for ordering the FVL test, the likelihood of ordering the FVL test for hypothetical patients, potential barriers to genetic testing, and practices and skills regarding FVL test ordering. Results: Responses between groups agreed concerning most clinical- and patient-related factors. Frequent-FVL physicians were more likely than infrequent-FVL physicians to report ordering the FVL test for hypothetical patients with mesenteric venous thrombosis (adjusted odds ratio, 4.57; 95% confidence interval, 1.55-13.53) or venous thrombosis after hospital discharge (adjusted odds ratio, 3.42; 95% confidence interval, 1.30-8.95). Frequent-FVL physicians were also less likely to identify several items on the survey as barriers to genetic testing and were more likely to report high confidence in interpreting and explaining FVL test results. Conclusions: Generally, both physician groups reported similar motivating factors for ordering FVL tests, and reported behaviors were consistent with existing guidelines. More striking differences were observed for measures such as barriers to and confidence in using genetic tests. Although additional research is necessary to evaluate the impact of these results, they inform several knowledge-to-practice translation issues that are important for the successful integration of genetic testing into primary care. C1 [Hindorff, Lucia A.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Burke, Wylie] Univ Washington, Dept Med Hist & Eth, Seattle, WA 98195 USA. [Rice, Kenneth M.; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Laberge, Anne-Marie] Univ Washington, Inst Publ Hlth Genet, Seattle, WA 98195 USA. [Larson, Eric B.; Psaty, Bruce M.] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Rosendaal, Frits R.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. RP Hindorff, LA (reprint author), NHGRI, NIH, 5635 Fishers Ln,Ste 4076, Bethesda, MD 20892 USA. EM hindorffl@mail.nih.gov RI Rice, Kenneth/A-4150-2013 OI Rice, Kenneth/0000-0001-5779-4495 FU National Heart, Lung, and Blood Institute [T32 HL07902]; Leducq Foundation FX This study was supported by grant T32 HL07902 from the National Heart, Lung, and Blood Institute and by the Leducq Foundation for the development of Transatlantic Networks of Excellence in Cardiovascular Research. NR 19 TC 11 Z9 11 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 EI 1538-3679 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 12 PY 2009 VL 169 IS 1 BP 68 EP 74 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 393UL UT WOS:000262398800009 PM 19139326 ER PT J AU Mejat, A Decostre, V Li, J Renou, L Kesari, A Hantai, D Stewart, CL Xiao, X Hoffman, E Bonne, G Misteli, T AF Mejat, Alexandre Decostre, Valerie Li, Juan Renou, Laure Kesari, Akanchha Hantai, Daniel Stewart, Colin L. Xiao, Xiao Hoffman, Eric Bonne, Gisele Misteli, Tom TI Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy SO JOURNAL OF CELL BIOLOGY LA English DT Article ID NUCLEAR-ENVELOPE INTEGRITY; CHAIN MESSENGER-RNA; ACETYLCHOLINE-RECEPTOR; SKELETAL-MUSCLE; GENE-EXPRESSION; PROTEIN ISOFORMS; MEMBRANE PROTEIN; MYOD PATHWAYS; SYNE PROTEINS; SOLEUS MUSCLE AB he LMNA gene encodes lamins A and C, two intermediate filament-type proteins that are important determinants of interphase nuclear architecture. Mutations in LMNA lead to a wide spectrum of human diseases including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), which affects skeletal and cardiac muscle. The cellular mechanisms by which mutations in LMNA cause disease have been elusive. Here, we demonstrate that defects in neuromuscular junctions (NMJs) are part of the disease mechanism in AD-EDMD. Two AD-EDMD mouse models show innervation defects including misexpression of electrical activity dependent genes and altered epigenetic chromatin modi. cations. Synaptic nuclei are not properly recruited to the NMJ because of mislocalization of nuclear envelope components. AD-EDMD patients with LMNA mutations show the same cellular defects as the AD-EDMD mouse models. These results suggest that lamin A/C mediated NMJ defects contribute to the AD-EDMD disease phenotype and provide insights into the cellular and molecular mechanisms for the muscle-specific phenotype of AD-EDMD. C1 [Mejat, Alexandre; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Decostre, Valerie; Renou, Laure; Hantai, Daniel; Bonne, Gisele] Inst Myol, Inst Natl Sante & Rech Med, UMR U582, F-75013 Paris, France. [Decostre, Valerie; Hantai, Daniel; Bonne, Gisele] Univ Paris 06, Inst Federatif Rech 14, UMR S582, F-75013 Paris, France. [Li, Juan; Xiao, Xiao] Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. [Kesari, Akanchha; Hoffman, Eric] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [Stewart, Colin L.] Inst Med Biol, Singapore 138668, Singapore. [Bonne, Gisele] Grp Hosp Pitie Salpetriere, AP HP, Unite Fonctionnelle Cardiogenet & Myogenet, Serv Biochim Metab, F-75013 Paris, France. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov RI MEJAT, Alexandre/G-8635-2013; Bonne, Gisele/G-3121-2013 FU National Institutes of Health (NIH); NCI; Center for Cancer Research; Institut National de la Santet de la Recherche Medicale (INSERM); Assistance Publique-Hopitaux de Paris; Association Francaise contreles Myopathies (AFM); European Union Fifth Framework [018690]; Association Francaise contre les Myopathies (AFM) [10722] FX Fluorescence imaging was in part done at the National Cancer Institute (NCI) Fluorescence Imaging Facility. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), NCI, and Center for Cancer Research; the Institut National de la Santet de la Recherche Medicale (INSERM), Assistance Publique-Hopitaux de Paris, Association Francaise contreles Myopathies (AFM), the European Union Fifth Framework (Euro-laminopathies contract No. 018690), and the Association Francaise contre les Myopathies (AFM) rare disorder network program (10722). NR 60 TC 61 Z9 63 U1 1 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 12 PY 2009 VL 184 IS 1 BP 31 EP 44 DI 10.1083/jcb.200811035 PG 14 WC Cell Biology SC Cell Biology GA 400KR UT WOS:000262867000006 PM 19124654 ER PT J AU Xu, R Nelson, CM Muschler, JL Veiseh, M Vonderhaar, BK Bissell, MJ AF Xu, Ren Nelson, Celeste M. Muschler, John L. Veiseh, Mandana Vonderhaar, Barbara K. Bissell, Mina J. TI Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PROTEIN GENE-EXPRESSION; RECONSTITUTED BASEMENT-MEMBRANE; GROWTH-FACTOR RECEPTOR; EPITHELIAL-CELLS; EXTRACELLULAR-MATRIX; TYROSINE PHOSPHORYLATION; TRANSCRIPTION FACTORS; IN-VIVO; PROLACTIN; CASEIN AB Epithelial cells, once dissociated and placed in two-dimensional (2D) cultures, rapidly lose tissue-specific functions. We showed previously that in addition to prolactin, signaling by laminin-111 was necessary to restore functional differentiation of mammary epithelia. Here, we elucidate two additional aspects of laminin-111 action. We show that in 2D cultures, the prolactin receptor is basolaterally localized and physically segregated from its apically placed ligand. Detachment of the cells exposes the receptor to ligation by prolactin leading to signal transducers and activators of transcription protein 5 (STAT5) activation, but only transiently and not sufficiently for induction of milk protein expression. We show that laminin-111 reorganizes mammary cells into polarized acini, allowing both the exposure of the prolactin receptor and sustained activation of STAT5. The use of constitutively active STAT5 constructs showed that the latter is necessary and sufficient for chromatin reorganization and beta-casein transcription. These results underscore the crucial role of continuous laminin signaling and polarized tissue architecture in maintenance of transcription factor activation, chromatin organization, and tissue-specific gene expression. C1 [Xu, Ren; Nelson, Celeste M.; Veiseh, Mandana; Bissell, Mina J.] Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Nelson, Celeste M.] Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. [Muschler, John L.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Vonderhaar, Barbara K.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bissell, MJ (reprint author), Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. EM RXu@lbl.gov; MJBissell@lbl.gov FU Office of Biological and Environmental Research (OBER) of the Department of Energy [DOE-AC03-76SF00098]; National Institutes of Health [R01CA057621]; National Cancer Institute [5R01CA64786]; Department of Defense; DOD BCRP [DAMD17-02-1-0441, W81XWH-04-1-0582]; Burroughs Wellcome Fund FX This work was supported by the Office of Biological and Environmental Research (OBER) of the Department of Energy (DOE; DOE-AC03-76SF00098), the National Institutes of Health (R01CA057621) to Z. Werb and M. J. Bissell, the National Cancer Institute (5R01CA64786) to M. J. Bissell, and the Breast Cancer Research Program (BCRP) of the Department of Defense (DOD; Innovator Award) to M. J. Bissell. M. J. Bissell is a Distinguished Scientist of the OBER of the DOE. Support was also provided by DOD BCRP postdoctoral fellowships DAMD17-02-1-0441 and W81XWH-04-1-0582 to R. Xu and C. M. Nelson. C. M. Nelson holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. NR 54 TC 68 Z9 70 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 12 PY 2009 VL 184 IS 1 BP 57 EP 66 DI 10.1083/jcb.200807021 PG 10 WC Cell Biology SC Cell Biology GA 400KR UT WOS:000262867000008 PM 19139262 ER PT J AU Wang, X Rao, RP Kosakowska-Cholody, T Masood, MA Southon, E Zhang, HL Berthet, C Nagashim, K Veenstra, TK Tessarollo, L Acharya, U Acharya, JK AF Wang, Xin Rao, Raghavendra Pralhada Kosakowska-Cholody, Teresa Masood, M. Athar Southon, Eileen Zhang, Helin Berthet, Cyril Nagashim, Kunio Veenstra, Timothy K. Tessarollo, Lino Acharya, Usha Acharya, Jairaj K. TI Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice SO JOURNAL OF CELL BIOLOGY LA English DT Article ID LECITHIN-CHOLESTEROL ACYLTRANSFERASE; ENDOPLASMIC-RETICULUM STRESS; RAT-LIVER; SPHINGOLIPID BIOSYNTHESIS; DROSOPHILA-MELANOGASTER; MOLECULAR MACHINERY; PROAPOPTOTIC BAX; OXIDATIVE STRESS; STEM-CELLS; LIFE-SPAN AB Ceramide transfer protein (CERT) functions in the transfer of ceramide from the endoplasmic reticulum (ER) to the Golgi. In this study, we show that CERT is an essential gene for mouse development and embryonic survival and, quite strikingly, is critical for mitochondrial integrity. CERT mutant embryos accumulate ceramide in the ER but also mislocalize ceramide to the mitochondria, compromising their function. Cells in mutant embryos show abnormal dilation of the ER and degenerating mitochondria. These subcellular changes manifest as heart defects and cause severely compromised cardiac function and embryonic death around embryonic day 11.5. In spite of ceramide accumulation, CERT mutant mice do not die as a result of enhanced apoptosis. Instead, cell proliferation is impaired, and expression levels of cell cycle-associated proteins are altered. Individual cells survive, perhaps because cell survival mechanisms are activated. Thus, global compromise of ER and mitochondrial integrity caused by ceramide accumulation in CERT mutant mice primarily affects organogenesis rather than causing cell death via apoptotic pathways. C1 [Wang, Xin; Rao, Raghavendra Pralhada; Kosakowska-Cholody, Teresa; Acharya, Jairaj K.] Sci Applicat Int Corp Frederick Inc, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Masood, M. Athar; Veenstra, Timothy K.] Sci Applicat Int Corp Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. [Nagashim, Kunio] Sci Applicat Int Corp Frederick Inc, Electron Microscopy Facil, Frederick, MD 21702 USA. [Southon, Eileen; Berthet, Cyril; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Zhang, Helin] Univ Maryland, Sch Med, Marlene Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Acharya, Usha] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. RP Acharya, JK (reprint author), Sci Applicat Int Corp Frederick Inc, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM acharyaj@ncifcrf.gov FU Intramural Research Program of the National Cancer Institute; National Institutes of Health; Department of Health and Human Services; National Institutes of Health [R01EY16469] FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. U. Acharya is supported by a grant from the National Institutes of Health (R01EY16469). NR 67 TC 50 Z9 50 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 12 PY 2009 VL 184 IS 1 BP 143 EP 158 DI 10.1083/jcb.200807176 PG 16 WC Cell Biology SC Cell Biology GA 400KR UT WOS:000262867000014 PM 19139267 ER PT J AU Nadjar, A Gerfen, CR Bezard, E AF Nadjar, Agnes Gerfen, Charles R. Bezard, Erwan TI Priming for L-dopa-induced dyskinesia in Parkinson's disease: A feature inherent to the treatment or the disease? SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Parkinson's disease; Dyskinesia; Sensitization; Dopamine; Behaviour; PKA-dependent signalling cascade; Ras-ERK pathway; 6-OHDA; Immediate early genes; MPTP ID LEVODOPA-INDUCED DYSKINESIA; CONTINUOUS DOPAMINERGIC STIMULATION; 6-HYDROXYDOPAMINE LESIONED RATS; ABNORMAL INVOLUNTARY MOVEMENTS; MPTP-INDUCED PARKINSONISM; TONICALLY ACTIVE NEURONS; ELEMENT-BINDING PROTEIN; RECEPTOR MESSENGER-RNA; C-FOS EXPRESSION; STRIATAL DOPAMINE AB Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease ultimately experienced by the vast majority of patients. This article does not review the increased understanding of dyskinesia pathophysiology we have seen during the past few years but, instead, specifically focuses upon the very first molecular events thought to be responsible for the establishment of dyskinesia and generally grouped under the term of "priming". Priming is classically defined as the process by which the brain becomes sensitized such that administration of a dopaminergic therapy modifies the response to subsequent dopaminergic treatments. In this way, over time, with repeated treatment, the chance of dopaminergic stimulation eliciting dyskinesia is increased and once dyskinesia has been established, the severity of dyskinesia increases. In this opinion review, however, we aim at strongly opposing the common view of priming. We propose, and hopefully will demonstrate, that priming does not exist per se but is the direct and intrinsic consequence of the loss of dopamine innervation of the striatum (and other target structures), meaning that the first injections of dopaminergic drugs only exacerbate those mechanisms (sensitization) but do not induce them. Chronicity and pulsatility of subsequent dopaminergic treatment only exacerbates the likelihood of developing dyskinesia. (C) 2008 Elsevier Ltd All rights reserved. C1 [Nadjar, Agnes; Bezard, Erwan] Univ Bordeaux 2, CNRS, Bordeaux Inst Neurosci, UMR 5227, F-33076 Bordeaux, France. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. RP Bezard, E (reprint author), Univ Bordeaux 2, CNRS, Bordeaux Inst Neurosci, UMR 5227, 146 Rue Leo Saignat, F-33076 Bordeaux, France. EM Erwan.bezard@u-bordeaux2.fr RI Nadjar, Agnes/D-3694-2011; OI Bezard, Erwan/0000-0002-0410-4638 FU Intramural NIH HHS [Z01 MH002497-19, Z99 MH999999, Z01 MH002497-18, ZIA MH002497-20] NR 114 TC 55 Z9 59 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JAN 12 PY 2009 VL 87 IS 1 BP 1 EP 9 DI 10.1016/j.pneurobio.2008.09.013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 406RL UT WOS:000263312500001 PM 18938208 ER PT J AU Srivastava, V AF Srivastava, Vibhuti TI Looking East: familial support as a crucial predictor of treatment management in psychiatric illnesses? SO CURRENT SCIENCE LA English DT Letter C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Srivastava, V (reprint author), NIAAA, Neurogenet Lab, NIH, 3S-32 MSC 9412,5625 Fishers Ln, Rockville, MD 20852 USA. EM vibhutisrivastava@yahoo.com NR 3 TC 0 Z9 0 U1 0 U2 1 PU INDIAN ACAD SCIENCES PI BANGALORE PA C V RAMAN AVENUE, SADASHIVANAGAR, P B #8005, BANGALORE 560 080, INDIA SN 0011-3891 J9 CURR SCI INDIA JI Curr. Sci. PD JAN 10 PY 2009 VL 96 IS 1 BP 10 EP 11 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 408KB UT WOS:000263432800007 ER PT J AU Boulton, AJM Jeffcoate, WJ Jones, TLZ Ulbrecht, JS AF Boulton, Andrew J. M. Jeffcoate, William J. Jones, Teresa L. Z. Ulbrecht, Jon S. TI International collaborative research on Charcot's disease SO LANCET LA English DT Editorial Material C1 [Jeffcoate, William J.] Nottingham Univ Hosp Trust, Foot Ulcer Trials Unit, Dept Diabet & Endocrinol, Nottingham NG5 1PB, England. [Boulton, Andrew J. M.] Manchester Royal Infirm, Dept Med, Manchester M13 9WL, Lancs, England. [Jones, Teresa L. Z.] NIDDK, DEM, NIH, Bethesda, MD USA. [Ulbrecht, Jon S.] Penn State Univ, Penn State Inst Diabet & Obes, University Pk, PA 16802 USA. RP Jeffcoate, WJ (reprint author), Nottingham Univ Hosp Trust, Foot Ulcer Trials Unit, Dept Diabet & Endocrinol, City Hosp Campus, Nottingham NG5 1PB, England. EM william.jeffcoate@tiscali.co.uk NR 1 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JAN 10 PY 2009 VL 373 IS 9658 BP 105 EP 106 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 392ZO UT WOS:000262340900009 PM 19135599 ER PT J AU Scharenberg, C Mannowetz, N Robey, RW Brendel, C Repges, P Sahrhage, T Jahn, T Wennemuth, G AF Scharenberg, Christian Mannowetz, Nadja Robey, Robert W. Brendel, Cornelia Repges, Philip Sahrhage, Tim Jaehn, Thomas Wennemuth, Gunther TI ABCG2 is expressed in late spermatogenesis and is associated with the acrosome SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE ABCG2; Spermatozoa; Acrosome; Cholesterol efflux ID RESISTANCE-ASSOCIATED PROTEIN; MOUSE SPERMATOZOA; STEM-CELLS; SPERM; CAPACITATION; TRANSPORTER; EFFLUX; GENE AB An increasingly exploited strategy for the isolation of stein cells is based on the increased efflux of Hoechst 33342 lipophilic dye mediated by ABCG2, all ATP-binding cassette transporter which is highly expressed it) various stern cells. We found ABCG2 expression to be present at later stages of spermatogenesis. Western Nor analysis using all anti-ABCG2 antibody revealed expression of a 72 kDa band in mature sperm obtained from mice, rats, bulls or humans. Immunocytochemistry Studies revealed acrosomal staining pattern of ABCG2 in spermatozoa. Experiments Using the Hoechst 33342 ABCG2 substrate and the ABCG2-specific inhibitor FTC demonstrated efflux activity of ABCG2 in mature sperm. Incubation of sperm in capacitating medium in the presence of the ABCG2-inhibitor FTC resulted in decreased cholesterol depletion compared to sperm incubated in the absence of FTC. Our results demonstrate that ABCG2 is expressed at the acrosome in mature sperm. ABCG2 may thus serve to mediate cholesterol removal. (c) 2008 Elsevier Inc. All rights reserved. C1 [Scharenberg, Christian; Mannowetz, Nadja; Repges, Philip; Sahrhage, Tim; Jaehn, Thomas; Wennemuth, Gunther] Univ Saarland, Dept Anat & Cell Biol, D-66421 Homburg, Germany. [Scharenberg, Christian; Brendel, Cornelia] Univ Marburg, Dept Hematol & Oncol, D-35037 Marburg, Germany. [Robey, Robert W.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wennemuth, G (reprint author), Univ Saarland, Dept Anat & Cell Biol, Bldg 61, D-66421 Homburg, Germany. EM gunther.wennemuth@uks.eu NR 24 TC 7 Z9 8 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 9 PY 2009 VL 378 IS 2 BP 302 EP 307 DI 10.1016/j.jbbrc.2008.11.058 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 389AU UT WOS:000262063100031 PM 19032939 ER PT J AU Pessoa, L Rossi, A Japee, S Desimone, R Ungerleider, LG AF Pessoa, Luiz Rossi, Andrew Japee, Shruti Desimone, Robert Ungerleider, Leslie G. TI Attentional control during the transient updating of cue information SO BRAIN RESEARCH LA English DT Article DE Attention; Vision; fMRI ID EVENT-RELATED FMRI; TOP-DOWN CONTROL; SELECTIVE VISUAL-ATTENTION; PREFRONTAL CORTEX; NEURAL MECHANISMS; COGNITIVE CONTROL; ANTERIOR CINGULATE; BRAIN; PARIETAL; AREAS AB The goal of the present study was to investigate the neural correlates of top-down control of switching behavior in humans and to contrast them to those observed during switching behavior guided by bottom-up mechanisms. In the main experimental condition (color-cue), which was guided by top-down control, a central cue indicated the color of a peripheral grating on which the subject performed an orientation judgment. For switch trials, the color of the cue on the current trial was different from the color on the previous trial, For non-switch trials, the color of the cue on the cur-rent trial was the same as the color in the preceding trial. During a control condition (pop-out), which was guided by bottom-up saliency, the target grating was defined by color contrast; again both switch and non-switch trials occurred. We observed stronger evoked responses during the color-cue task relative to the pop-out task in the inferior parietal lobule (IPL), frontal eye field (FEF), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG). The contrast of switch vs. non-switch trials revealed activations in regions that were engaged when there was a change in the identity of the target. Collectively, switch trials evoked stronger responses relative to non-switch trials in fronto-parietal regions that appeared to be left lateralized, including left intraparietal sulcus (IPS) and left MFG/IFG. Task by trial type interactions (switch>non-switch during color-cue relative to pop-out) were observed in several fronto-parietal regions, including IPS, FEF, MFG and IFG, in addition to regions in visual cortex. Our findings suggest that, within the fronto-parietal attentional network, the IPS and MFG/IFG appear to be most heavily involved in attentive cue updating. Furthermore, several visual regions engaged by oriented gratings were strongly affected by cue updating, raising the possibility that they were the recipient of top-down signals that were generated when cue information was updated. (C) 2008 Elsevier B.V. All rights reserved. C1 [Pessoa, Luiz] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. [Rossi, Andrew] NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. [Japee, Shruti; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Desimone, Robert] MIT, McGovern Inst, Cambridge, MA 02139 USA. RP Pessoa, L (reprint author), Indiana Univ, Dept Psychol & Brain Sci, 1101 E 10th St, Bloomington, IN 47405 USA. EM lpessoa@indiana.edu FU NIMH Intramural Research Program; [R01MH071589]; [5R01EY017292] FX We thank David Sturman and Aurora Ramos for assistance in this project and Ziad Saad for help with surface mapping. This work was supported by the NIMH Intramural Research Program. L.P. was supported in part by R01MH071589 and R. D. was supported in part by 5R01EY017292. NR 51 TC 17 Z9 17 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 9 PY 2009 VL 1247 BP 149 EP 158 DI 10.1016/j.brainres.2008.10.010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 401FR UT WOS:000262925700016 PM 18992228 ER PT J AU Cui, KR Zang, CZ Roh, TY Schones, DE Childs, RW Peng, WQ Zhao, K AF Cui, Kairong Zang, Chongzhi Roh, Tae-Young Schones, Dustin E. Childs, Richard W. Peng, Weiqun Zhao, Keji TI Chromatin Signatures in Multipotent Human Hematopoietic Stem Cells Indicate the Fate of Bivalent Genes during Differentiation SO Cell Stem Cell LA English DT Article ID BETA-GLOBIN GENE; HUMAN GENOME; DNA METHYLATION; HISTONE MODIFICATIONS; ERYTHROID-CELLS; TRANSCRIPTION; LINEAGE; PLURIPOTENT; PROGENITORS; EXPRESSION AB Histone modifications have been implicated in stem cell maintenance and differentiation. We have analyzed genome-wide changes in gene expression and histone modifications during differentiation of multipotent human primary hematopoietic stem cells/progenitor cells (HSCs/HPCs) into erythrocyte precursors. Our data indicate that H3K4me1, H3K9me1, and H3K27me1 associate with enhancers of differentiation genes prior to their activation and correlate with basal expression, suggesting that these monomethylations are involved in the maintenance of activation potential required for differentiation. In addition, although the majority of genes associated with both H3K4me3 and H3K27me3 in HSCs/HPCs become silent and lose H3K4me3 after differentiation, those that lose H3K27me3 and become activated after differentiation are associated with increased levels of H2A.Z, H3K4me1, H3K9me1, H4K20me1, and RNA polymerase 11 in HSCs/HPCs. Thus, our data suggest that gene expression changes during differentiation are programmed by chromatin modifications present at the HSC/HPC stage and provide a resource for enhancer and promoter identification. C1 [Cui, Kairong; Roh, Tae-Young; Schones, Dustin E.; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Zang, Chongzhi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP Zhao, K (reprint author), NHLBI, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov RI Zang, Chongzhi/D-1445-2011 FU National Institutes of Health, National Heart, Lung, and Blood Institute FX We thank Dr. Susan Wong for helpful discussions and Dr. Warren Leonard for critical reading of the manuscript. The gene expression analysis using the Affymetrix microarrays was performed by the Gene Expression Core Facility of the National Heart, Lung, and Blood Institute. This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. NR 46 TC 349 Z9 355 U1 3 U2 12 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 JAN 9 PY 2009 VL 4 IS 1 BP 80 EP 93 DI 10.1016/j.stem.2008.11.011 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 395YN UT WOS:000262559500014 PM 19128795 ER PT J AU Jarczowski, F Jahreis, G Erdmann, F Schierhorn, A Fischer, G Edlich, F AF Jarczowski, Franziska Jahreis, Guenther Erdmann, Frank Schierhorn, Angelika Fischer, Gunter Edlich, Frank TI FKBP36 Is an Inherent Multifunctional Glyceraldehyde-3-phosphate Dehydrogenase Inhibitor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PACHYTENE PRIMARY SPERMATOCYTES; GENE-EXPRESSION; RAT TESTES; HSP90; TISSUES; PROTEIN; CELLS; GAPDH; RNA AB FKBP36 has been previously shown to be a crucial factor in spermatogenesis because of its interplay with the synaptonemal complex protein SCPI. Here we show that beyond this function, FKBP36 forms complexes with glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12) and Hsp90. Both proteins bind independently to different sites of the FKBP36 tetratricopeptide repeat domain. The interaction between FKBP36 and GAPDH directly inhibits the catalytic activity of GAPDH. In addition, FKBP36 expression causes a significant reduction of the GAPDH level and activity in COS-7 cells. Particularly in the cytosolic fraction, GAPDH was depleted by FKBP36 expression. Thus, FKBP36 diminishes GAPDH activity by direct interaction and down-regulation of GAPDH, which represents a previously unknown mechanism of GAPDH regulation and a novel function of FKBP36 in testis-specific signaling. C1 [Jarczowski, Franziska; Jahreis, Guenther; Erdmann, Frank; Schierhorn, Angelika; Fischer, Gunter; Edlich, Frank] Max Planck Res Unit Enzymol Prot Folding, D-06120 Halle, Germany. RP Edlich, F (reprint author), NINDS, Surg Neurol Branch, NIH, Porter Neurosci Res Ctr, 35 Convent Dr,MSC 3704, Bethesda, MD 20892 USA. EM fischer@enzyme-halle.mpg.de; edlichf@ninds.nih.gov FU Sonderforschungsbereich 604 of the Deutsche Forschungsgemeinschaft FX This work was supported by Sonderforschungsbereich 604 of the Deutsche Forschungsgemeinschaft. 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 33 TC 10 Z9 12 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 JAN 9 PY 2009 VL 284 IS 2 BP 766 EP 773 DI 10.1074/jbc.M709779200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 389VP UT WOS:000262122900010 PM 19001379 ER PT J AU Isenberg, JS Annis, DS Pendrak, ML Ptaszynska, M Frazier, WA Mosher, DF Roberts, DD AF Isenberg, Jeff S. Annis, Douglas S. Pendrak, Michael L. Ptaszynska, Malgorzata Frazier, William A. Mosher, Deane F. Roberts, David D. TI Differential Interactions of Thrombospondin-1,-2, and-4 with CD47 and Effects on cGMP Signaling and Ischemic Injury Responses SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTEGRIN-ASSOCIATED PROTEIN; C-TERMINAL DOMAIN; GROWTH-FACTOR-I; NITRIC-OXIDE; TISSUE SURVIVAL; CELL RESPONSES; MYOCARDIAL-INFARCTION; SIGNATURE DOMAINS; LIGAND-BINDING; RECEPTOR AB Thrombospondin-1 regulates nitric oxide (NO) signaling in vascular cells via CD47. Because CD47 binding motifs are conserved in the C-terminal signature domains of all five thrombospondins and indirect evidence has implied CD47 interactions with other family members, we compared activities of recombinant signature domains of thrombospondin-1, -2, and -4 to interact with CD47 and modulate cGMP signaling. Signature domains of thrombospondin-2 and -4 were less active than that of thrombospondin-1 for inhibiting binding of radiolabeled signature domain of thrombospondin-1 or SIRP alpha (signal-regulatory protein) to cells expressing CD47. Consistent with this binding selectivity, the signature domain of thrombospondin-1 was more potent than those of thrombospondin-2 or -4 for inhibiting NO-stimulated cGMP synthesis in vascular smooth muscle cells and downstream effects on cell adhesion. In contrast to thrombospondin-1-and CD47-null cells, primary vascular cells from thrombospondin-2-null mice lack enhanced basal and NO-stimulated cGMP signaling. Effects of endogenous thrombospondin-2 on NO/cGMP signaling could be detected only in thrombospondin-1-null cells. Furthermore, tissue survival of ischemic injury and acute recovery of blood flow in thrombospondin-2-nulls resembles that of wild type mice. Therefore, thrombospondin-1 is the dominant regulator of NO/cGMP signaling via CD47, and its limiting role in acute ischemic injury responses is not shared by thrombospondin-2. C1 [Isenberg, Jeff S.; Pendrak, Michael L.; Ptaszynska, Malgorzata; Roberts, David D.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Annis, Douglas S.; Mosher, Deane F.] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 USA. [Annis, Douglas S.; Mosher, Deane F.] Univ Wisconsin, Dept Med, Madison, WI 53706 USA. [Frazier, William A.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Rm 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 National Institutes of Health [HL54462, HL54390]; Intramural Research Program of the NCI; Center for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Grants National HL54462 (to D. F. M.) and HL54390 (to W. A. F.) and by the Intramural Research Program of the NCI, National Institutes of Health, Center for Cancer Research (to D. D. R.). 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 57 Z9 58 U1 3 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 JAN 9 PY 2009 VL 284 IS 2 BP 1116 EP 1125 DI 10.1074/jbc.M804860200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 389VP UT WOS:000262122900048 PM 19004835 ER PT J AU Pu, YM Garfield, SH Kedei, N Blumberg, PM AF Pu, Yongmei Garfield, Susan H. Kedei, Noemi Blumberg, Peter M. TI Characterization of the Differential Roles of the Twin C1a and C1b Domains of Protein Kinase C delta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHORBOL ESTER BINDING; 12-MYRISTATE 13-ACETATE; INDUCED TRANSLOCATION; THERAPEUTIC TARGET; DOWN-REGULATION; NIH 3T3-CELLS; DIACYLGLYCEROL; ACTIVATION; LIGANDS; PKC AB Classic and novel protein kinase C (PKC) isozymes contain two zinc finger motifs, designated "C1a" and "C1b" domains, which constitute the recognition modules for the second messenger diacylglycerol (DAG) or the phorbol esters. However, the individual contributions of these tandem C1 domains to PKC function and, reciprocally, the influence of protein context on their function remain uncertain. In the present study, we prepared PKC delta constructs in which the individual C1a and C1b domains were deleted, swapped, or substituted for one another to explore these issues. As isolated fragments, both the delta C1a and delta C1b domains potently bound phorbol esters, but the binding of [(3)H] phorbol 12,13-dibutyrate ([(3)H]PDBu) by the delta C1a domain depended much more on the presence of phosphatidylserine than did that of the delta C1b domain. In intact PKC delta, the delta C1b domain played the dominant role in [(3)H]PDBu binding, membrane translocation, and down-regulation. A contribution from the delta C1a domain was nonetheless evident, as shown by retention of [(3)H]PDBu binding at reduced affinity, by increased [(3)H]PDBu affinity upon expression of a second delta C1a domain substituting for the delta C1b domain, and by loss of persistent plasma membrane translocation for PKC delta expressing only the delta C1b domain, but its contribution was less than predicted from the activity of the isolated domain. Switching the position of the delta C1b domain to the normal position of the delta C1a domain (or vice versa) had no apparent effect on the response to phorbol esters, suggesting that the specific position of the C1 domain within PKC delta was not the primary determinant of its activity. C1 [Garfield, Susan H.; Blumberg, Peter M.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Pu, Yongmei; Kedei, Noemi; Blumberg, Peter M.] Lab Canc Biol & Genet, Mol Mech Tumor Promot Sect, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Rm 4048,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov FU National Institutes of Health; NCI; Center for Cancer Research FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, NCI, Center for Cancer Research. NR 46 TC 11 Z9 11 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 9 PY 2009 VL 284 IS 2 BP 1302 EP 1312 DI 10.1074/jbc.M804796200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 389VP UT WOS:000262122900065 PM 19001377 ER PT J AU Kann, MG Shoemaker, BA Panchenko, AR Przytycka, TM AF Kann, Maricel G. Shoemaker, Benjamin A. Panchenko, Anna R. Przytycka, Teresa M. TI Correlated Evolution of Interacting Proteins: Looking Behind the Mirrortree SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE domain-domain interactions; protein coevolution; protein-protein interactions; phylogenetic tree; mirrortree ID DOMAIN INTERACTIONS; DISTANCE MATRICES; REVEALS INSIGHTS; COEVOLUTION; INFORMATION; SPECIFICITY; PREDICTION; NETWORKS; TREE AB It has been observed that the evolutionary distances of interacting proteins often display a higher level of similarity than those of noninteracting proteins. This finding indicates that interacting proteins are subject to common evolutionary constraints and constitutes the basis of a method to predict protein interactions known as mirrortree. It has been difficult, however, to identify the direct cause of the observed similarities between evolutionary trees. One possible explanation is the existence of compensatory mutations between partners' binding sites to maintain proper binding. This explanation, though, has been recently challenged, and it has been suggested that the signal of correlated evolution uncovered by the mirrortree method is unrelated to any correlated evolution between binding sites. We examine the contribution of binding sites to the correlation between evolutionary trees of interacting domains. We show that binding neighborhoods of interacting proteins have, on average, higher coevolutionary signal compared with the regions outside binding sites; however, when the binding neighborhood is removed, the remaining domain sequence still contains some coevolutionary signal. In conclusion, the correlation between evolutionary trees of interacting domains cannot exclusively be attributed to the correlated evolution of the binding sites or to common evolutionary pressure exerted on the whole protein domain sequence, each of which contributes to the signal measured by the mirrortree approach. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Kann, Maricel G.] Univ Maryland, Dept Biol Sci, Baltimore Cty, MD 21250 USA. [Shoemaker, Benjamin A.; Panchenko, Anna R.; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, US Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Kann, MG (reprint author), Univ Maryland, Dept Biol Sci, Baltimore Cty, MD 21250 USA. EM mkann@umbc.edu; przytyck@ncbi.nlm.nih.gov RI Kann, Maricel/E-5701-2012 FU Intramural Research Program of the National Institutes of Health; National Library of Medicine; University of Maryland Baltimore County Special Research Initiative Support FX Support for this work was provided in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, and through funding from the University of Maryland Baltimore County Special Research Initiative Support. NR 31 TC 33 Z9 34 U1 1 U2 9 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 JAN 9 PY 2009 VL 385 IS 1 BP 91 EP 98 DI 10.1016/j.jmb.2008.09.078 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 400LT UT WOS:000262870200011 PM 18930732 ER PT J AU Abbadessa, G Accolla, R Aiuti, F Albini, A Aldovini, A Alfano, M Antonelli, G Bartholomew, C Bentwich, Z Bertazzoni, U Berzofsky, JA Biberfeld, P Boeri, E Buonaguro, L Buonaguro, FM Bukrinsky, M Burny, A Caruso, A Cassol, S Chandra, P Ceccherini-Nelli, L Chieco-Bianchi, L Clerici, M Colombini-Hatch, S Morghen, CDG De Maria, A De Rossi, A Dierich, M Della-Favera, R Dolei, A Douek, D Erfle, V Felber, B Fiorentini, S Franchini, G Gershoni, JM Gotch, F Green, P Greene, WC Hall, W Haseltine, W Jacobson, S Kallings, LO Kalyanaraman, VS Katinger, H Khalili, K Klein, G Klein, E Klotman, M Klotman, P Kotler, M Kurth, R Lafeuillade, A La Placa, M Lewis, J Lillo, F Lisziewicz, J Lomonico, A Lopalco, L Lori, F Lusso, P Macchi, B Malim, M Margolis, L Markham, PD Mcclure, M Miller, N Mingari, MC Moretta, L Noonan, D O'Brien, S Okamoto, T Pal, R Palese, P Panet, A Pantaleo, G Pavlakis, G Pistello, M Plotkin, S Poli, G Pomerantz, R Radaelli, A Robert-Guroff, M Roederer, M Sarngadharan, MG Schols, D Secchiero, P Shearer, G Siccardi, A Stevenson, M Svoboda, J Tartaglia, J Torelli, G Tornesello, ML Tschachler, E Vaccarezza, M Vallbracht, A Van Lunzen, J Varnier, O Vicenzi, E Von Melchner, H Witz, I Zagury, D Zagury, JF Zauli, G Zipeto, D AF Abbadessa, Giovanni Accolla, Roberto Aiuti, Fernando Albini, Adriana Aldovini, Anna Alfano, Massimo Antonelli, Guido Bartholomew, Courtenay Bentwich, Zvi Bertazzoni, Umberto Berzofsky, Jay A. Biberfeld, Peter Boeri, Enzo Buonaguro, Luigi Buonaguro, Franco M. Bukrinsky, Michael Burny, Arsene Caruso, Arnaldo Cassol, Sharon Chandra, Prakash Ceccherini-Nelli, Luca Chieco-Bianchi, Luigi Clerici, Mario Colombini-Hatch, Sandra Morghen, Carlo De Giuli De Maria, Andrea De Rossi, Anita Dierich, Manfred Della-Favera, Riccardo Dolei, Antonina Douek, Daniel Erfle, Volker Felber, Barbara Fiorentini, Simona Franchini, Genoveffa Gershoni, Jonathan M. Gotch, Frances Green, Patrick Greene, Warner C. Hall, William Haseltine, William Jacobson, Stephens Kallings, Lars O. Kalyanaraman, Vaniambadi S. Katinger, Hermann Khalili, Kamel Klein, George Klein, Eva Klotman, Mary Klotman, Paul Kotler, Moshe Kurth, Reinhard Lafeuillade, Alain La Placa, Michelangelo Lewis, Jonathan Lillo, Flavia Lisziewicz, Julianna Lomonico, Anita Lopalco, Lucia Lori, Franco Lusso, Paolo Macchi, Beatrice Malim, Michael Margolis, Leonid Markham, Phillip D. Mcclure, Myra Miller, Nancy Mingari, Maria C. Moretta, Lorenzo Noonan, Douglas O'Brien, Steve Okamoto, Takashi Pal, Ranajit Palese, Peter Panet, Amos Pantaleo, Giuseppe Pavlakis, George Pistello, Mauro Plotkin, Stanley Poli, Guido Pomerantz, Roger Radaelli, Antonia Robert-Guroff, Marjorie Roederer, Mario Sarngadharan, Mangalasseril G. Schols, Dominique Secchiero, Paola Shearer, Gene Siccardi, Antonio Stevenson, Mario Svoboda, Jan Tartaglia, Jim Torelli, Giuseppe Tornesello, Maria Lina Tschachler, Erwin Vaccarezza, Mauro Vallbracht, Angelika Van Lunzen, Jan Varnier, Oliviero Vicenzi, Elisa Von Melchner, Harald Witz, Isaac Zagury, Daniel Zagury, Jean-Francois Zauli, Giorgio Zipeto, Donato TI Unsung Hero Robert C. Gallo SO SCIENCE LA English DT Letter ID RETROVIRUSES HTLV-III; AIDS C1 [Alfano, Massimo; Boeri, Enzo; Lopalco, Lucia; Poli, Guido; Vicenzi, Elisa] San Raffaele Univ & Sci Inst, Milan, Italy. [Abbadessa, Giovanni; Lewis, Jonathan] ZIOPHARM Oncol Inc, Boston, MA USA. [Accolla, Roberto; Noonan, Douglas] Univ Insubria, Varese, Italy. [Aiuti, Fernando; Antonelli, Guido] Univ Roma La Sapienza, Rome, Italy. [Albini, Adriana] IRCCS Multimedica, Milan, Italy. [Aldovini, Anna] Childrens Hosp, Boston, MA 02115 USA. [Aldovini, Anna] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bartholomew, Courtenay] Med Res Fdn Trinidad & Tobago, Port Of Spain, Trinid & Tobago. [Bentwich, Zvi] Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. [Bertazzoni, Umberto; Zipeto, Donato] Univ Verona, I-37100 Verona, Italy. [Berzofsky, Jay A.; Franchini, Genoveffa; Lomonico, Anita; Robert-Guroff, Marjorie; Shearer, Gene] NCI, Bethesda, MD 20892 USA. [Biberfeld, Peter; Klein, George; Klein, Eva] Karolinska Inst, Stockholm, Sweden. [Buonaguro, Luigi; Buonaguro, Franco M.; Tornesello, Maria Lina] Ist Nazl Tumori Fdn G Pascale, Naples, Italy. [Bukrinsky, Michael] George Washington Univ, Washington, DC USA. [Burny, Arsene] Ctr Cellular & Mol Biol, Gembloux, Belgium. [Caruso, Arnaldo; Fiorentini, Simona] Univ Brescia, Brescia, Italy. [Cassol, Sharon] Univ Pretoria, ZA-0002 Pretoria, South Africa. [Chandra, Prakash; Von Melchner, Harald] Univ Frankfurt, Sch Med, Frankfurt, Germany. [Ceccherini-Nelli, Luca; Pistello, Mauro] Univ Pisa, Pisa, Italy. [Chieco-Bianchi, Luigi; De Rossi, Anita] Univ Padua, Padua, Italy. [Clerici, Mario; Morghen, Carlo De Giuli; Radaelli, Antonia; Siccardi, Antonio] Univ Milan, Milan, Italy. [Colombini-Hatch, Sandra] NHLBI, Bethesda, MD 20892 USA. [De Maria, Andrea; Mingari, Maria C.; Varnier, Oliviero] Univ Genoa, Genoa, Italy. [Dierich, Manfred] Innsbruck Med Univ, Innsbruck, Austria. [Della-Favera, Riccardo] Columbia Univ, New York, NY USA. [Dolei, Antonina] Univ Sassari, I-07100 Sassari, Italy. [Douek, Daniel; Lusso, Paolo; Miller, Nancy; Roederer, Mario] NIAID, Bethesda, MD 20892 USA. [Erfle, Volker] GSF, Inst Mol Virol, Munich, Germany. [Felber, Barbara; O'Brien, Steve; Pavlakis, George] NCI, Frederick, MD 21701 USA. [Gershoni, Jonathan M.; Witz, Isaac] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Gotch, Frances; Mcclure, Myra] Univ London Imperial Coll Sci Technol & Med, London, England. [Green, Patrick] Ohio State Univ, Columbus, OH 43210 USA. [Greene, Warner C.] Gladstone Inst Virol & Immunol, San Francisco, CA USA. [Hall, William] Univ Coll Dublin, Dublin 2, Ireland. [Haseltine, William] William A Haseltine Fdn Med Sci & Arts, Rockville, MD USA. [Jacobson, Stephens] NINDS, Bethesda, MD 20892 USA. [Kallings, Lars O.] UN, Secretariat Gen, New York, NY 10017 USA. [Kalyanaraman, Vaniambadi S.; Markham, Phillip D.; Pal, Ranajit; Sarngadharan, Mangalasseril G.] Adv Biosci Labs, Kensington, MD USA. [Katinger, Hermann] Univ Nat Resources & Appl Life, Vienna, Austria. [Khalili, Kamel] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Klotman, Mary; Klotman, Paul; Palese, Peter] Mt Sinai Sch Med, New York, NY USA. [Kotler, Moshe; Panet, Amos] Hebrew Univ Jerusalem, Hadassah Med Sch, IL-91010 Jerusalem, Israel. [Kurth, Reinhard] Robert Koch Inst, D-1000 Berlin, Germany. [Lafeuillade, Alain] Hosp Font Pre, Toulon, France. [La Placa, Michelangelo] Univ Bologna, Bologna, Italy. [Lillo, Flavia] Fdn San Raffaele G Giglio, Cefalu, Italy. [Lisziewicz, Julianna; Lori, Franco] Genet Immun, Budapest, Hungary. [Macchi, Beatrice] Univ Roma Tor Vergata, I-00173 Rome, Italy. [Malim, Michael] Kings Coll London, Sch Med, London WC2R 2LS, England. [Margolis, Leonid] NICHHD, Bethesda, MD 20892 USA. [Moretta, Lorenzo] Ist Giannina Gaslini, I-16148 Genoa, Italy. [Okamoto, Takashi] Nagoya City Univ, Nagoya, Aichi, Japan. [Pantaleo, Giuseppe] CHU Vaudois, CH-1011 Lausanne, Switzerland. [Plotkin, Stanley] Sanofi Pasteur, Doylestown, PA USA. [Pomerantz, Roger] Tibotec Pharmaceut Ltd, Yardley, PA USA. [Schols, Dominique] Katholieke Univ Leuven, Rega Inst, Louvain, Belgium. [Secchiero, Paola; Zauli, Giorgio] Univ Ferrara, I-44100 Ferrara, Italy. [Stevenson, Mario] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Svoboda, Jan] Inst Mol Genet, Prague, Czech Republic. [Tartaglia, Jim] Sanofi Pasteur, Toronto, ON, Canada. [Torelli, Giuseppe] Univ Modena, I-41100 Modena, Italy. [Tschachler, Erwin] Med Univ Vienna, Vienna, Austria. [Vaccarezza, Mauro] Univ Cassino, I-03043 Cassino, Italy. [Vallbracht, Angelika] Univ Bremen, Bremen, Germany. [Van Lunzen, Jan] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Zagury, Daniel] Neovscs SA, Paris, France. [Zagury, Jean-Francois] Conservatoire Natl Arts & Metiers, Paris, France. RP Poli, G (reprint author), San Raffaele Univ & Sci Inst, Milan, Italy. EM poli.guido@hsr.it RI Svoboda, Jan/G-4393-2014; Tornesello, Maria Lina/A-1564-2009; secchiero, paola/G-9689-2015; De Rossi, Anita/L-3128-2015; klotman, mary/A-1921-2016; de maria, andrea/F-7116-2016; Pantaleo, Giuseppe/K-6163-2016; Noonan, Douglas/A-8620-2010; OI Lopalco, Lucia/0000-0003-3812-1759; Tornesello, Maria Lina/0000-0002-3523-3264; secchiero, paola/0000-0003-4101-7987; De Rossi, Anita/0000-0001-6435-7509; de maria, andrea/0000-0001-5782-333X; Noonan, Douglas/0000-0001-8058-0719; Radaelli, Antonia/0000-0002-5683-6216; Palese, Peter/0000-0002-0337-5823; Vicenzi, Elisa/0000-0003-0051-3968; Malim, Michael/0000-0002-7699-2064; Accolla, Roberto/0000-0003-2493-7378; Zauli, Giorgio/0000-0002-3750-8698; VACCAREZZA, Mauro/0000-0003-3060-318X NR 5 TC 2 Z9 2 U1 2 U2 16 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 JAN 9 PY 2009 VL 323 IS 5911 BP 206 EP 207 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 392GG UT WOS:000262290600012 PM 19131607 ER PT J AU Turanov, AA Lobanov, AV Fomenko, DE Morrison, HG Sogin, ML Klobutcher, LA Hatfield, DL Gladyshev, VN AF Turanov, Anton A. Lobanov, Alexey V. Fomenko, Dmitri E. Morrison, Hilary G. Sogin, Mitchell L. Klobutcher, Lawrence A. Hatfield, Dolph L. Gladyshev, Vadim N. TI Genetic Code Supports Targeted Insertion of Two Amino Acids by One Codon SO SCIENCE LA English DT Article ID SEQUENCE ELEMENT; TRANSFER-RNA; EXPRESSION AB Strict one- to- one correspondence between codons and amino acids is thought to be an essential feature of the genetic code. However, we report that one codon can code for two different amino acids with the choice of the inserted amino acid determined by a specific 3 ' untranslated region structure and location of the dual- function codon within the messenger RNA ( mRNA). We found that the codon UGA specifies insertion of selenocysteine and cysteine in the ciliate Euplotes crassus, that the dual use of this codon can occur even within the same gene, and that the structural arrangements of Euplotes mRNA preserve location- dependent dual function of UGA when expressed in mammalian cells. Thus, the genetic code supports the use of one codon to code for multiple amino acids. C1 [Turanov, Anton A.; Lobanov, Alexey V.; Fomenko, Dmitri E.; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Turanov, Anton A.; Lobanov, Alexey V.; Fomenko, Dmitri E.; Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Morrison, Hilary G.; Sogin, Mitchell L.] Marine Biol Lab, Josephine Bay Paul Ctr, Woods Hole, MA 02543 USA. [Klobutcher, Lawrence A.] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT 06032 USA. [Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. EM vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013; OI Morrison, Hilary/0000-0003-0281-326X FU NIH [GM061603, GM065204, AI058054]; NSF [0343813]; Intramural Research Program; National Cancer Institute FX We thank K. Hammar for constructing the EST library and I. Sorokina (Midwest Bio Services) for protein sequencing. This work was supported by NIH GM061603 and GM065204 to V.N.G., AI058054 to M.L.S., NSF 0343813 to L.A.K., and the Intramural Research Program, National Cancer Institute, NIH, to D.L.H. Sequences for tRNA and selenoprotein genes have been deposited in the GenBank database under accession numbers FJ440148 to FJ440159. NR 10 TC 54 Z9 56 U1 1 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 9 PY 2009 VL 323 IS 5911 BP 259 EP 261 DI 10.1126/science.1164748 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 392GG UT WOS:000262290600040 PM 19131629 ER PT J AU Wei, J Rega, MF Kitada, S Yuan, HB Zhai, D Risbood, P Seltzman, HH Twine, CE Reed, JC Pellecchia, M AF Wei, Jun Rega, Michele F. Kitada, Shinichi Yuan, Hongbin Zhai, Dayong Risbood, Prabhakar Seltzman, Herbert H. Twine, Charles E. Reed, John C. Pellecchia, Maurizio TI Synthesis and evaluation of Apogossypol atropisomers as potential Bcl-x(L) antagonists SO CANCER LETTERS LA English DT Article DE Apogossypol atropisomers; Gossypol; Apoptosis; Bcl-2; Bcl-x(L); Apogossypol; Chemotherapy; Mcl-1 ID SMALL-MOLECULE INHIBITORS; BCL-2 FAMILY PROTEINS; GOSSYPOL ENANTIOMERS; APOPTOSIS; CANCER; DISCOVERY; COMPOUND; COMPLEX; DESIGN; CELLS AB Anti-apoptotic Bcl-2 family proteins such as Bcl-2 and Bcl-X-L have been recently validated as targets for the discovery of novel anti-cancer agents. We previously reported that racemic (+/-) Apogossypol, a semi-synthetic compound derived from the natural product Gossypol, binds and inhibits Bcl-2 and Bcl-X-L. in vitro and in cell. Given that (+) and (-) Gossypol display different proapoptotic activities, here we report on the synthesis of (+) and (-) Apogossypol and the evaluation of their in vitro and cellular activity. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Wei, Jun; Rega, Michele F.; Kitada, Shinichi; Yuan, Hongbin; Zhai, Dayong; Reed, John C.; Pellecchia, Maurizio] Burnham Inst Med Res, La Jolla, CA 92037 USA. [Risbood, Prabhakar] NCI, Drug Synth & Chem Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. [Seltzman, Herbert H.; Twine, Charles E.] RTI Int, Res Triangle Pk, NC 27709 USA. RP Pellecchia, M (reprint author), Burnham Inst Med Res, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM mpellecchia@burnham.org FU NIH [U01 A1061139]; Coronado Biosciences; [CSRA 08-02] FX We thank NIH (Grant No. U01 A1061139) and Coronado Biosciences (CSRA #08-02) for financial support and the NCI-RAID program for technical and scientific support. NR 26 TC 18 Z9 19 U1 0 U2 3 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 JAN 8 PY 2009 VL 273 IS 1 BP 107 EP 113 DI 10.1016/j.canlet.2008.07.031 PG 7 WC Oncology SC Oncology GA 396HS UT WOS:000262583400012 PM 18782651 ER PT J AU Munday, JN Capasso, F Parsegian, VA AF Munday, J. N. Capasso, Federico Parsegian, V. Adrian TI Measured long-range repulsive Casimir-Lifshitz forces SO NATURE LA English DT Article ID DER-WAALS FORCES; MU-M; ATTRACTION; PHYSICS; SOLIDS; SILICA AB Quantum fluctuations create intermolecular forces that pervade macroscopic bodies(1-3). At molecular separations of a few nanometres or less, these interactions are the familiar van der Waals forces(4). However, as recognized in the theories of Casimir, Polder and Lifshitz(5-7), at larger distances and between macroscopic condensed media they reveal retardation effects associated with the finite speed of light. Although these long- range forces exist within all matter, only attractive interactions have so far been measured between material bodies(8-11). Here we show experimentally that, in accord with theoretical prediction(12), the sign of the force can be changed from attractive to repulsive by suitable choice of interacting materials immersed in a fluid. The measured repulsive interaction is found to be weaker than the attractive. However, in both cases the magnitude of the force increases with decreasing surface separation. Repulsive Casimir - Lifshitz forces could allow quantum levitation of objects in a fluid and lead to a new class of switchable nanoscale devices with ultra-low static friction(13-15). C1 [Capasso, Federico] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Munday, J. N.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Parsegian, V. Adrian] NIH, Bethesda, MD 20892 USA. RP Capasso, F (reprint author), Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM capasso@seas.harvard.edu RI Munday, Jeremy/E-6512-2016 OI Munday, Jeremy/0000-0002-0881-9876 FU Center for Nanoscale Systems at Harvard University; Intramural Research Program of the NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NSF FX We thank D. Iannuzzi, R. Podgornik, J. Zimmerberg, S. M. Bezrukov and M. B. Romanowsky for discussions. This project was partially supported by the Center for Nanoscale Systems at Harvard University, and by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. J.N.M. acknowledges support from the NSF. NR 30 TC 282 Z9 292 U1 3 U2 93 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 8 PY 2009 VL 457 IS 7226 BP 170 EP 173 DI 10.1038/nature07610 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 393GS UT WOS:000262360200027 PM 19129843 ER PT J AU Tita, ATN Landon, MB Spong, CY Lai, YL Leveno, KJ Varner, MW Moawad, AH Caritis, SN Meis, PJ Wapner, RJ Sorokin, Y Miodovnik, M Carpenter, M Peaceman, AM O'Sullivan, MJ Sibai, BM Langer, O Thorp, JM Ramin, SM Mercer, BM AF Tita, Alan T. N. Landon, Mark B. Spong, Catherine Y. Lai, Yinglei Leveno, Kenneth J. Varner, Michael W. Moawad, Atef H. Caritis, Steve N. Meis, Paul J. Wapner, Ronald J. Sorokin, Yoram Miodovnik, Menachem Carpenter, Marshall Peaceman, Alan M. O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded Thorp, John M. Ramin, Susan M. Mercer, Brian M. CA Eunice Kennedy Shriver NICHD TI Timing of Elective Repeat Cesarean Delivery at Term and Neonatal Outcomes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RESPIRATORY MORBIDITY; SECTION; LABOR; RISK; MODE; PREGNANCIES; STILLBIRTH; INFANTS; TRIAL AB Background Because of increased rates of respiratory complications, elective cesarean delivery is discouraged before 39 weeks of gestation unless there is evidence of fetal lung maturity. We assessed associations between elective cesarean delivery at term ( 37 weeks of gestation or longer) but before 39 weeks of gestation and neonatal outcomes. Methods We studied a cohort of consecutive patients undergoing repeat cesarean sections performed at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal - Fetal Medicine Units Network from 1999 through 2002. Women with viable singleton pregnancies delivered electively ( i. e., before the onset of labor and without any recognized indications for delivery before 39 weeks of gestation) were included. The primary outcome was the composite of neonatal death and any of several adverse events, including respiratory complications, treated hypoglycemia, newborn sepsis, and admission to the neonatal intensive care unit ( ICU). Results Of 24,077 repeat cesarean deliveries at term, 13,258 were performed electively; of these, 35.8% were performed before 39 completed weeks of gestation ( 6.3% at 37 weeks and 29.5% at 38 weeks) and 49.1% at 39 weeks of gestation. One neonatal death occurred. As compared with births at 39 weeks, births at 37 weeks and at 38 weeks were associated with an increased risk of the primary outcome ( adjusted odds ratio for births at 37 weeks, 2.1; 95% confidence interval [ CI], 1.7 to 2.5; adjusted odds ratio for births at 38 weeks, 1.5; 95% CI, 1.3 to 1.7; P for trend < 0.001). The rates of adverse respiratory outcomes, mechanical ventilation, newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization for 5 days or more were increased by a factor of 1.8 to 4.2 for births at 37 weeks and 1.3 to 2.1 for births at 38 weeks. Conclusions Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes. C1 [Tita, Alan T. N.] Univ Alabama, Dept Obstet & Gynecol, Div Maternal Fetal Med, Birmingham, AL 35249 USA. [Landon, Mark B.] Ohio State Univ, Columbus, OH 43210 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Varner, Michael W.] Univ Utah, Salt Lake City, UT USA. [Moawad, Atef H.] Univ Chicago, Chicago, IL 60637 USA. [Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. [Meis, Paul J.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Miodovnik, Menachem] Univ Cincinnati, Cincinnati, OH USA. [Miodovnik, Menachem] Columbia Univ, New York, NY USA. [Carpenter, Marshall] Brown Univ, Providence, RI 02912 USA. [Peaceman, Alan M.] Northwestern Univ, Chicago, IL 60611 USA. [O'Sullivan, Mary J.] Univ Miami, Miami, FL USA. [Sibai, Baha M.] Univ Tennessee, Memphis, TN USA. [Langer, Oded] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Thorp, John M.] Univ N Carolina, Chapel Hill, NC USA. [Ramin, Susan M.] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. [Mercer, Brian M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Tita, ATN (reprint author), Univ Alabama, Dept Obstet & Gynecol, Div Maternal Fetal Med, 619 19th St S, Birmingham, AL 35249 USA. EM alan.tita@obgyn.uab.edu RI Varner, Michael/K-9890-2013; OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU NICHD NIH HHS [U10 HD040560, HD001258, HD21410, HD21414, HD27860, HD27861, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD34210, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, K12 HD001258, R24 HD050924, U01 HD036801, U10 HD021410, U10 HD027860, U10 HD027869, U10 HD027869-19, U10 HD027905, U10 HD027915, U10 HD027917, U10 HD034116, U10 HD034122, U10 HD034136, U10 HD034208, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040544, U10 HD040545, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 30 TC 347 Z9 369 U1 2 U2 13 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 JAN 8 PY 2009 VL 360 IS 2 BP 111 EP U29 DI 10.1056/NEJMoa0803267 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 391UG UT WOS:000262258300004 PM 19129525 ER PT J AU Rouse, DJ Hirtz, DG Thom, EA AF Rouse, Dwight J. Hirtz, Deborah G. Thom, Elizabeth A. CA Eunice Shriver Kennedy NICHHD TI Magnesium Sulfate for the Prevention of Cerebral Palsy Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID TRIAL C1 [Rouse, Dwight J.] Univ Alabama, Birmingham, AL 35249 USA. [Hirtz, Deborah G.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. [Thom, Elizabeth A.] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. RP Rouse, DJ (reprint author), Univ Alabama, Birmingham, AL 35249 USA. EM drouse@uab.edu NR 2 TC 3 Z9 3 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 JAN 8 PY 2009 VL 360 IS 2 BP 190 EP 190 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 391UG UT WOS:000262258300025 ER PT J AU Alcaraz, A Nestorovich, EM Lopez, ML Garcia-Gimenez, E Bezrukov, SM Aguilella, VM AF Alcaraz, Antonio Nestorovich, Ekaterina M. Lidon Lopez, M. Garcia-Gimenez, Elena Bezrukov, Sergey M. Aguilella, Vicente M. TI Diffusion, Exclusion, and Specific Binding in a Large Channel: A Study of OmpF Selectivity Inversion SO BIOPHYSICAL JOURNAL LA English DT Article ID LIQUID JUNCTION POTENTIALS; ELECTRICAL PROPERTIES; MEMBRANE-POTENTIALS; PROTECTIVE ANTIGEN; CRYSTAL-STRUCTURES; IONIC SELECTIVITY; ESCHERICHIA-COLI; CHARGE INVERSION; ANTHRAX TOXIN; PORIN AB We find that moderate cationic selectivity of the general bacterial porin OmpF in sodium and potassium chloride solutions is inversed to anionic selectivity in concentrated solutions of barium, calcium, nickel, and magnesium chlorides. To understand the origin of this phenomenon, we consider several factors, which include the binding of divalent cations, electrostatic and steric exclusion of differently charged and differently sized ions, size-dependent hydrodynamic hindrance, electrokinetic effects, and significant "anionic" diffusion potential for bulk solutions of chlorides of divalent cations. Though all these factors contribute to the measured selectivity of this large channel, the observed selectivity inversion is mostly due to the following two. First, binding divalent cations compensates, or even slightly overcompensates, for the negative charge of the OmpF protein, which is known to be the main cause of cationic selectivity in sodium and potassium chloride solutions. Second, the higher anionic (versus cationic) transport rate expected for bulk solutions of chloride salts of divalent cations is the leading cause of the measured anionic selectivity of the channel. Interestingly, at high concentrations the binding of cations does not show any pronounced specificity within the divalent series because the reversal potentials measured in the series correlate well with the corresponding bulk diffusion potentials. Thus our study shows that, in contrast to the highly selective channels of neurophysiology that employ mostly the exclusion mechanism, quite different factors account for the selectivity of large channels. The elucidation of these factors is essential for understanding large channel selectivity and its regulation in vivo. C1 [Alcaraz, Antonio; Lidon Lopez, M.; Garcia-Gimenez, Elena; Aguilella, Vicente M.] Univ Jaume 1, Dept Fis, Castellon de La Plana, Spain. [Nestorovich, Ekaterina M.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. RP Aguilella, VM (reprint author), Univ Jaume 1, Dept Fis, Castellon de La Plana, Spain. EM aguilell@fca.uji.es RI Aguilella, Vicente/B-7592-2008; Lopez Peris, Maria Lidon/P-5027-2014; Alcaraz, Antonio/F-8498-2016 OI Aguilella, Vicente/0000-0002-2420-2649; Lopez Peris, Maria Lidon/0000-0002-9599-8760; FU Spanish Ministry of Education [FIS2007-60205]; National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors are grateful to Adrian Parsegian for fruitful discussions and reading parts of the manuscript.; We acknowledge support from the Spanish Ministry of Education (project FIS2007-60205). This study was also supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 53 TC 46 Z9 46 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 JAN 7 PY 2009 VL 96 IS 1 BP 56 EP 66 DI 10.1016/j.bpj.2008.09.024 PG 11 WC Biophysics SC Biophysics GA 450BO UT WOS:000266376200008 PM 19134471 ER PT J AU Sathyanarayana, BK Hahn, Y Patankar, MS Pastan, I Lee, B AF Sathyanarayana, Bangalore K. Hahn, Yoonsoo Patankar, Manish S. Pastan, Ira Lee, Byungkook TI Mesothelin, Stereocilin, and Otoancorin are predicted to have superhelical structures with ARM-type repeats SO BMC STRUCTURAL BIOLOGY LA English DT Article ID INNER-EAR; SEQUENCE ALIGNMENT; MOLECULAR-CLONING; PROTEIN REPEATS; COILED COILS; OVARIAN; RECOGNITION; ANNOTATION; EXPRESSION; PROFILES AB Background: Mesothelin is a 40 kDa protein present on the surface of normal mesothelial cells and overexpressed in many human tumours, including mesothelioma and ovarian and pancreatic adenocarcinoma. It forms a strong and specific complex with MUC16, which is also highly expressed on the surface of mesothelioma and ovarian cancer cells. This binding has been suggested to be the basis of ovarian cancer metastasis. Knowledge of the structure of this protein will be useful, for example, in building a structural model of the MUC16-mesothelin complex. Mesothelin is produced as a precursor, which is cleaved by furin to produce the N-terminal half, which is called the megakaryocyte potentiating factor (MPF), and the C-terminal half, which is mesothelin. Little is known about the function of mesothelin and there is no information on its possible three-dimensional structure. Mesothelin has been reported to be homologous to the deafness-related inner ear proteins otoancorin and stereocilin, for neither of which the three-dimensional structure is known. Results: The BLAST and PSI-BLAST searches confirmed that mesothelin and mesothelin precursor proteins are remotely homologous to stereocilin and otoancorin and more closely homologous to the hypothetical protein MPFL (MPF-like). Secondary structure prediction servers predicted a predominantly helical structure for both mesothelin and mesothelin precursor proteins and also for stereocilin and otoancorin. Three-dimensional structure prediction servers INHUB and I-TASSER produced structural models for mesothelin, which consisted of superhelical structures with ARM-type repeats in conformity with the secondary structure predictions. Similar ARM-type superhelical repeat structures were predicted by 3D-PSSM server for mesothelin precursor and for stereocilin and otoancorin proteins. Conclusion: The mesothelin superfamily of proteins, which includes mesothelin, mesothelin precursor, megakaryocyte potentiating factor, MPFL, stereocilin and otoancorin, are predicted to have superhelical structures with ARM-type repeats. We suggest that all of these function as superhelical lectins to bind the carbohydrate moieties of extracellular glycoproteins. C1 [Sathyanarayana, Bangalore K.; Hahn, Yoonsoo; Pastan, Ira; Lee, Byungkook] NIH, Natl Canc Inst, Ctr Canc Res, Lab Mol Biol, Bethesda, MD 20892 USA. [Hahn, Yoonsoo] Chung Ang Univ, Coll Nat Sci, Dept Life Sci, Seoul 156756, South Korea. [Patankar, Manish S.] Univ Wisconsin, Dept Obstet & Gynecol, Madison, WI USA. RP Lee, B (reprint author), NIH, Natl Canc Inst, Ctr Canc Res, Lab Mol Biol, Bethesda, MD 20892 USA. EM sathya@helix.nih.gov; yoonsoo.hahn@gmail.com; patankar@wisc.edu; pastani@mail.nih.gov; bk@nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX We thank Ms Chin-Hsien Tai for making the stereo drawing of Figure 3. This research was supported in part by the Intramural Research Program of the NIH, the National Cancer Institute, Center for Cancer Research. NR 55 TC 14 Z9 14 U1 1 U2 2 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 JAN 7 PY 2009 VL 9 AR 1 DI 10.1186/1472-6807-9-1 PG 11 WC Biophysics SC Biophysics GA 407BE UT WOS:000263337800001 PM 19128473 ER PT J AU Hall, KD Heymsfield, SB AF Hall, Kevin D. Heymsfield, Steven B. TI Models Use Leptin and Calculus to Count Calories SO CELL METABOLISM LA English DT Editorial Material ID BODY-WEIGHT; SET POINTS; FAT AB Thermostats have "set-points" that engineers design with mathematical rigor. Work in this issue of Cell Metabolism (Tam et al., 2009) applies similar modeling strategies to explore the control of murine energy and body weight homeostasis by leptin. C1 [Heymsfield, Steven B.] Merck Res Labs, Rahway, NJ 07065 USA. [Hall, Kevin D.] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Heymsfield, SB (reprint author), Merck Res Labs, POB 2000,RY34A-A238, Rahway, NJ 07065 USA. EM steven_heymsfield@merck.com RI Hall, Kevin/F-2383-2010 NR 12 TC 5 Z9 5 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JAN 7 PY 2009 VL 9 IS 1 BP 3 EP 4 DI 10.1016/j.cmet.2008.12.006 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 392WN UT WOS:000262333000002 PM 19117539 ER PT J AU Lippman, SM Klein, EA Goodman, PJ Lucia, MS Thompson, IM Ford, LG Parnes, HL Minasian, LM Gaziano, JM Hartline, JA Parsons, JK Bearden, JD Crawford, ED Goodman, GE Claudio, J Winquist, E Cook, ED Karp, DD Walther, P Lieber, MM Kristal, AR Darke, AK Arnold, KB Ganz, PA Santella, RM Albanes, D Taylor, PR Probstfield, JL Jagpal, TJ Crowley, JJ Meyskens, FL Baker, LH Coltman, CA AF Lippman, Scott M. Klein, Eric A. Goodman, Phyllis J. Lucia, M. Scott Thompson, Ian M. Ford, Leslie G. Parnes, Howard L. Minasian, Lori M. Gaziano, J. Michael Hartline, Jo Ann Parsons, J. Kellogg Bearden, James D., III Crawford, E. David Goodman, Gary E. Claudio, Jaime Winquist, Eric Cook, Elise D. Karp, Daniel D. Walther, Philip Lieber, Michael M. Kristal, Alan R. Darke, Amy K. Arnold, Kathryn B. Ganz, Patricia A. Santella, Regina M. Albanes, Demetrius Taylor, Philip R. Probstfield, Jeffrey L. Jagpal, T. J. Crowley, John J. Meyskens, Frank L., Jr. Baker, Laurence H. Coltman, Charles A., Jr. TI Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers The Selenium and Vitamin E Cancer Prevention Trial ( SELECT) SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; NUTRITIONAL PREVENTION; ALPHA-TOCOPHEROL; BREAST-CANCER; CELL-LINES; SUPPLEMENTATION; MORTALITY; CARCINOMA AB Context Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. Objective To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. Design, Setting, and Participants A randomized, placebo- controlled trial ( Selenium and Vitamin E Cancer Prevention Trial [ SELECT]) of 35 533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups ( selenium, vitamin E, selenium + vitamin E, and placebo) in a double- blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older ( African American men) or 55 years or older ( all other men), a serum prostate- specific antigen level of 4 ng/ mL or less, and a digital rectal examination not suspicious for prostate cancer. Interventions Oral selenium ( 200 mu g/d from L- selenomethionine) and matched vitamin E placebo, vitamin E ( 400 IU/ d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. Main Outcome Measures Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. Results As of October 23, 2008, median overall follow- up was 5.46 years ( range, 4.17- 7.33 years). Hazard ratios ( 99% confidence intervals [ CIs]) for prostate cancer were 1.13 ( 99% CI, 0.95- 1.35; n= 473) for vitamin E, 1.04 ( 99% CI, 0.87- 1.24; n= 432) for selenium, and 1.05 ( 99% CI, 0.88- 1.25; n= 437) for selenium + vitamin E vs 1.00 ( n= 416) for placebo. There were no significant differences ( all P >. 15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group ( P=. 06) and type 2 diabetes mellitus in the selenium group ( relative risk, 1.07; 99% CI, 0.94- 1.22; P=. 16) but not in the selenium + vitamin E group. Conclusion Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men. Trial Registration clinicaltrials. gov identifier: NCT00006392. C1 [Lippman, Scott M.; Karp, Daniel D.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Thorac & Head & Neck Med Oncol, Div Canc Med,Unit 432, Houston, TX 77030 USA. [Lippman, Scott M.; Cook, Elise D.] Univ Texas Houston, MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Klein, Eric A.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Goodman, Phyllis J.; Hartline, Jo Ann; Darke, Amy K.; Arnold, Kathryn B.; Crowley, John J.] SW Oncol Grp, Ctr Stat, Seattle, WA USA. [Lucia, M. Scott] Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO USA. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Div Urol Oncol, Denver, CO USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX USA. [Coltman, Charles A., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Hematol, San Antonio, TX USA. [Coltman, Charles A., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Oncol, San Antonio, TX USA. [Ford, Leslie G.; Parnes, Howard L.; Minasian, Lori M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Albanes, Demetrius; Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gaziano, J. Michael] Boston VA Healthcare Ctr, Vet Affairs Cooperat Studies Program, Boston, MA USA. [Gaziano, J. Michael] Boston VA Healthcare Ctr, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Parsons, J. Kellogg] Moores Canc Ctr, La Jolla, CA USA. [Bearden, James D., III] Upstate Carolina CCOP, Spartanburg, SC USA. [Goodman, Phyllis J.] Swedish Canc Inst, Div Hematol & Oncol, Seattle, WA USA. [Claudio, Jaime] Altamira Family Med, Rio Piedras, PR USA. [Winquist, Eric] London Hlth Sci Ctr, London Reg Canc Program, London, ON, Canada. [Walther, Philip] Duke Univ, Med Ctr, Dept Urol Surg, Durham, NC USA. [Lieber, Michael M.] Mayo Clin, Dept Urol, Rochester, MN USA. [Kristal, Alan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Probstfield, Jeffrey L.] Univ Washington, Dept Med & Cardiol, Seattle, WA 98195 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. [Santella, Regina M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Jagpal, T. J.] Univ British Columbia, Ctr Clin Epidemiol & Evaluat, Vancouver, BC V5Z 1M9, Canada. [Meyskens, Frank L., Jr.] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. [Baker, Laurence H.] Univ Michigan, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. [Baker, Laurence H.; Coltman, Charles A., Jr.] SW Oncol Grp, Ann Arbor, MI USA. RP Lippman, SM (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Thorac & Head & Neck Med Oncol, Div Canc Med,Unit 432, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM slippman@mdanderson.org; kleine@ccf.org RI Albanes, Demetrius/B-9749-2015; OI Kristal, Alan/0000-0002-7329-1617 FU Public Health Service Cooperative Agreement [CA37429]; National Cancer Institute; National Institutes of Health; Department of Health and Human Services; National Center for Complementary and Alternative Medicine FX This work was supported in part by Public Health Service Cooperative Agreement grant CA37429 awarded by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and in part by the National Center for Complementary and Alternative Medicine (National Institutes of Health). Study agents and packaging were provided by Perrigo Company ( Allegan, Michigan), Sabinsa Corporation ( Piscataway, NewJersey), Tishcon Corporation (Westbury, New York), and DSM Nutritional Products Inc ( Parsipanny, New Jersey). NR 48 TC 976 Z9 1008 U1 7 U2 113 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 7 PY 2009 VL 301 IS 1 BP 39 EP 51 DI 10.1001/jama.2008.864 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 391FY UT WOS:000262220400019 PM 19066370 ER PT J AU Weaver, FM Follett, K Stern, M Hur, K Harris, C Marks, WJ Rothlind, J Sagher, O Reda, D Moy, CS Pahwa, R Burchiel, K Hogarth, P Lai, EC Duda, JE Holloway, K Samii, A Horn, S Bronstein, J Stoner, G Heemskerk, J Huang, GD AF Weaver, Frances M. Follett, Kenneth Stern, Matthew Hur, Kwan Harris, Crystal Marks, William J., Jr. Rothlind, Johannes Sagher, Oren Reda, Domenic Moy, Claudia S. Pahwa, Rajesh Burchiel, Kim Hogarth, Penelope Lai, Eugene C. Duda, John E. Holloway, Kathryn Samii, Ali Horn, Stacy Bronstein, Jeff Stoner, Gatana Heemskerk, Jill Huang, Grant D. CA CSP 468 Study Grp TI Bilateral Deep Brain Stimulation vs Best Medical Therapy for Patients With Advanced Parkinson Disease A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; SUBTHALAMIC STIMULATION; MOTOR FLUCTUATIONS; ADVERSE EVENTS; FOLLOW-UP; MULTICENTER; NUCLEUS; METAANALYSIS; VALIDATION AB Context Deep brain stimulation is an accepted treatment for advanced Parkinson disease ( PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. Objective To compare 6- month outcomes for patients with PD who received deep brain stimulation or best medical therapy. Design, Setting, and Patients Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age ( < 70 years vs >= 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD ( Hoehn and Yahr stage >= 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6- month follow- up visit occurred in May 2006. Intervention Bilateral deep brain stimulation of the subthalamic nucleus ( n= 60) or globus pallidus ( n= 61). Patients receiving best medical therapy ( n= 134) were actively managed by movement disorder neurologists. Main Outcome Measures The primary outcome was time spent in the "on" state ( good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. Results Patients who received deep brain stimulation gained a mean of 4.6 h/ d of on time without troubling dyskinesia compared with 0 h/ d for patients who received best medical therapy ( between group mean difference, 4.5 h/ d [ 95% CI, 3.7- 5.4 h/ d]; P <. 001). Motor function improved significantly ( P <. 001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements ( >= 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality- of- life scores ( P <. 001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients ( P <. 001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. Conclusion In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. Trial Registration clinicaltrials. gov Identifier: NCT00056563. C1 [Weaver, Frances M.] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL 60141 USA. [Hur, Kwan; Reda, Domenic] Edward Hines Jr VA Hosp, Cooperat Studies Coordinating Ctr, Hines, IL 60141 USA. [Weaver, Frances M.] Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA. [Follett, Kenneth] Univ Nebraska, Dept Neurosurg, Omaha, NE 68182 USA. [Stern, Matthew; Duda, John E.; Horn, Stacy] Univ Penn Hlth Syst, Dept Neurol, Philadelphia, PA USA. [Stern, Matthew; Duda, John E.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Harris, Crystal] Clin Res Pharm, VA Cooperat Studies Program, Albuquerque, NM USA. [Marks, William J., Jr.; Rothlind, Johannes] San Francisco VA Med Ctr, San Francisco, CA USA. [Marks, William J., Jr.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Rothlind, Johannes] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Sagher, Oren] Univ Michigan, Med Ctr, Dept Neurosurg, Ann Arbor, MI 48109 USA. [Moy, Claudia S.; Heemskerk, Jill] NINDS, Rockville, MD USA. [Pahwa, Rajesh] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. [Burchiel, Kim; Hogarth, Penelope] Portland VA Med Ctr, Portland, OR USA. [Burchiel, Kim] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97201 USA. [Hogarth, Penelope] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Lai, Eugene C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Lai, Eugene C.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Holloway, Kathryn] Richmond VA Med Ctr, Richmond, VA USA. [Holloway, Kathryn] Virginia Commonwealth Univ, Dept Neurosurg, Richmond, VA USA. [Samii, Ali] Puget Sound Hlth Care Syst, Seattle, WA USA. [Bronstein, Jeff] W Los Angeles VA Med Ctr, Los Angeles, CA USA. [Stoner, Gatana] Univ Iowa Health Care, Dept Neurosurg, Iowa City, IA USA. [Huang, Grant D.] VA Off Res & Dev, Dept Vet Affairs, Cooperat Studies Program Cent Off, Washington, DC USA. RP Weaver, FM (reprint author), Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, 5000 S 5th Ave 151H, Hines, IL 60141 USA. EM Frances.Weaver@va.gov FU The Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; National Institute of Neurological Disorders and Stroke; Medtronic Neuromodulation FX The Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, the National Institute of Neurological Disorders and Stroke, and Medtronic Neuromodulation provided financial support for this study. NR 31 TC 542 Z9 557 U1 7 U2 50 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 7 PY 2009 VL 301 IS 1 BP 63 EP 73 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 391FY UT WOS:000262220400021 PM 19126811 ER PT J AU Albanes, D AF Albanes, Demetrius TI Vitamin Supplements and Cancer Prevention: Where Do Randomized Controlled Trials Stand? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BETA-CAROTENE; LUNG-CANCER; CARDIOVASCULAR-DISEASE; COMBINATION; HEALTH; RISK C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Albanes, D (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Natl Inst Hlth,Dept Hlth & Human Serv, 6120 Execut Blvd,Room 3044, Bethesda, MD 20892 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015 NR 13 TC 10 Z9 11 U1 0 U2 2 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 JAN 7 PY 2009 VL 101 IS 1 BP 2 EP 3 DI 10.1093/jnci/djn453 PG 2 WC Oncology SC Oncology GA 392WS UT WOS:000262333500003 PM 19116387 ER PT J AU Martin, B Pearson, M Brenneman, R Golden, E Wood, W Prabhu, V Becker, KG Mattson, MP Maudsley, S AF Martin, Bronwen Pearson, Michele Brenneman, Randall Golden, Erin Wood, William, III Prabhu, Vinayakumar Becker, Kevin G. Mattson, Mark P. Maudsley, Stuart TI Gonadal Transcriptome Alterations in Response to Dietary Energy Intake: Sensing the Reproductive Environment SO PLOS ONE LA English DT Article AB Reproductive capacity and nutritional input are tightly linked and animals' specific responses to alterations in their physical environment and food availability are crucial to ensuring sustainability of that species. We have assessed how alterations in dietary energy intake (both reductions and excess), as well as in food availability, via intermittent fasting (IF), affect the gonadal transcriptome of both male and female rats. Starting at four months of age, male and female rats were subjected to a 20% or 40% caloric restriction (CR) dietary regime, every other day feeding (IF) or a high fat-high glucose (HFG) diet for six months. The transcriptional activity of the gonadal response to these variations in dietary energy intake was assessed at the individual gene level as well as at the parametric functional level. At the individual gene level, the females showed a higher degree of coherency in gonadal gene alterations to CR than the males. The gonadal transcriptional and hormonal response to IF was also significantly different between the male and female rats. The number of genes significantly regulated by IF in male animals was almost 5 times greater than in the females. These IF males also showed the highest testosterone to estrogen ratio in their plasma. Our data show that at the level of gonadal gene responses, the male rats on the IF regime adapt to their environment in a manner that is expected to increase the probability of eventual fertilization of females that the males predict are likely to be sub-fertile due to their perception of a food deficient environment. C1 [Martin, Bronwen; Pearson, Michele; Brenneman, Randall; Golden, Erin; Mattson, Mark P.] NIA, Neurosci Lab, Baltimore, MD 21224 USA. [Wood, William, III; Prabhu, Vinayakumar; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Baltimore, MD USA. [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Baltimore, MD USA. RP Martin, B (reprint author), NIA, Neurosci Lab, Baltimore, MD 21224 USA. EM maudsleyst@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; OI Becker, Kevin/0000-0002-6794-6656 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 23 Z9 23 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 JAN 7 PY 2009 VL 4 IS 1 AR e4146 DI 10.1371/journal.pone.0004146 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437FX UT WOS:000265473300011 PM 19127293 ER PT J AU Spearman, P Kalams, S Elizaga, M Metch, B Chiu, YL Allen, M Weinhold, KJ Ferrari, G Parker, SD McElrath, MJ Frey, SE Fuchs, JD Keefer, MC Lubeck, MD Egan, M Braun, R Eldridge, JH Haynes, BF Corey, L AF Spearman, Paul Kalams, Spyros Elizaga, Marnie Metch, Barbara Chiu, Ya-Lin Allen, Mary Weinhold, Kent J. Ferrari, Guido Parker, Scott D. McElrath, M. Juliana Frey, Sharon E. Fuchs, Jonathan D. Keefer, Michael C. Lubeck, Michael D. Egan, Michael Braun, Ralph Eldridge, John H. Haynes, Barton F. Corey, Lawrence CA NIAID HIV Vaccine Trials Network TI Safety and immunogenicity of a CTL multiepitope peptide vaccine for HIV with or without GM-CSF in a phase I trial SO VACCINE LA English DT Article DE HIV vaccine; Multiepitope peptide; GM-CSF; CD8+cytotoxic T cells; Anti-GM-CSF antibody ID COLONY-STIMULATING FACTOR; T-CELL RESPONSES; IMMUNE-RESPONSES; DENDRITIC CELLS; RHESUS-MONKEYS; VIRUS-VACCINE; DNA VACCINE; ADJUVANT; PROTECTION; MELANOMA AB There is an urgent need for a vaccine capable of preventing HIV infection or the development of HIV-related disease. A number of approaches designed to stimulate HIV-specific CD8+ cytotoxic T cell responses together with helper responses are presently under evaluation. In this phase 1, multi-center, placebo-controlled trial, we tested the ability of a novel multiepitope peptide vaccine to elicit HIV-specific immunity. To enhance the immunogenicity of the peptide vaccine, half of the vaccine recipients received recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) protein as a coadjuvant. The vaccine was safe; tolerability was moderate, with a number of adverse events related to local injection site reactogenicity. Anti-GM-CSF antibody responses developed in the majority of GM-CSF recipients but were not associated with adverse hematologic events. The vaccine was only minimally immunogenic. Six of 80 volunteers who received vaccine developed HIV-specific responses as measured by interferon-gamma ELISPOT assay, and measurable responses were transient. This study failed to demonstrate that GM-CSF can substantially improve the overall weak immunogenicity of a multiepitope peptide-based HIV vaccine. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Spearman, Paul] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Kalams, Spyros] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Elizaga, Marnie; Metch, Barbara; Chiu, Ya-Lin; McElrath, M. Juliana; Corey, Lawrence] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Allen, Mary] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Weinhold, Kent J.; Ferrari, Guido; Haynes, Barton F.] Duke Univ, Sch Med, Durham, NC USA. [Parker, Scott D.] Univ Alabama, Sch Med, Birmingham, AL USA. [Frey, Sharon E.] St Louis Univ, St Louis, MO 63103 USA. [Fuchs, Jonathan D.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Keefer, Michael C.] Univ Rochester, Sch Med, Rochester, NY USA. [Lubeck, Michael D.; Egan, Michael; Braun, Ralph; Eldridge, John H.] Wyeth Vaccines Res, Pearl River, NY USA. RP Spearman, P (reprint author), Emory Univ, Sch Med, Dept Pediat, 2015 Uppergate Dr, Atlanta, GA 30322 USA. EM paul.spearman@emory.edu RI Ferrari, Guido/A-6088-2015; OI Allen, Mary/0000-0001-8163-0714 FU NIAID NIH HHS [U01 AI069418, U01 AI069418-03, U01 AI047985, U01 AI047985-05] NR 38 TC 38 Z9 43 U1 0 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 JAN 7 PY 2009 VL 27 IS 2 BP 243 EP 249 DI 10.1016/j.vaccine.2008.10.051 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 399DM UT WOS:000262780600013 PM 18996425 ER PT J AU Baid, SK Lai, EW Wesley, RA Ling, A Timmers, HJLM Adams, KT Kozupa, A Pacak, K AF Baid, Smita K. Lai, Edwin W. Wesley, Robert A. Ling, Alex Timmers, Henri J. L. M. Adams, Karen T. Kozupa, Anna Pacak, Karel TI Brief Communication: Radiographic Contrast Infusion and Catecholamine Release in Patients With Pheochromocytoma SO ANNALS OF INTERNAL MEDICINE LA English DT Article AB Background: Contrast-enhanced computed tomography (CT) is useful for localizing pheochromocytoma. However, in patients with suspected pheochromocytoma, CT is often canceled or not performed because of the strong belief that intravenous contrast may induce hypertensive crisis. Objective: To examine whether intravenous low-osmolar contrast administration during CT induces catecholamine release that increases blood pressure or heart rate. Design: Prospective study. Setting: Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland. Participants: 22 patients with pheochromocytoma (15 nonadrenal and 7 adrenal) and 8 unmatched control participants without pheochromocytoma. Measurements: Plasma catecholamine levels, blood pressure, and heart rate. Results: Plasma catecholamine levels within and between groups did not significantly differ before and after intravenous administration of low-osmolar CT contrast. Patients with pheochromocytoma experienced a clinically and statistically significant increase in diastolic blood pressure that was not accompanied by corresponding increases in plasma catecholamine levels. The difference became non -statistically significant after adjustment for use of alpha-and beta-blockers. Limitation: The study lacked a placebo group, and the sample was relatively small. Conclusion: Intravenous low-osmolar contrast-enhanced CT can safely be used in patients with pheochromocytoma who are not receiving alpha-or beta-blockers. C1 [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Adult Endocrinol Program, Sect Med Neuroendocrinol, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Adult Endocrinol Program, Sect Med Neuroendocrinol, NIH, Bldg 10,CRC,Room 1E-1-3140,10 Ctr Dr,MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Development; National Institutes of Health FX Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health. NR 5 TC 12 Z9 12 U1 0 U2 0 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 JAN 6 PY 2009 VL 150 IS 1 BP 27 EP W6 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 397IC UT WOS:000262655100004 PM 19124817 ER PT J AU Goldstein, DS Sharabi, Y AF Goldstein, David S. Sharabi, Yehonatan TI Neurogenic Orthostatic Hypotension A Pathophysiological Approach SO CIRCULATION LA English DT Review DE hypotension; nervous system, sympathetic; norepinephrine; orthostatic hypotension; tomography ID MULTIPLE SYSTEM ATROPHY; CARDIAC SYMPATHETIC DENERVATION; AUTONOMIC FAILURE; BLOOD-PRESSURE; PARKINSONS-DISEASE; PLASMA-LEVELS; NOREPINEPHRINE; HYPERTENSION; CATECHOLS; AUTOIMMUNE C1 [Goldstein, David S.; Sharabi, Yehonatan] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD USA. [Sharabi, Yehonatan] Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. [Sharabi, Yehonatan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Goldstein, DS (reprint author), Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU National Institutes of Health FX The research was supported by the intramural research program of the National Institutes of Health. NR 49 TC 51 Z9 52 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 JAN 6 PY 2009 VL 119 IS 1 BP 139 EP 146 DI 10.1161/CIRCULATIONAHA.108.805887 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 390YT UT WOS:000262200300020 PM 19124673 ER EF